bluuebunny/crossref_metadata_2025_split huggingface dataset:
Connective tissue growth factor–specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer
Authors: Aikawa Takuma , Gunn Jason , Spong Suzanne M. , Klaus Stephen J. , Korc Murray 
Published: May 2006

Abstract
Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell migration and cell growth but may also modify tumor growth and metastasis. Because CTGF is overexpressed in pancreatic ductal adenocarcinoma, we investigated the in vitro effects of CTGF on the proliferation and invasiveness of PANC-1 pancreatic cancer cells and examined the consequences of its in vivo inhibition on the growth and metastasis of these cells using a fully human CTGF-specific monoclonal antibody (FG-3019) in an orthotopic nude mouse model. Although PANC-1 cells expressed relatively high levels of endogenous CTGF mRNA, the addition of CTGF to conditioned medium increased the proliferation and invasiveness of PANC-1 cells. Moreover, transforming growth factor-β1 caused a further increase in CTGF expression in these cells. In vivo, the twice weekly i.p. administration of FG-3019 decreased tumor growth and metastasis and attenuated tumor angiogenesis and cancer cell proliferation. FG-3019 did not enhance apoptosis and did not attenuate the inhibitory effects of gemcitabine on tumor growth and metastasis. These findings suggest that CTGF may contribute to aberrant autocrine and paracrine pathways that promote pancreatic cancer cell growth, invasion, metastasis, and angiogenesis. Therefore, blocking CTGF actions with FG-3019 may represent a novel therapeutic approach in pancreatic ductal adenocarcinoma. [Mol Cancer Ther 2006;5(5):1108–16]
Identification of new biomarkers for clinical trials of Hsp90 inhibitors
Authors: Zhang Hong , Chung Daun , Yang Yong-Ching , Neely Laura , Tsurumoto Steven , Fan Junhua , Zhang Lin , Biamonte Marco , Brekken John , Lundgren Karen , Burrows Francis 
Published: May 2006

Abstract
The selective heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) is currently in phase I/II clinical studies at numerous institutions. Heretofore, the biomarkers to detect 17-AAG bioactivity (Hsp70, Raf-1, and cyclin-dependent kinase 4) had to be analyzed by Western blot of cellular samples, either from tumor biopsies or peripheral blood leukocytes, a method that is both laborious and invasive. We have identified two new biomarkers [insulin-like growth factor binding protein-2 (IGFBP2) and HER-2 extracellular domain] that can be readily detected in patient sera by ELISA. Both secreted proteins are derived from or regulated by Hsp90 client proteins, raising hopes that they might be sensitive serum markers of HSP90 inhibitor activity. Several structurally unrelated HSP90 inhibitors dose-dependently decreased secretion of both IGFBP-2 and HER-2 extracellular domain into culture medium, and both proteins were more sensitive to HSP90 inhibitors than previously identified biomarkers. In sera from BT474 tumor-bearing mice, both IGFBP-2 and HER-2 extracellular domain were down-regulated by 17-AAG in a time-dependent and dose-dependent manner, coincident with the degradation of HER-2 and attenuation of AKT activity in the tumors. Furthermore, IGFBP-2 levels at the end of treatment correlated with residual tumor load, suggesting that IGFBP-2 might serve as an early indicator of therapeutic response. In addition, we also found that both IGFBP-2 and HER-2 extracellular domain levels are elevated in patient sera from several cancer types, suggesting that these novel secreted biomarkers could be valuable pharmacodynamic tools in clinical trials of HSP90 inhibitors. [Mol Cancer Ther 2006;5(5):1256–64]
The role of neuropilins in cancer
Authors: Ellis Lee M. 
Published: May 2006

Abstract
Neuropilins are multifunctional non–tyrosine kinase receptors that bind to class 3 semaphorins and vascular endothelial growth factor. NRP-1 and NRP-2 were first identified for their key role in mediating axonal guidance in the developing nervous system through their interactions with class 3 semaphorins. Growing evidence supports a critical role for these receptors in tumor progression. Neuropilin expression is up-regulated in multiple tumor types, and correlates with tumor progression and prognosis in specific tumors. Neuropilins may indirectly mediate effects on tumor progression by affecting angiogenesis or directly through effects on tumor cells. This article reviews emerging evidence for the role of neuropilins in tumor biology. The therapeutic implications of these data are far-reaching and suggest that neuropilin-targeted interventions may be useful as a component of antineoplastic therapy. [Mol Cancer Ther 2006;5(5):1099–107]
Genes regulated by hepatocyte growth factor as targets to sensitize ovarian cancer cells to cisplatin
Authors: Olivero Martina , Ruggiero Tina , Saviozzi Silvia , Rasola Andrea , Coltella Nadia , Crispi Stefania , Di Cunto Ferdinando , Calogero Raffaele , Di Renzo Maria Flavia 
Published: May 2006

AbstractAdvanced ovarian cancers are initially responsive to chemotherapy with platinum drugs but develop drug resistance in most cases. We showed recently that hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and that this effect is mediated by the p38 mitogen-activated protein kinase. In this work, we integrated genome-wide expression profiling, in silico data survey, and functional assays to identify transcripts regulated in SK-OV-3 ovarian cancer cells made more responsive to CDDP by HGF. Using oligonucleotide microarrays, we found that HGF pretreatment changes the transcriptional response to CDDP. Quantitative reverse transcription-PCR not only validated all the 15 most differentially expressed genes but also confirmed that they were primarily modulated by the combined treatment with HGF and CDDP and reversed by suppressing p38 mitogen-activated protein kinase activity. Among the differentially expressed genes, we focused functional analysis on two regulatory subunits of the protein phosphatase 2A, which were down-modulated by HGF plus CDDP. Decrease of each subunit by RNA interference made ovarian cancer cells more responsive to CDDP, mimicking the effect of HGF. In conclusion, we show that HGF and CDDP modulate transcription in ovarian cancer cells and that this transcriptional response is involved in apoptosis regulation. We also provide the proof-of-concept that the identified genes might be targeted to either increase the efficacy of chemotherapeutics or revert chemotherapy resistance. [Mol Cancer Ther 2006;5(5):1126–35]
Synthetic curcuminoids modulate the arachidonic acid metabolism of human platelet 12-lipoxygenase and reduce sprout formation of human endothelial cells
Authors: Jankun Jerzy , Aleem Ansari M. , Malgorzewicz Sylvia , Szkudlarek Maria , Zavodszky Maria I. , DeWitt David L. , Feig Michael , Selman Steven H. , Skrzypczak-Jankun Ewa 
Published: May 2006

Abstract
Platelet 12-lipoxygenase (P-12-LOX) is overexpressed in different types of cancers, including prostate cancer, and the level of expression is correlated with the grade of this cancer. Arachidonic acid is metabolized by 12-LOX to 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], and this biologically active metabolite is involved in prostate cancer progression by modulating cell proliferation in multiple cancer-related pathways inducing angiogenesis and metastasis. Thus, inhibition of P-12-LOX can reduce these two processes. Several lipoxygenase inhibitors are known, including plant and mammalian lipoxygenases, but only a few of them are known inhibitors of P-12-LOX. Curcumin is one of these lipoxygenase inhibitors. Using a homology model of the three-dimensional structure of human P-12-LOX, we did computational docking of synthetic curcuminoids (curcumin derivatives) to identify inhibitors superior to curcumin. Docking of the known inhibitors curcumin and NDGA to P-12-LOX was used to optimize the docking protocol for the system in study. Over 75% of the compounds of interest were successfully docked into the active site of P-12-LOX, many of them sharing similar binding modes. Curcuminoids that did not dock into the active site did not inhibit P-12-LOX. From a set of the curcuminoids that were successfully docked and selected for testing, two were found to inhibit human lipoxygenase better than curcumin. False-positive curcuminoids showed high LogP (theoretical) values, indicating poor water solubility, a possible reason for lack of inhibitory activity or/and nonrealistic binding. Additionally, the curcuminoids inhibiting P-12-LOX were tested for their ability to reduce sprout formation of endothelial cells (in vitro model of angiogenesis). We found that only curcuminoids inhibiting human P-12-LOX and the known inhibitor NDGA reduced sprout formation. Only limited inhibition of sprout formation at ∼IC50 concentrations has been seen. At IC50, a substantial amount of 12-HETE can be produced by lipoxygenase, providing a stimulus for angiogenic sprouting of endothelial cells. Increasing the concentration of lipoxygenase inhibitors above IC50, thus decreasing the concentration of 12(S)-HETE produced, greatly reduced sprout formation for all inhibitors tested. This universal event for all tested lipoxygenase inhibitors suggests that the inhibition of sprout formation was most likely due to the inhibition of human P-12-LOX but not other cancer-related pathways. [Mol Cancer Ther 2006;5(5):1371–82]
Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases
Authors: Smalley Keiran S.M. , Haass Nikolas K. , Brafford Patricia A. , Lioni Mercedes , Flaherty Keith T. , Herlyn Meenhard 
Published: May 2006

Abstract
Although &gt;66% of melanomas harbor activating mutations in BRAF and exhibit constitutive activity in the mitogen-activated protein kinase/extracellular signal–regulated kinase kinase (MEK)/extracellular signal–regulated kinase signaling pathway, it is unclear how effective MEK inhibition will be as a sole therapeutic strategy for melanoma. We investigated the anticancer activity of MEK inhibition in a panel of cell lines derived from radial growth phase (WM35) and vertical growth phase (WM793) of primary melanomas and metastatic melanomas (1205Lu, 451Lu, WM164, and C8161) in a three-dimensional spheroid model and found that the metastatic lines were completely resistant to MEK inhibition (U0126 and PD98059) but the earlier stage cell lines were not. Similarly, these same metastatic melanoma lines were also resistant to inhibitors of the phosphatidylinositol 3-kinase/Akt pathway (LY294002 and wortmannin). Under adherent culture conditions, the MEK inhibitors blocked growth through the induction of cell cycle arrest and up-regulation of p27, but this was readily reversible following inhibitor washout. However, when the phosphatidylinositol 3-kinase and MEK inhibitors were combined, the growth and invasion of the metastatic melanoma three-dimensional spheroids were blocked. Taken together, these results suggest that the most aggressive melanomas are resistant to strategies targeting one signaling pathway and that multiple signaling pathways may need to be targeted for maximal therapeutic efficacy. It is further suggested that BRAF mutational status is not predictive of response to MEK inhibition under three-dimensional culture conditions. [Mol Cancer Ther 2006;5(5):1136–44]
Adrenoceptor Polymorphisms and the Risk of Cardiac Injury and Dysfunction After Subarachnoid Hemorrhage
Authors: Zaroff Jonathan G. , Pawlikowska Ludmila , Miss Jacob C. , Yarlagadda Sirisha , Ha Connie , Achrol Achal , Kwok Pui-Yan , McCulloch Charles E. , Lawton Michael T. , Ko Nerissa , Smith Wade , Young William L. 
Published: May 2006

Background and Purpose—Cardiac abnormalities occur commonly after subarachnoid hemorrhage (SAH) and may be caused by excessive release of catecholamines from the myocardial sympathetic nerves. We hypothesized that adrenoceptor polymorphisms resulting in greater catecholamine sensitivity would be associated with an increased risk of cardiac injury.Methods—This was a prospective cohort study. The primary outcome variables were the serum level of cardiac troponin I (cTi, abnormal if >1.0 μg/L) and the left ventricular ejection fraction (LVEF, abnormal if <50%). Six adrenoceptor polymorphisms were genotyped:β1ARArg389Gly,β1ARSer49Gly,β2ARGly16Arg,β2ARGln27Glu,β2ARThr164Ile, andα2ARdel322-325. The effect of each polymorphism on the risk of developing cardiac abnormalities was quantified using multivariable logistic regression.Results—The study included 182 patients. The CC genotype (Arg/Arg) ofβ1ARArg389Gly (odds ratio [OR] 3.4,P=0.030) and the CC genotype (Gln/Gln) ofβ2ARGln27Glu (OR 3.1,P=0.032) were predictive of cTi release. The presence of theα2ARdeletion was predictive of reduced LVEF (OR 4.2,P=0.023). The combination of theβ1AR389 CC and theβ2AR27 CC genotypes resulted in a marked increase in the odds of cTi release (OR 15.5,P=0.012). The combination of theβ1AR389 CC and theα2ARdeletion genotypes resulted in a marked increase in the odds of developing a reduced LVEF (OR 10.3,P=0.033).Conclusions—Genetic polymorphisms of the adrenoceptors are associated with an increased risk of cardiac abnormalities after SAH. These data support the hypothesis that cardiac dysfunction after SAH is a form of neurocardiogenic injury.
Reproductive Morbidity of Women in Karnataka
Authors: Mutharayappa R. 
Published: May 2006

The main objective of the present study is to highlight the extent of reproductive health problems, the factors responsible for increasing RTI cases and to suggest appropriate strategies. Five types of obstetric problems and seven types of gynaecological problems were listed in both National Family Health Survey-2 (NFHS-2) and Reproductive and Child Health (RCH) surveys. Fewer than half the women reported at least one obstetric morbidity and more than one-tenth reported at least one gynaecological morbidity. More women in urban areas had reported obstetric morbidity whereas more women from rural areas reported gynaecological morbidity. Educated women, women who work in other activities and Scheduled Caste and Scheduled Tribe women reported that they are suffering from obstetric problems. Women who do not have toilet facilities at home and women who live in semipucca houses reported gynaecological problems. There is a relationship between age at first delivery or ‘child-birth’ and the reproductive morbidity of women. Reproductive morbidity due to abortion is high among rural women. Data reveals that fewer than half the women who reported gynaecological problems did not seek treatment. Of the women who reported at least one symptom of gynaecological problems nearly half were in the 25–34 age group and only 50–60 per cent of them sought treatment. Education played a major role in women's health-seeking behaviour. Among those who sought treatment majority had gone to private health facilities. There is need to expand informed choices among women. Women must be empowered to take charge of their pregnancy-related needs. It is important to raise community awareness regarding early marriage and pregnancy. Misconceptions about nutrition and health care during pregnancy must be confronted at the community level and among pregnant women, and the families in which they reside.
Building Learning Practices with Self-Empowered Teams for Improving Patient Safety
Authors: Singh Ranjit , Singh Ashok , Taylor John S. , Rosenthal Thomas , Singh Sonjoy , Singh Gurdev 
Published: May 2006

BACKGROUND AND OBJECTIVES: Each primary care practice should be viewed as a complex adaptive micro-system with its own unique characteristics. To improve safety, under constraints of limited resources and numerous competing demands, practices need to identify those vulnerabilities that pose the greatest risks and focus efforts on these. The Objective was to develop and test a novel methodology that forms self-empowered learning teams that can prioritise safety problems based on the combination of error frequency and severity of consequences, and then devise feasible interventions. METHODS: A survey instrument was designed and used to elicit, in qualitative terms, staff perceptions of frequency, p, and severity, s, of various types/causes of primary care errors. The qualitative responses were quantified using an algorithm that allowed for risk aversion. Relative hazard rate, h = pxs, was used as the basis for prioritising safety problems in two primary care test practices. RESULTS: Each site identified its own set of priorities with very little overlap. Within each site there was high concordance between priorities identified by physicians, nursing and administrative staff but each site appeared to be unique. Priorities also remained stable with variation in the degree of risk aversiveness assumed in the Hazard calculation. INTERPRETATION AND CONCLUSIONS: The method aided formation of central ‘attractors’ in the form of self-empowered effective learning teams with a common vision to help their complex micro-systems to adapt and thrive. This pro-active type of methodology helps in creating a sustainable safety culture, and has been adapted for other health-care settings and physician training.
The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera
Authors: Lippert Eric , Boissinot Marjorie , Kralovics Robert , Girodon François , Dobo Irène , Praloran Vincent , Boiret-Dupré Nathalie , Skoda Radek C. , Hermouet Sylvie 
Published: May 2006

AbstractWe determined the allelic frequency of the JAK2-V617F mutation in DNA and assessed the expression levels of the mutant and wild-type JAK2 mRNA in granulocytes from 60 patients with essential thrombocythemia (ET) and 62 patients with polycythemia vera (PV) at the time of diagnosis. Using allele-specific quantitative polymerase chain reaction (qPCR), we detected JAK2-V617F in 75% of ET and 97% of PV at diagnosis. The total JAK2 mRNA levels were elevated in ET, PV, and secondary and idiopathic erythrocytosis, suggesting that hyperactive hematopoiesis alters JAK2 expression. The expression levels of JAK2-V617F mRNA were variable but strongly correlated with the allelic ratio of JAK2-V617F determined in DNA. Thus, differences in JAK2-V617F expression, markedly lower in ET than in PV, reflected different percentages of granulocytes carrying the mutation. Moreover, allelic ratios higher than 50% JAK2-V617F, indicating the presence of granulocytes homozygous for JAK2-V617F, were found in 70% of PV at diagnosis but never in ET.
Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma: an analysis of patients receiving conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials
Authors: Drayson Mark , Begum Gulnaz , Basu Supratik , Makkuni Sudhaker , Dunn Janet , Barth Nicola , Child J. Anthony 
Published: May 2006

AbstractWhile investigating 2592 patients enrolled in multicenter myeloma trials, we found light chain–only (LCO) patients had worse median survival times (1.9 years) than patients with IgA and IgG paraproteins (2.3 and 2.5 years, respectively) (P < .001). However, IgA and IgG patients with levels of LC excretion similar to those of LCO patients also had poor survival times because of renal failure, resulting in worse survival during induction therapy and at relapse with no difference in progression-free survival between LCO and IgG patients. LC excretion was higher for λ than for κ types, but there was no difference in survival between the 2 LC types when stratified for level of LC excretion, indicating that care of renal function is vital to improving the survival of any patient with LC excretion. LCO patients were younger (P = .001), had worse performance status (P = .001), and had more lytic lesions (P < .001), perhaps reflecting late and missed diagnoses in younger and older LCO patients, respectively. No differences were observed between IgA and IgG patients in presentation characteristics, response, or survival from disease progression. The worse survival of IgA patients was attributed to shorter progression-free survival (median, 1.2 vs 1.6 years; P < .001), which is important for maintenance therapy.
Association of Ig/BCL6 translocations with germinal center B lymphocytes in human lymphoid tissues: implications for malignant transformation
Authors: Yang Xuwei , Lee Koutetsu , Said Jonathan , Gong Xun , Zhang Ke 
Published: May 2006

AbstractChromosomal translocations (CTs) between immunoglobulin (Ig) genes and the BCL6 proto-oncogene are frequently associated with diffuse large B-cell lymphomas (DLBCLs) and follicular lymphomas (FLs) and are implicated in the development of these lymphomas. However, whether Ig/BCL6 translocation per se is sufficient to drive malignant transformation is not clear. To understand the biology of Ig/BCL6-translocated cells prior to their malignant transformation, we developed a system capable of detecting 1 to 3 Igμ/BCL6 CT cells in 1 million mixed cells through the detection of chimeric Iμ-BCL6E2 and BCL6E1-Cμ1 transcripts that reflect reciprocal Igμ/BCL6 translocations. The chimeric transcripts that existed in the vast majority of normal lymphoid tissues are due to Igμ/BCL6 CT and were not generated from trans-splicing. Both Iμ-BCL6E2 and BCL6E1-Cμ1 transcripts were coexpressed in the same cell populations. The Ig/BCL6 recombination junctions themselves were isolated from B-cell subpopulations expressing the Iμ-BCL6 transcripts. The appearance of Igμ/BCL6 CT was associated with cells expressing germinal center but not naive B-cell markers. This study shows that Ig/BCL6 translocations occur in germinal center–stage B cells in healthy humans, and that Ig/BCL6 CTs per se are not likely sufficient to cause the malignant transformation in the context of human B cells.
Mucosal but not peripheral FOXP3+ regulatory T cells are highly increased in untreated HIV infection and normalize after suppressive HAART
Authors: Epple Hans-Jörg , Loddenkemper Christoph , Kunkel Desirée , Tröger Hanno , Maul Jochen , Moos Verena , Berg Erika , Ullrich Reiner , Schulzke Jörg-Dieter , Stein Harald , Duchmann Rainer , Zeitz Martin , Schneider Thomas 
Published: May 2006

Abstract
Recent evidence indicates that regulatory T cells (Tregs) play an important role in HIV infection. However, although the gastrointestinal mucosa is a key compartment in HIV disease, no data on mucosal Tregs in HIV infection are available. In this study, we compared the frequency of Tregs in duodenal mucosa and peripheral blood (PB) of 13 treatment-naive and 13 suppressively treated HIV-infected patients with that of 6 patients with norovirus infection and 12 healthy controls. Tregs were quantified by immunohistochemistry (CD3/FOXP3) and further characterized (CD25, CTLA-4, GITR) by immunohistochemistry, immunofluorescence, and fluorescence-activated cell sorting (FACS). Both the frequency and the absolute count of mucosal Tregs were highly increased in untreated HIV patients but were normal in treated HIV patients. In contrast, in peripheral blood of HIV patients, the absolute number of Tregs was not increased, and their frequency was only slightly elevated. In norovirus infection, frequency of mucosal Tregs in the CD4+ T-cell subset was not elevated. The high increase in count and frequency of mucosal Tregs seems to be a characteristic feature of untreated HIV infection, suggesting a significant contribution of Tregs to the pathogenesis of HIV disease. Their role may be 2-edged: attenuating HIV-induced immune hyperactivation while suppressing the immune response to HIV and mucosal pathogens.