bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Antibodies Targeting CSF1 Impede Macrophage Recruitment in a Xenograft Model of Tenosynovial Giant Cell Tumor
Authors: Cheng Hongwei , Clarkson Paul W. , Gao Dongxia , Pacheco Marina , Wang Yuzhuo , Nielsen Torsten O.
Published: October 2010

Tenosynovial giant cell tumor is a neoplastic disease of joints that can cause severe morbidity. Recurrences are common following local therapy, and no effective medical therapy currently exists. Recent work has demonstrated that all cases overexpress macrophage colony-stimulating factor (CSF1), usually as a consequence of an activating gene translocation, resulting in an influx of macrophages that form the bulk of the tumor. New anti-CSF1 drugs have been developed; however there are no preclinical models suitable for evaluation of drug benefits in this disease. In this paper, we describe a novel renal subcapsular xenograft model of tenosynovial giant cell tumor. Using this model, we demonstrate that an anti-CSF1 monoclonal antibody significantly inhibits host macrophage infiltration into this tumor. The results from this model support clinical trials of equivalent humanized agents and anti-CSF1R small molecule drugs in cases of tenosynovial giant cell tumor refractory to conventional local therapy.
Identification of Motive Forces on the Whole Body System during Walking
Authors: AlKhoury Raghdan J. , Joshi Suraj , Bhat Rama B. , Ma Shiping
Published: October 2010

Motive forces by muscles are applied to different parts of the human body in a periodic fashion when walking at a uniform rate. In this study, the whole human body is modeled as a multidegree of freedom (MDOF) system with seven degrees of freedom. In view of the changing contact conditions with the ground due to alternating feet movements, the system under study is considered piecewise time invariant for each half‐period when one foot is in contact with the ground. Forces transmitted from the body to the ground while walking at a normal pace are experimentally measured and numerically simulated. Fourth‐order Runge‐Kutta method is employed to numerically simulate the forces acting on different masses of the body. An optimization problem is formulated with the squared difference between the measured and simulated forces transmitted to the ground as the objective function, and the motive forces on the body masses as the design variables to solve.
Constant Rate Distributions on Partially Ordered Sets
Authors: Siegrist Kyle
Published: October 2010

We consider probability distributions with constant rate on partially
ordered sets, generalizing distributions in the usual reliability setting
([0, ∞), ≤) that have constant failure rate. In spite of the minimal algebraic structure, there is a surprisingly rich theory, including moment
results and results concerning ladder variables and point processes. We
concentrate mostly on discrete posets, particularly posets whose graphs
are rooted trees. We pose some questions on the existence of constant
rate distributions for general discrete posets.
The Properties of Red Blood Cells from Patients Heterozygous for HbS and HbC (HbSC Genotype)
Authors: Hannemann A. , Weiss E. , Rees D. C. , Dalibalta S. , Ellory J. C. , Gibson J. S.
Published: October 2010

Sickle cell disease (SCD) is one of the commonest severe inherited disorders, but specific treatments are lacking and the pathophysiology remains unclear. Affected individuals account for well over 250,000 births yearly, mostly in the Tropics, the USA, and the Caribbean, also in Northern Europe as well. Incidence in the UK amounts to around 12–15,000 individuals and is increasing, with approximately 300 SCD babies born each year as well as with arrival of new immigrants. About two thirds of SCD patients are homozygous HbSS individuals. Patients heterozygous for HbS and HbC (HbSC) constitute about a third of SCD cases, making this the second most common form of SCD, with approximately 80,000 births per year worldwide. Disease in these patients shows differences from that in homozygous HbSS individuals. Their red blood cells (RBCs), containing approximately equal amounts of HbS and HbC, are also likely to show differences in properties which may contribute to disease outcome. Nevertheless, little is known about the behaviour of RBCs from HbSC heterozygotes. This paper reviews what is known about SCD in HbSC individuals and will compare the properties of their RBCs with those from homozygous HbSS patients. Important areas of similarity and potential differences will be emphasised.
Chemical Composition and, Cellular Evaluation of the Antioxidant Activity of Desmodium adscendens Leaves
Authors: Muanda François Nsemi , Bouayed Jaouad , Djilani Abdelouaheb , Yao Chunyan , Soulimani Rachid , Dicko Amadou
Published: October 2010

Desmodium adscendens plant is widely used as juice or tea in various parts of the world against a wide range of diseases. This study determines the quality and the quantity of polyphenols, flavonoids, anthocyanins, and tannins in D. adscendens leaves by UV‐spectrophotometry and RP‐HPLC methods. In addition, the antioxidant capacity of these phenolic compounds is evaluated by ABTS (2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic)), DPPH (2,2‐diphenyl‐1 picrylhydrazyl), and Cellular tests. D. adscendens leaves are mainly composite of flavonoid compounds with 12.8 mg of catechin equivalent (CE)/g dw. The amounts of total polyphenol compounds are 11.1 mg of gallic acid equivalent (GAE)/g dw. The quantity of total anthocyanin and total tannin compounds is not considerable 0.0182 mg CgE/g dw and 0.39 mg CE/g dw, respectively. A direct correlation between phenolic compounds and antioxidant activity is observed (R2 = 0.96). The RP‐HPLC analyses reveal that the main phenolic compound identified in the methanol‐water extract is quercetrin dihydrat (2.11 mg/mL). According to the results, it is observed that D. adscendens leaves possess a considerable scavenging antioxidant and antiradical capacity, therefore these antioxidant properties might increase the therapeutic value of this medicinal plant.
Self‐Tuning Random Early Detection Algorithm to Improve Performance of Network Transmission
Authors: Chen Jianyong , Hu Cunying , Ji Zhen
Published: October 2010

We use a discrete‐time dynamical feedback system model of TCP/RED to study the performance of Random Early Detection (RED) for different values of control parameters. Our analysis shows that the queue length is able to keep stable at a given target if the maximum probabilitypmax and exponential averaging weightwsatisfy some conditions. From the mathematical analysis, a new self‐tuning RED is proposed to improve the performance of TCP‐RED network. The appropriatepmax is dynamically obtained according to history information of bothpmax and the average queue size in a period of time. Andwis properly chosen according to a linear stability condition of the average queue length. From simulations withns‐2, it is found that the self‐tuning RED is more robust to stabilize queue length in terms of less deviation from the target and smaller fluctuation amplitude, compared to adaptive RED, Random Early Marking (REM), and Proportional‐Integral (PI) controller.
Cdc42-Interacting Protein 4 Promotes Breast Cancer Cell Invasion and Formation of Invadopodia through Activation of N-WASp
Authors: Pichot Christina S. , Arvanitis Constadina , Hartig Sean M. , Jensen Samuel A. , Bechill John , Marzouk Saad , Yu Jindan , Frost Jeffrey A. , Corey Seth J.
Published: October 2010

In the earliest stages of metastasis, breast cancer cells must reorganize the cytoskeleton to affect cell shape change and promote cell invasion and motility. These events require the cytoskeletal regulators Cdc42 and Rho, their effectors such as N-WASp/WAVE, and direct inducers of actin polymerization such as Arp2/3. Little consideration has been given to molecules that shape the cell membrane. The F-BAR proteins CIP4, TOCA-1, and FBP17 generate membrane curvature and act as scaffolding proteins for activated Cdc42 and N-WASp. We found that expression of CIP4, but not TOCA-1 or FBP17, was increased in invasive breast cancer cell lines in comparison with weakly or noninvasive breast cancer cell lines. Endogenous CIP4 localized to the leading edge of migrating cells and to invadopodia in cells invading gelatin. Because CIP4 serves as a scaffolding protein for Cdc42, Src, and N-WASp, we tested whether loss of CIP4 could result in decreased N-WASp function. Interaction between CIP4 and N-WASp was epidermal growth factor responsive, and CIP4 silencing by small interfering RNA caused decreased tyrosine phosphorylation of N-WASp at a Src-dependent activation site (Y256). CIP4 silencing also impaired the migration and invasion of MDA-MB-231 cells and was associated with decreased formation of invadopodia and gelatin degradation. This study presents a new role for CIP4 in the promotion of migration and invasion of MDA-MB-231 breast cancer cells and establishes the contribution of F-BAR proteins to cancer cell motility and invasion. Cancer Res; 70(21); 8347–56. ©2010 AACR.
Protein Kinase D1 Suppresses Epithelial-to-Mesenchymal Transition through Phosphorylation of Snail
Authors: Du Cheng , Zhang Chuanyou , Hassan Sazzad , Biswas Md. Helal Uddin , Balaji K.C.
Published: October 2010

Cancer cells undergo epithelial-mesenchymal transition (EMT) as a program of increased invasion and metastasis during cancer progression. Here, we report that a novel regulator of EMT in cancer cells is protein kinase D1 (PKD1), which is downregulated in advanced prostate, breast, and gastric cancers. Ectopic reexpression of PKD1 in metastatic prostate cancer cells reversibly suppressed expression of mesenchyme-specific genes and increased epithelial markers such as E-cadherin, whereas small interfering RNA–mediated knockdown of PKD1 increased expression of mesenchyme markers. Further, PKD1 inhibited tumor growth and metastasis in a tumor xenograft model. PKD1 phosphorylates Ser11 (S11) on transcription factor Snail, a master EMT regulator and repressor of E-cadherin expression, triggering nuclear export of Snail via 14-3-3σ binding. Snail S11 mutation causes acquisition of mesenchymal traits and expression of stem cell markers. Together, our results suggest that PKD1 functions as a tumor and metastasis suppressor, at least partly by regulating Snail-mediated EMT, and that loss of PKD1 may contribute to acquisition of an aggressive malignant phenotype. Cancer Res; 70(20); 7810–9. ©2010 AACR.
Ionizing Radiation Activates the Nrf2 Antioxidant Response
Authors: McDonald J. Tyson , Kim Kwanghee , Norris Andrew J. , Vlashi Erina , Phillips Tiffany M. , Lagadec Chann , Della Donna Lorenza , Ratikan Josephine , Szelag Heather , Hlatky Lynn , McBride William H.
Published: October 2010

The transcription factor NF-E2-related factor 2 (Nrf2) binds the antioxidant DNA response element (ARE) to activate important cellular cytoprotective defense systems. Recently several types of cancers have been shown to overexpress Nrf2, but its role in the cellular response to radiation therapy has yet to be fully determined. In this study, we report that single doses of ionizing radiation from 2 to 8 Gy activate ARE-dependent transcription in breast cancer cells in a dose-dependent manner, but only after a delay of five days. Clinically relevant daily dose fractions of radiation also increased ARE-dependent transcription, but again only after five days. Downstream activation of Nrf2-ARE-dependent gene and protein markers, such as heme oxygenase-1, occurred, whereas Nrf2-deficient fibroblasts were incapable of these responses. Compared with wild-type fibroblasts, Nrf2-deficient fibroblasts had relatively high basal levels of reactive oxygen species that increased greatly five days after radiation exposure. Further, in vitro clonogenic survival assays and in vivo sublethal whole body irradiation tests showed that Nrf2 deletion increased radiation sensitivity, whereas Nrf2-inducing drugs did not increase radioresistance. Our results indicate that the Nrf2-ARE pathway is important to maintain resistance to irradiation, but that it operates as a second-tier antioxidant adaptive response system activated by radiation only under specific circumstances, including those that may be highly relevant to tumor response during standard clinical dose-fractionated radiation therapy. Cancer Res; 70(21); 8886–95. ©2010 AACR.
Tumor Cell Kill by c-MYC Depletion: Role of MYC-Regulated Genes that Control DNA Double-Strand Break Repair
Authors: Luoto Kaisa R. , Meng Alice X. , Wasylishen Amanda R. , Zhao Helen , Coackley Carla L. , Penn Linda Z. , Bristow Robert G.
Published: October 2010

MYC regulates a myriad of genes controlling cell proliferation, metabolism, differentiation, and apoptosis. MYC also controls the expression of DNA double-strand break (DSB) repair genes and therefore may be a potential target for anticancer therapy to sensitize cancer cells to DNA damage or prevent genetic instability. In this report, we studied whether MYC binds to DSB repair gene promoters and modulates cell survival in response to DNA-damaging agents. Chromatin immunoprecipitation studies showed that MYC associates with several DSB repair gene promoters including Rad51, Rad51B, Rad51C, XRCC2, Rad50, BRCA1, BRCA2, DNA-PKcs, XRCC4, Ku70, and DNA ligase IV. Endogenous MYC protein expression was associated with increased RAD51 and KU70 protein expression of a panel of cancer cell lines of varying histopathology. Induction of MYC in G0-G1 and S-G2-M cells resulted in upregulation of Rad51 gene expression. MYC knockdown using small interfering RNA (siRNA) led to decreased RAD51 expression but minimal effects on homologous recombination based on a flow cytometry direct repeat green fluorescent protein assay. siRNA to MYC resulted in tumor cell kill in DU145 and H1299 cell lines in a manner independent of apoptosis. However, MYC-dependent changes in DSB repair protein expression were not sufficient to sensitize cells to mitomycin C or ionizing radiation, two agents selectively toxic to DSB repair–deficient cells. Our results suggest that anti-MYC agents may target cells to prevent genetic instability but would not lead to differential radiosensitization or chemosensitization. Cancer Res; 70(21); 8748–59. ©2010 AACR.
Phosphorylation of RalB Is Important for Bladder Cancer Cell Growth and Metastasis
Authors: Wang Hong , Owens Charles , Chandra Nidhi , Conaway Mark R. , Brautigan David L. , Theodorescu Dan
Published: October 2010

RalA and RalB are monomeric G proteins that are 83% identical in amino acid sequence but have paralogue-specific effects on cell proliferation, metastasis, and apoptosis. Using in vitro kinase assays and phosphosite-specific antibodies, here we show phosphorylation of RalB by protein kinase C (PKC) and RalA by protein kinase A. We used mass spectrometry and site-directed mutagenesis to identify S198 as the primary PKC phosphorylation site in RalB. Phorbol ester [phorbol 12-myristate 13-acetate (PMA)] treatment of human bladder carcinoma cells induced S198 phosphorylation of stably expressed FLAG-RalB as well as endogenous RalB. PMA treatment caused RalB translocation from the plasma membrane to perinuclear regions in a S198 phosphorylation–dependent manner. Using RNA interference depletion of RalB followed by rescue with wild-type RalB or RalB(S198A) as well as overexpression of wild-type RalB or RalB(S198A) with and without PMA stimulation, we show that phosphorylation of RalB at S198 is necessary for actin cytoskeletal organization, anchorage-independent growth, cell migration, and experimental lung metastasis of T24 or UMUC3 human bladder cancer cells. In addition, UMUC3 cells transfected with a constitutively active RalB(G23V) exhibited enhanced subcutaneous tumor growth, whereas those transfected with phospho-deficient RalB(G23V-S198A) were indistinguishable from control cells. Our data show that RalA and RalB are phosphorylated by different kinases, and RalB phosphorylation is necessary for in vitro cellular functions and in vivo tumor growth and metastasis. Cancer Res; 70(21); 8760–9. ©2010 AACR.
Cell Surface Tetraspanin CD9 Mediates Chemoresistance in Small Cell Lung Cancer
Authors: Kohmo Satoshi , Kijima Takashi , Otani Yasushi , Mori Masahide , Minami Toshiyuki , Takahashi Ryo , Nagatomo Izumi , Takeda Yoshito , Kida Hiroshi , Goya Sho , Yoshida Mitsuhiro , Kumagai Toru , Tachibana Isao , Yokota Soichiro , Kawase Ichiro
Published: October 2010

Small cell lung cancer (SCLC) is an aggressive malignancy with extremely high mortality due to the appearance of widespread metastases early in its clinical course and rapid acquisition of chemoresistance after initial therapy. A theory of cell adhesion–mediated drug resistance is thought to be a principal mechanism in which extracellular matrix proteins provide a survival advantage against cytotoxic drug-induced apoptosis. We found that the tetraspanin family member CD9 was expressed preferentially in SCLC tumors and metastases from three of seven relapsed patients, whereas chemonaïve primary tumors from 16 patients were CD9 negative with only one exception. Additionally, CD9 was highly expressed on SCLC cell lines rendered resistant to cisplatin or etoposide, and was upregulated in parental chemosensitive cells within 48 hours after exposure to either of these compounds. CD9-expressing chemoresistant SCLC cells adhered more tightly to fibronectin via β1 integrin, but they were less motile than the respective chemosensitive parental lines. Notably, treatment of the chemoresistant cells with chemokine CXCL12 downregulated CD9 and transiently restored motility. Moreover, selective targeting of CD9 by treatment with specific monoclonal antibody ALB6 or a small interfering RNA triggered apoptosis in the chemoresistant cells. Taken together, our findings implicate CD9 in the cell adhesion–mediated drug resistance mechanism, highlighting CD9 as an attractive therapeutic target to improve therapeutic outcomes in SCLC. Cancer Res; 70(20); 8025–35. ©2010 AACR.
Transforming Properties of 8p11-12 Amplified Genes in Human Breast Cancer
Authors: Yang Zeng-Quan , Liu Gang , Bollig-Fischer Aliccia , Giroux Craig N. , Ethier Stephen P.
Published: October 2010

Amplification of the 8p11-12 region has been found in about 15% of human breast cancers and is associated with poor prognosis. Earlier, we used genomic analysis of copy number and gene expression to perform a detailed analysis of the 8p11-12 amplicon to identify candidate oncogenes in breast cancer. We identified 21 candidate genes and provided evidence that three genes, namely, LSM-1, TC-1, and BAG4, have transforming properties when overexpressed. In the present study, we systematically investigated the transforming properties of 13 newly identified 8p11-12 candidate oncogenes in vitro. WHSC1L1, DDHD2, and ERLIN2 were most potently transforming oncogenes based on the number of altered phenotypes expressed by the cells. WHSC1L1 contains a PWWP-domain that is a methyl-lysine recognition motif involved in histone code modification and epigenetic regulation of gene expression. Knockdown of WHSC1L1 in 8p11-12–amplified breast cancer cells resulted in profound loss of growth and survival of these cells. Further, we identified several WHSC1L1 target genes, one of which is iroquois homeobox 3 gene (IRX3), a member of the Iroquois homeobox transcription factor family. Cancer Res; 70(21); 8487–97. ©2010 AACR.
The Myc–miR-17∼92 Axis Blunts TGFβ Signaling and Production of Multiple TGFβ-Dependent Antiangiogenic Factors
Authors: Dews Michael , Fox Jamie L. , Hultine Stacy , Sundaram Prema , Wang Wenge , Liu Yingqiu Y. , Furth Emma , Enders Gregory H. , El-Deiry Wafik , Schelter Janell M. , Cleary Michele A. , Thomas-Tikhonenko Andrei
Published: October 2010

c-Myc stimulates angiogenesis in tumors through mechanisms that remain incompletely understood. Recent work indicates that c-Myc upregulates the miR-17∼92 microRNA cluster and downregulates the angiogenesis inhibitor thrombospondin-1, along with other members of the thrombospondin type 1 repeat superfamily. Here, we show that downregulation of the thrombospondin type 1 repeat protein clusterin in cells overexpressing c-Myc and miR-17∼92 promotes angiogenesis and tumor growth. However, clusterin downregulation by miR-17∼92 is indirect. It occurs as a result of reduced transforming growth factor-β (TGFβ) signaling caused by targeting of several regulatory components in this signaling pathway. Specifically, miR-17-5p and miR-20 reduce the expression of the type II TGFβ receptor and miR-18 limits the expression of Smad4. Supporting these results, in human cancer cell lines, levels of the miR-17∼92 primary transcript MIR17HG negatively correlate with those of many TGFβ-induced genes that are not direct targets of miR-17∼92 (e.g., clusterin and angiopoietin-like 4). Furthermore, enforced expression of miR-17∼92 in MIR17HGlow cell lines (e.g., glioblastoma) results in impaired gene activation by TGFβ. Together, our results define a pathway in which c-Myc activation of miR-17∼92 attenuates the TGFβ signaling pathway to shut down clusterin expression, thereby stimulating angiogenesis and tumor cell growth. Cancer Res; 70(20); 8233–46. ©2010 AACR.
Antiangiogenic Activity of a Neutralizing Human Single-Chain Antibody Fragment against Fibroblast Growth Factor Receptor 1
Authors: Ronca Roberto , Benzoni Patrizia , Leali Daria , Urbinati Chiara , Belleri Mirella , Corsini Michela , Alessi Patrizia , Coltrini Daniela , Calza Stefano , Presta Marco , Dell'Era Patrizia
Published: October 2010

Fibroblast growth factor receptor-1 (FGFR-1) transduces proangiogenic and proliferative signals in human cancers. Thus, FGFR-1 may represent a target for the development of antiangiogenic/antineoplastic therapies. We screened a human single-chain fragment variable (scFv) antibody phage display library against the extracellular domain of the FGFR-1-IIIc isoform that harbors the FGF binding site. Several phages were isolated and tested for specificity and sensitivity, and the most promising antibody fragment RR-C2 was characterized for its biochemical and biological properties. ScFv RR-C2 specifically recognizes FGFR-1α and FGFR-1β isoforms in ELISA, Western blotting, and surface plasmon resonance analysis with a Kd value of 300 and 144 nmol/L for the 2 receptor isoforms, respectively. The antibody fragment also recognizes FGFR-1 when the receptor is exposed on the cell surface, thus preventing the formation of the ternary complex among FGFR-1, its ligand FGF2, and cell surface heparan sulfate proteoglycans. Accordingly, scFv RR-C2 specifically inhibits FGF2-mediated mitogenic activity in endothelial cells of human, bovine, and murine origin in a nanomolar range of concentrations. Also, the antibody fragment prevents FGF2-triggered sprouting of both human umbilical vein endothelial cell spheroids and of murine endothelium from aortic rings. Finally, the antibody fragment hampers the angiogenic activity exerted both by FGF2 in the chick embryo chorioallantoic membrane assay and by S115 mouse mammary tumor cells in the Matrigel plug assay. Taken together, the data show that scFv RR-C2 recognizes and neutralizes FGFR-1 activity in different animal species, including humans, thus representing a novel tool for the development of antiangiogenic/antineoplastic therapies. Mol Cancer Ther; 9(12); 3244–53. ©2010 AACR.
Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis
Authors: DeCensi Andrea , Puntoni Matteo , Goodwin Pamela , Cazzaniga Massimiliano , Gennari Alessandra , Bonanni Bernardo , Gandini Sara
Published: October 2010

Metformin, an insulin-lowering agent, has been associated with decreased cancer risk in epidemiologic studies in diabetic patients. We performed a comprehensive literature search and meta-analysis of epidemiologic studies to assess the effect of metformin on cancer incidence and mortality in diabetic patients, using Pubmed, ISI Web of Science, Embase, and the Cochrane library until May 2009, with no language or time restrictions. Independent reports with sufficient information to allow risk estimation of cancer risk/mortality and a measure of uncertainty were reviewed and cross-checked independently by three investigators. Eleven studies were selected for relevance in terms of intervention, population studied, independence, and reporting of cancer incidence or mortality data, reporting 4,042 cancer events and 529 cancer deaths. A 31% reduction in overall summary relative risk (0.69; 95% confidence interval, 0.61-0.79) was found in subjects taking metformin compared with other antidiabetic drugs. The inverse association was significant for pancreatic and hepatocellular cancer, and nonsignificant for colon, breast, and prostate cancer. A trend to a dose-response relationship was noted. Metformin is associated with a decreased risk of cancer incidence compared with other treatments among diabetic patients. Given the retrospective nature of most studies and the possibility that the control treatments increase risk, phase II trials are needed before large cancer prevention trials are launched. Cancer Prev Res; 3(11); 1451–61. ©2010 AACR.
Dendritic Spine Alterations in Neocortical Pyramidal Neurons following Postnatal Neuronal Nogo-A Knockdown
Authors: Pradhan A.D. , Case A.M. , Farrer R.G. , Tsai S.Y. , Cheatwood J.L. , Martin J.L. , Kartje G.L.
Published: October 2010

The myelin-associated protein Nogo-A is a well-known inhibitor of axonal regeneration and compensatory plasticity, yet functions of neuronal Nogo-A are not as clear. The present study examined the effects of decreased levels of neuronal Nogo-A on dendritic spines of developing neocortical neurons. Decreased Nogo-A levels in these neurons resulted in lowered spine density and an increase in filopodial type protrusions. These results suggest a role for neuronal Nogo-A in maintaining a spine phenotype in neocortical pyramidal cells.
Evaluation of Surgical Outcome Scores according to ISGPS Definitions in Patients Undergoing Pancreatic Resection
Authors: Knight B.C. , Kausar A. , Manu M. , Ammori B.A. , Sherlock D.J. , O’Reilly D.A.
Published: October 2010

Aims: To evaluate the role of the Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM), the Portsmouth variant (p-POSSUM) and the Glasgow Prognostic Score (GPS) in predicting outcome after pancreatic surgery with reference to the International Study Group of Pancreatic Surgery (ISGPS) definitions of post-pancreatectomy complications. Methods: All consecutive patients undergoing major pancreatic resection over a 32- month period were included. POSSUM, p-POSSUM and GPS score were calculated for each patient and correlated against the observed mortality and morbidity using the ISGPS definitions. Results: The observed:expected ratios for POSSUM mortality, POSSUM morbidity and p-POSSUM mortality were 0.24 (p < 0.0001), 0.86 (p < 0.0001) and 0.79 (p = 0.09), respectively. POSSUM had a ‘poor fit’ with respect to predicting morbidity (χ2 = 16.4, 8 d.f., p = 0.04). Multifactorial regression analysis revealed the GPS as an independent predictor of post-operative outcome (GPS 1, p = 0.03, OR 2.99, 95% CI 1.4–7.9, and GPS 2, p = 0.02, OR 4.3, 95% CI 1.8–15.5). Conclusion: POSSUM has a limited role as an outcome score in pancreatic resection. The GPS may be a novel alternative to POSSUM as a pre-operative predictor of outcome.
Decreased Susceptibility to Azithromycin and Doxycycline in Clinical Isolates of Chlamydia trachomatis Obtained from Recurrently Infected Female Patients in India
Authors: Bhengraj Apurb Rashmi , Vardhan Harsh , Srivastava Pragya , Salhan Sudha , Mittal Aruna
Published: October 2010

Background: Recurrent genital Chlamydia trachomatis infection often results in serious sequelae and has a major impact on reproductive health. Materials and Methods: Recurrent infections were determined in symptomatic female patients. In vitro susceptibility assay was performed for azithromycin and doxycycline using the cell culture technique against 21 clinical isolates obtained from C. trachomatis-positive patients including those who were recurrently infected. Results: Thirteen isolates (61.9%) were found to be susceptible to azithromycin and doxycycline with minimum inhibitory concentration (MIC) values ≤0.125 and ≤0.25 µg/ml, respectively. Eight isolates (38%) were found to be less susceptible to the drugs. Two of them had MICs of 8 µg/ml for both the drugs and could not be completely eradicated as observed by minimum bactericidal concentration assay. Conclusions: Decreased antibiotic susceptibility to the current first-line drugs (azithromycin and doxycycline) for chlamydial infection treatment was observed in isolates obtained from recurrently infected patients.
Laparoscopic and Open Cholecystectomy in Surgical Training
Authors: Suuronen Satu , Koski Anu , Nordstrom Pia , Miettinen Pekka , Paajanen Hannu
Published: October 2010

Background: Open cholecystectomy (OC) may still be necessary in surgical training to perform safe conversions of laparoscopic cholecystectomy (LC). Our aim was to study the outcome of LCs and OCs performed by surgical trainees. Methods: All consecutive cholecystectomies (1,581 LCs and 984 OCs) were retrospectively analyzed from 1995 until 2008. Operative complications were compared between the cholecystectomies performed by 20 trainees alone (n = 822), assisted operations (n = 754, trainees/specialist surgeons) and 9 specialists alone (n = 989). Results: Surgical trainees performed 787 (50%) LCs and 789 (80%) OCs either alone or assisted. The conversion rate of LC for trainees and specialist surgeons were 34 (7.0%) and 44 (5.5%), respectively. Complication rates and mortality were similar between the trainees and specialist surgeons. No bile duct injuries were associated with LCs or OCs performed by trainees alone. LCs were associated with 9 (0.57%) cases of bile leakage from cystic stump and 2 (0.13%) other bile duct injuries. Conclusion: Surgical trainees performed over half of our cholecystectomies with good results. The patient selection for LC versus OC was good, because no total transection of the common bile duct was observed in over 1,500 LC operations.
Serum Cytokine Profiles at the Onset of Severe, Diffuse Alveolar Hemorrhage Complicating Allogeneic Hematopoietic Stem Cell Transplantation, Treated Successfully with Pulse Intravenous Cyclophosphamide
Authors: Koh Hideo , Nakamae Hirohisa , Koh Ki-Ryang , Ohsawa Masahiko , Nakane Takahiko , Takeoka Yasunobu , Aimoto Ran , Aimoto Mizuki , Wada-Inoue Eri , Terada Yoshiki , Yamane Takahisa , Hino Masayuki
Published: October 2010

A 59-year-old man with lymphoma-type adult T-cell leukemia/lymphoma was admitted to hospital for treatment of a skin relapse on day 398 after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To induce a graft-versus-adult T-cell leukemia/lymphoma effect, we discontinued methylprednisolone and tacrolimus. About a month after the discontinuation, he developed grade II acute graft-versus-host disease (GVHD) with a high fever. Soon after the development of GVHD, all the skin lesions regressed in size and finally vanished. However, he developed diffuse alveolar hemorrhage (DAH), which was resistant to high-dose corticosteroid therapy. He was intubated for respiratory insufficiency on day 451. Cyclophosphamide pulse therapy was administered at a dose of 1 g per day for 2 days and his oxygen saturation then improved, and ventilatory support was released on day 465. On analysis of cytokine profiles at the onset of DAH, we found elevated serum levels of T-helper 2 cytokines as well as T-helper 1 cytokines, suggesting that both T-helper 1 and T-helper 2 cytokines might play a role in the occurrence of DAH following allo-HSCT. Pulse cyclophosphamide treatment might be very effective in suppressing the exaggerated allogeneic immune response in DAH.
The Effects of Isolated versus Multiple Lipid Disorders on Resource Utilization among Metabolic Syndrome Patients with Lipid Abnormalities despite Lipid-Modifying Treatment
Authors: Ambegaonkar Baishali , Chirovsky Diana , Wu Wenchen , Colclough Hayley , Milligan Gary , Sazonov Vasilisa
Published: October 2010

Objective: The aim of this study was to compare resource utilization among metabolic syndrome (MetS) patients with multiple (≧2) lipid disorders (MLD) versus isolated (any 1) lipid disorder (ILD). Methods: Data for MetS patients on lipid-modifying therapy (LMT) were collected from the 2006 Adelphi Metabolic Syndrome Disease Specific Programme© cross-sectional study of patients from 5 European countries. The presence of MetS and lipid disorders, including elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), and low high-density lipoprotein (HDL-C), were based on the National Cholesterol Education Program definitions. Analyses compared primary care physician (PCP) and specialist visits over the past 6 months among ILD versus MLD patients. Results: Among 4,836 MetS patients, 2,843 had ≧1 lipid disorders and were on LMT. Controlling for other risk factors, MLD patients had significantly higher physician visits than those with ILD (p = 0.009), but hospitalizations were not significantly different. Patients experiencing all 3 lipid disorders had significantly more endocrinologist visits (p = 0.002) as compared with ILD patients, while patients with elevated LDL-C and abnormal HDL-C and/or TG compared with isolated elevated LDL-C had significantly more PCP (p = 0.001) and cardiologist visits (p < 0.001). Conclusion: Among MetS patients on LMT, presence of MLD resulted in significantly higher PCP and specialist visits compared with ILD.
Outcome of 232 Morbidly Obese Patients Treated with Laparoscopic Adjustable Gastric Banding between 1995–2003
Authors: Polat F. , Poyck P.P.C. , Dickhoff C. , Gouma D.J. , Hesp W.L.E.M.
Published: October 2010

Background: Laparoscopic adjustable gastric banding (LAGB) is widely used for the treatment of morbidly obese patients. We prospectively evaluated the effect of LAGB since 1995. Methods: Between March 1995 and August 2003, 232 morbidly obese patients underwent LAGB. The pars flaccida technique was used in the majority of the patients. Data were prospectively collected. Results: The median age was 35 years and 93% were female. Initial median body weight was 129 kg with a median BMI of 46. After 5 years of follow-up, median BMI decreased to 36 and the median body weight decreased to 98 kg. Median excess weight loss was 37% after 1 year, 42% after 3 years and 42% after 5 years of follow-up. Late postoperative complications were pouch dilatation (n = 33), port revision (n = 19), erosion (n = 4) and necrosis (n = 1). Conclusion: LAGB is a safe and successful treatment for patients with morbid obesity. Maximal weight reduction is achieved within 12 months and remains stable up to at least 5 years. These results suggest that LAGB could have a positive outcome on morbid obesity-associated morbidity and overall life expectancy.
Baseline Predictors of Clinical Progression among Patients with Dysexecutive Mild Cognitive Impairment
Authors: Johnson Julene K. , Pa Judy , Boxer Adam L. , Kramer Joel H. , Freeman Katie , Yaffe Kristine
Published: October 2010

Background/Aims: There are few studies that evaluate the clinical outcomes of individuals with non-amnestic mild cognitive impairment (MCI). The purpose of this study was to evaluate baseline predictors of clinical progression after 2 years for patients with dysexecutive MCI (dMCI), a single-domain non-amnestic MCI subgroup. Methods:We evaluated clinical progression in a sample of 31 older adults with dMCI. Clinical progression was defined as a worsening on the Clinical Dementia Rating sum of boxes at the 2-year visit, whereas patients were classified as stable if the score did not worsen over 2 years. We compared baseline brain MRI, neuropsychological tests, and health risk factors. Results: Twelve individuals with dMCI progressed clinically, and 19 individuals remained stable over 2 years. Compared to the stable dMCI patients, the dMCI patients who progressed showed brain atrophy in the bilateral insula and left lateral temporal lobe on MRI. dMCI patients who progressed were also older, had lower baseline performance on category fluency and a spatial location task, and reported fewer dysexecutive symptoms. Health risk factors, except hypertension, did not differ between groups. Conclusion: The results suggest that dMCI patients who progress relatively quickly over 2 years may have unique clinical and brain MRI features.
Effects of cAMP and β-Adrenergic Receptor Antagonists on the Function of Peripheral T Helper Lymphocytes in Patients with Heart Failure
Authors: Tian Xiuqing , Zhang Lei , Hou Yinglong , Xu Wanju , Dong Yuling , Liu Jianhua , Liang Jiangjiu
Published: October 2010

Objective: To observe the effects of cyclic adenosine monophosphate (cAMP) in peripheral lymphocytes on T helper 1 (TH1)/TH2 cytokine ratios and to investigate the potential impact and mechanism of β-adrenergic receptor antagonists on immune function in patients with chronic heart failure (CHF). Methods: Sixty-nine patients with New York Heart Association functional class II–IV CHF and a radionuclide left ventricular ejection fraction of less than 45% received carvedilol or metoprolol in a randomized fashion. Thirty healthy persons were studied as controls. Interferon (IFN)-γ and interleukin (IL)-10 in CD4+ T lymphocytes were quantified by three-color flow cytometry. cAMP levels in peripheral blood mononuclear cells were tested by radioimmunoassay at baseline and 6 months after treatment. Results: The levels of lymphocyte cAMP in CHF patients were significantly lower than in normal controls (p < 0.01). The IFN-γ/IL-10 ratio was significantly higher in CHF patients (p < 0.01). The levels of cAMP, IFN-γ and IL-10 among CHF patients with different pathogenic factors displayed no significant differences (p > 0.05). The lymphocyte cAMP level was negatively correlated with the IFN-γ/IL-10 ratio (p < 0.01). After treatment with metoprolol and carvedilol, the IFN-γ/IL-10 ratio in the CHF patients was dramatically decreased (p < 0.01 for each drug) and lymphocyte cAMP was remarkably increased (p < 0.01 for each drug). Conclusion: These results suggest that the decrease of cAMP affects the TH1/TH2 phenotype in peripheral lymphocytes of CHF patients. β-Blocking medications appear to have a beneficial effect on the TH1/TH2 balance and on the immune system through increasing production of cAMP, offering further evidence to support the use of β-adrenergic receptor blockers to treat CHF.
Association of Alveolar Nitric Oxide Levels with Pulmonary Function and Its Reversibility in Stable Asthma
Authors: Matsumoto Hisako , Niimi Akio , Jinnai Makiko , Nakaji Hitoshi , Takeda Tomoshi , Oguma Tsuyoshi , Otsuka Kojiro , Inoue Hideki , Yamaguchi Masafumi , Matsuoka Hirofumi , Ito Isao , Hirai Toyohiro , Chin Kazuo , Mishima Michiaki
Published: October 2010

Background: Inflammation of peripheral airways is implicated in the pathophysiology of severe asthma. However, contributions of peripheral airway inflammation to airway caliber/function in patients with stable asthma, including those with mild to moderate disease, remain to be confirmed. Objectives: To determine whether peripheral airway inflammation affects airway function in patients with asthma. Methods: In 70 patients with mild to severe asthma, alveolar nitric oxide [CANO(TMAD)] levels were examined as a noninvasive biomarker of peripheral airway/alveolar inflammation. CANO(TMAD) and maximal nitric oxide (NO) flux in the airway compartment, J’awNO, were estimated with a model that incorporated trumpet-shaped airways and axial diffusion using exhaled NO output at different flow rates. Measures of pulmonary function were then assessed by spirometry and an impulse oscillometry system, and their bronchodilator reversibility was examined. Results: CANO(TMAD) levels were not correlated with pre- or postbronchodilator spirometric values, but were significantly associated with prebronchodilator reactance at low frequency (Xrs5) (rho = –0.31, p = 0.011), integrated area of low-frequency Xrs (AX) (rho = 0.35, p = 0.003) and negative frequency dependence of resistance (Rrs5-Rrs20) (rho = 0.35, p = 0.004). Furthermore, CANO(TMAD) levels were associated with bronchodilator reversibility of FEV1, FEF25–75%, Xrs5 and AX (rho = 0.35, 0.31, –0.24 and –0.31, respectively; p ≤ 0.05 for all). No variables were related to J’awNO. Conclusions: Elevated CANO(TMAD), but not J’awNO, partly reflects reversible airway obstruction originating in the peripheral airway. These findings indicate the involvement of peripheral airway inflammation in physiological abnormalities in asthma.
The Diagnostic Yield and Safety of Ultrasound-Assisted Transthoracic Fine-Needle Aspiration of Drowned Lung
Authors: Koegelenberg Coenraad F.N. , Bolliger Chris T. , Irusen Elvis M. , Wright Colleen A. , Louw Mercia , Schubert Pawel T. , Diacon Andreas H.
Published: October 2010

Background: Proximal lung tumors, though not discernable by means of transthoracic ultrasound (US), may cause varying degrees of pulmonary collapse and postobstructive pneumonitis which may give rise to a ‘drowned lung’ appearance on chest computed tomography (CT) and US. The diagnostic yield for malignancy of US-assisted transthoracic fine-needle aspiration (FNA) of these areas of drowned lung is unknown. Objectives: We aimed to explore the feasibility of US-assisted FNA in this setting by prospectively investigating its diagnostic yield and safety. Methods: We enrolled 31 patients (aged 59.4 ± 9.7 years, 17 males) with central tumors and secondary drowned lung on CT scan. A respiratory physician performed transthoracic US to identify the target drowned lung tissue. Three US-assisted superficial FNA passes (≤20 mm from the pleura) were followed by 3 deeper FNA passes (>20 mm) aimed in the direction of a visible or approximated central mass. Rapid on-site evaluation of specimens was used. Results: Superficial FNA was diagnostic in 11 patients (35.5%), whereas deeper FNA was diagnostic in 23 patients (74.2%, p = 0.002). Deeper FNA confirmed malignancy in all cases with diagnostic superficial FNA. We observed no pneumothoraces or major hemorrhage. All patients were ultimately diagnosed with malignancy (bronchogenic carcinoma, n = 30; lymphoma, n = 1). Conclusions: US-assisted FNA of drowned lung has an acceptable diagnostic yield and is safe.
MPTP-Induced Neuroinflammation Increases the Expression of Pro-Inflammatory Cytokines and Their Receptors in Mouse Brain
Authors: Lofrumento Dario Domenico , Saponaro Concetta , Cianciulli Antonia , De Nuccio Francesco , Mitolo Vincenzo , Nicolardi Giuseppe , Panaro Maria Antonietta
Published: October 2010

Parkinson’s disease (PD) is a common neurodegenerative disease characterised by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Despite intensive research, the cause of neuronal loss in PD is poorly understood. Inflammatory mechanisms have been implicated in the pathophysiology of PD. In this study, conducted on an experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, we investigated the expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6 and their receptors (IL-1RI, TNF-αRI, IL-6Rα) at the SN and caudate-putamen (CP) levels. In MPTP-treated animals we observed a significant increase in IL-1β, TNF-α and IL-6 mRNA expression levels both in the SN and CP in comparison with untreated mice. In addition, both mRNA and protein levels of IL-1RI, TNF-αRI and IL-6Rα were significantly enhanced in the SN of MPTP-treated mice in comparison to controls, whereas no significant differences were observed in the CP between treated and untreated mice. Overall, these results indicate a role of both pro-inflammatory cytokines and their receptors in the pathogenesis of PD.
Review of Dairy Consumption and Cognitive Performance in Adults: Findings and Methodological Issues
Authors: Crichton Georgina E. , Bryan Janet , Murphy Karen J. , Buckley Jonathan
Published: October 2010

Background: Diet is a modifiable factor that could be targeted as an appropriate intervention to optimise cognitive health and well-being in ageing. Aim: The aim of this systematic review was to consider current evidence for an association between dairy intake and cognitive functioning. Methods: Searches of the electronic databases Medline, Embase, Web of Science, CINAHL, and PsychInfo were undertaken to identify peer-reviewed journal articles that reported on associations between dairy consumption and cognitive outcomes. Results: Three cross-sectional and 5 prospective studies were identified. Poorer cognitive function and an increased risk for vascular dementia were found to be associated with a lower consumption of milk or dairy products. However, the consumption of whole-fat dairy products may be associated with cognitive decline in the elderly. Conclusion: Methodological variability and study limitations do not enable conclusions regarding optimal dairy intake and cognitive performance to be drawn. Randomised controlled trials are needed to confirm the relationship between dairy intake and cognition.
Construction of a New Sensitive Molecular Tool for the Study of Gene Expression in Enterococcus faecalis
Authors: Le Jeune André , Touchet Florent , Zhao Chen , Hartke Axel , Auffray Yanick , Benachour Abdellah
Published: October 2010

A promoter-probe vector designated pVEPhoZ-P has been developed to provide a convenient system to analyze transcription activities of promoters. It was constructed on the basis of pVE14218, a plasmid which lacks the replication protein and in which the 5′ part of alkaline phosphatase (AP) phoZ gene of Enterococcus faecalis was inserted. The pVEPhoZ vector was used to clone promoters of interest. The resulting promoter-probe vectors were integrated in the phoZ chromosomal locus by homologous recombination. This procedure generates recombinant clones with a single copy of phoZ functional allele placed under the control of the desired promoter. This system was investigated with different promoters of E. faecalis genes, namely those of sigV encoding an ECF sigma factor, croRS encoding a two-component system and dhaK operon. In all cases, expression data obtained previously for the three promoters were properly reported for this new tool. The pVEPhoZ-P promoter-probe vector is easy to use and it showed higher reporter activity in comparison to systems based on β-galactosidase. Therefore, this system constitutes a useful molecular tool for the study of promoters in E. faecalis or other bacterial species that possess a homologous phoZ gene.