bluuebunny/crossref_metadata_2025_split huggingface dataset:
Degree of tapering of xylem conduits in stems and roots of small Pinus cembra and Larix decidua trees
Authors: Petit Giai , Anfodillo Tommaso , De Zan Carlo 
Published: May 2009

Xylem conduits increase in size from the apex downwards. While conduit tapering in the stem has often been reported to converge towards a common pattern among all plants, information on conduit tapering in small plants and roots is extremely scarce. We selected 10 small trees (height < 3 m) of Pinus cembra L. and Larix decidua Miller along an altitudinal gradient and measured diameter and conduit dimensions along stems and roots in the last annual ring. Sections of 10 µm were cut from wooden disks taken at different heights in the stem and in the roots and then stained with safranine. Slides were observed under a microscope, the lumen areas of conduits were measured and mean hydraulic diameters (Dh) calculated. Dh increased from stem tip (Dh at 1 cm from the apex averaged 10.75 µm; s = 2.33) to base (Dh from 20.70 to 30.54 µm), following a power trajectory (i.e., Dh = a·Lb, with L being the distance from the tip). Such degrees of conduit tapering may have a considerable effect in minimizing the hydraulic constraints. Despite trees at the treeline being older and smaller than in the subalpine forest (age: 28–70 years at the treeline; 18–39 years in the subalpine forest), conduit tapering did not differ significantly between sites, suggesting that tree height is the main factor controlling the basipetal increase in conduit lumens. In the roots, the increase in conduit dimensions continued towards their tips, even more steeply than in the stem. The widest conduits were measured around the root tips (around 40 µm). Conduit tapering resulted as a stable structural feature in small plants as well as in tall trees.
Phase I Study of YM155, a Novel Survivin Suppressant, in Patients with Advanced Solid Tumors
Authors: Satoh Taroh , Okamoto Isamu , Miyazaki Masaki , Morinaga Ryotaroh , Tsuya Asuka , Hasegawa Yoshikazu , Terashima Masaaki , Ueda Shinya , Fukuoka Masahiro , Ariyoshi Yutaka , Saito Toshikazu , Masuda Noriyuki , Watanabe Hirokazu , Taguchi Tetsuo , Kakihara Toru , Aoyama Yumiko , Hashimoto Yohko , Nakagawa Kazuhiko 
Published: May 2009

Abstract
Purpose: YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors.
Experimental Design: Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles.
Results: Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m2/d. The MTD was determined to be 8.0 mg/m2/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m2/d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients.
Conclusions: YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m2/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.
Impairment of APE1 Function Enhances Cellular Sensitivity to Clinically Relevant Alkylators and Antimetabolites
Authors: McNeill Daniel R. , Lam Wing , DeWeese Theodore L. , Cheng Yung-Chi , Wilson David M. 
Published: May 2009

AbstractBase excision repair (BER) is the major pathway for removing mutagenic and cytotoxic oxidative and alkylation DNA modifications. Using a catalytically inactive, dominant negative protein form of human APE1, termed ED, which binds with high affinity to substrate DNA and blocks subsequent repair steps, we assessed the role of BER in mediating cellular resistance to clinically relevant alkylating drugs and antimetabolites. Colony formation assays revealed that ED expression enhanced cellular sensitivity to melphalan not at all; to decarbazine, thiotepa, busulfan and carmustine moderately (1.2- to 2.4-fold); and to streptozotocin and temozolomide significantly (2.0- to 5.3-fold). The effectiveness of ED to promote enhanced cytotoxicity generally correlated with the agent's (a) monofunctional nature, (b) capacity to induce N7-guanine and N3-adenine modifications, and (c) inability to generate O6-guanine adducts or DNA cross-links. ED also enhanced the cell killing potency of the antimetabolite troxacitabine, apparently by blocking the processing of DNA strand breaks, yet had no effect on the cytotoxicity of gemcitabine, results that agree well with the known efficiency of APE1 to excise these nucleoside analogues from DNA. Most impressively, ED expression produced an ∼5- and 25-fold augmentation of the cell killing effect of 5-fluorouracil and 5-fluorodeoxyuridine, respectively, implicating BER in the cellular response to such antimetabolites; the increased 5-fluorouracil sensitivity was associated with an accumulation of abasic sites and active caspase–positive staining. Our data suggest that APE1, and BER more broadly, is a potential target for inactivation in anticancer treatment paradigms that involve select alkylating agents or antimetabolites. (Mol Cancer Res 2009;7(6):897–906)
3,3′-Diindolylmethane Induction of p75NTR-Dependent Cell Death via the p38 Mitogen-Activated Protein Kinase Pathway in Prostate Cancer Cells
Authors: Khwaja Fatima S. , Wynne Shehla , Posey Isadora , Djakiew Daniel 
Published: May 2009

Abstract
The p75NTR functions as a tumor suppressor in prostate epithelial cells, where its expression declines with progression to malignant cancer. Previously, we showed that treatment with the nonsteroidal anti-inflammatory drug, indomethacin, induced p75NTR expression in the T24 cancer cell line leading to p75NTR-mediated decreased survival. Utilizing the indole moiety of indomethacin as a pharmacophore, we identified in rank-order with least efficacy, ketorolac, etodolac, indomethacin, 5-methylindole-3-acetic acid, indole-3-carbinol, and 3,3′-diindolylmethane (DIM) exhibiting greatest activity for induction of p75NTR levels and inhibition of cell survival. Prostate (PC-3, DU-145) and bladder (T24) cancer cells were more sensitive to DIM induction of p75NTR-associated loss of survival than breast (MCF7) and fibroblast (3T3) cells. Transfection of the PC-3 prostate cell line with a dominant-negative form of p75NTR before DIM treatment significantly rescued cell survival demonstrating a cause and effect relationship between DIM induction of p75NTR levels and inhibition of survival. Furthermore, siRNA knockdown of the p38 mitogen-activated protein kinase (MAPK) protein prevented induction of p75NTR by DIM in the PC-3 prostate cell line. DIM treatment induced phosphorylation of p38 MAPK as early as within 1 minute. Collectively, we identify DIM as an indole capable of inducing p75NTR-dependent apoptosis via the p38 MAPK pathway in prostate cancer cells.
Noninvasive Detection of Candidate Molecular Biomarkers in Subjects with a History of Insulin Resistance and Colorectal Adenomas
Authors: Zhao Chen , Ivanov Ivan , Dougherty Edward R. , Hartman Terryl J. , Lanza Elaine , Bobe Gerd , Colburn Nancy H. , Lupton Joanne R. , Davidson Laurie A. , Chapkin Robert S. 
Published: May 2009

Abstract
We have developed novel molecular methods using a stool sample, which contains intact sloughed colon cells, to quantify colonic gene expression profiles. In this study, our goal was to identify diagnostic gene sets (combinations) for the noninvasive classification of different phenotypes. For this purpose, the effects of a legume-enriched, low glycemic index, high fermentable fiber diet was evaluated in subjects with four possible combinations of risk factors, including insulin resistance and a history of adenomatous polyps. In a randomized crossover design controlled feeding study, each participant (a total of 23; 5–12 per group) consumed the experimental diet (1.5 cups of cooked dry beans) and a control diet (isocaloric average American diet) for 4 weeks with a 3-week washout period between diets. Using prior biological knowledge, the complexity of feature selection was reduced to perform an exhaustive search on all allowable feature (gene) sets of size 3, and among these, 27 had (unbiased) error estimates of 0.15 or less. Linear discriminant analysis was successfully used to identify the best single genes and two- to three-gene combinations for distinguishing subjects with insulin resistance, a history of polyps, or exposure to a chemoprotective legume-rich diet. These results support our premise that gene products (RNA) isolated from stool have diagnostic value in terms of assessing colon cancer risk.
A Novel Sulindac Derivative That Does Not Inhibit Cyclooxygenases but Potently Inhibits Colon Tumor Cell Growth and Induces Apoptosis with Antitumor Activity
Authors: Piazza Gary A. , Keeton Adam B. , Tinsley Heather N. , Gary Bernard D. , Whitt Jason D. , Mathew Bini , Thaiparambil Jose , Coward Lori , Gorman Gregory , Li Yonghe , Sani Brahma , Hobrath Judith V. , Maxuitenko Yulia Y. , Reynolds Robert C. 
Published: May 2009

Abstract
Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human colon tumor cell lines, HT-29, SW480, and HCT116 with IC50 values of 2 to 5 μmol/L compared with 73 to 85 μmol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC50 for tumor growth inhibition. In the human HT-29 colon tumor xenograft mouse model, SSA significantly inhibited tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy.
Biochemical and pharmacological effects of the direct thrombin inhibitor AR-H067637
Authors: Mattsson Christer , Inghardt Tord , Elg Margareta , Deinum Johanna 
Published: May 2009

SummaryAZD0837 is in development as a new oral anticoagulant for use in thromboembolic disorders. In vivo, AZD0837 is converted to AR-H067637, a selective and reversible direct thrombin inhibitor. Established biochemical methods were used to assess and measure the biochemical and pharmacological properties of AR-H067637. Both direct Biacore binding studies of AR-H067637 with immobilised α-thrombin and inhibition studies using pre-steady state kinetics with thrombin in the fluid phase confirmed that AR-H067637 is a rapid-binding, reversible and potent (inhibition constant K
i = 2–4 nM), competitive inhibitor of thrombin, as well as of thrombin bound to fibrin (clot-bound thrombin) or to thrombomodulin. The total amount of free thrombin generated in platelet-poor clotting plasma was inhibited concentration-dependently by AR-H067637, with a concentration giving half maximal inhibition (IC50) of 0.6 μM. Moreover, AR-H067637 is, with the exception of trypsin, a se-lective inhibitor for thrombin without inhibiting other serine proteases involved in haemostasis. Furthermore, no anticoagulant effect of the prodrug was found. AR-H067637 prolonged the clotting time concentration-dependently in a range of plasma coagulation assays including activated partial thromboplastin time, prothrombin time, prothrombinase-induced clotting time, thrombin time and ecarin clotting time. The two latter assays were found to be most sensitive for assessing the anticoagulant effect of AR-H067637 (plasma IC50 93 and 220 nM, respectively). AR-H067637 also inhibited thrombin-induced platelet activation (by glycoprotein IIb/IIIa exposure, IC50 8.4 nM) and aggregation (IC50 0.9 nM). In conclusion, AR-H067637 is a selective, reversible, competitive inhibitor of α-thrombin, with a predictable anticoagulant effect demonstrated in plasma coagulation assays.
Monitoring thrombin generation: Is addition of corn trypsin inhibitor needed?
Authors: Dielis Arne , Panova-Noeva Marina , Oerle René van , Govers-Riemslag José , Hamulyák Karly , Falanga Anna , Cate Hugo Ten , Spronk Henri 
Published: May 2009

SummaryThrombin generation monitoring has the potential to be used as a clinical diagnostic tool in the near future. However, robust pre-analytical conditions may be required, and one factor that has been reported is in-vitro contact activation that might influence in-vitro measurements of thrombin generation and thereby act as an unpredictable pre-analytical variable. The aim of the current study was to investigate the influence of contact activation and the necessity of corn trypsin inhibitor (CTI) to abolish contact activation in thrombin generation measurements at low tissue factor (TF) concentrations. Thrombin generation was performed using the calibrated automated thrombinoscopy (CAT), thereby determining the endogenous thrombin potential (ETP), peak height, and the lag time, in plasma obtained from healthy volunteers. Addition of CTI after plasma preparation had no significant influence on thrombin generation triggered with 0.5 pM TF or higher, as demonstrated by unaltered ETP and lag time values between analyses with and without CTI. Addition of CTI before blood collection reduced thrombin generation triggered with 0.5 pM TF: both the ETP and peak height were significantly reduced compared to no CTI addition. In contrast, thrombin generation remained unaltered at a 1 pM TF trigger or above. This study demonstrates that addition of CTI after plasma separation is not necessary when triggering with TF concentrations of 0.5 pM and higher. Furthermore, it was demonstrated that it is not needed to pre-fill blood collecting tubes with CTI when measuring thrombin generation at TF concentrations of ≥1 pM.
Obstetric analgesia and anaesthesia in women with inherited bleeding disorders
Authors: Chi Claudia , Lee Christine , England Adrian , Hingorani Jaishree , Paintsil James , Kadir Rezan 
Published: May 2009

SummaryA retrospective review was carried out on the methods of obstetric analgesia/anesthesia used in 80 pregnancies amongst 63 women with inherited bleeding disorders (19 factor XI deficiency, 16 carriers of haemophilia, 15 von Willebrand disease, seven platelet function disorders, four factor VII deficiency, one factor VII and XI deficiency and one factor X deficiency). In 72 pregnancies, the woman was seen antenatally in a multidisciplinary clinic to discuss and plan pain relief options. Regional block was performed for 41 pregnancies. The mothers were known to have a bleeding disorder in 35 of these pregnancies. Prophylactic cover was given in 10 pregnancies prior to the insertion of regional block but not required in the remaining 25 pregnancies because the coagulation defects had spontaneously normalised at term. There were six reported adverse effects from regional block similar to that found in the general population: inadequate anesthesia/analgesia (2), bloody tap (2), hypotension and a possible dural puncture which was treated conservatively. There were no reports of long-term complications. The findings show that it is possible to offer women with inherited bleeding disorders the option of regional block provided their coagulation defects have normalised, either spontaneously during pregnancy or following adequate haemostatic cover.
Anticoagulant mechanisms of covalent antithrombin-heparin investigated by thrombelastography
Authors: Atkinson Helen M. , Mewhort-Buist Tracy A. , Berry Leslie R. , Chan Anthony K. C. 
Published: May 2009

SummaryWe have developed an antithrombin-heparin covalent complex (ATH) which inhibits coagulation enzymes by two mechanisms: directly, or by catalytic activation of plasma antithrombin (AT). Anticoagulation by ATH was compared to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) using a blood-based, tissue factor (TF)-activated thrombelastography (TEG) assay. Simplified TEG assays with plasma or purified plasma components were used to determine the contribution of the direct and catalytic mechanisms to ATH efficacy. Low anti-Xa concentrations of UFH inhibited clot formation significantly more than equivalent concentrations of ATH or LMWH in blood and plasma. ATH had reduced ability to catalyse AT-mediated thrombin (IIa) inhibition compared to UFH. However, at high anti-Xa concentrations, ATH had similar anticoagulant activity to UFH. ATH and non-covalent AT+UFH directly inhibited clotting to a similar degree in AT-deficient plasma. IIa-ATH complexes, which are limited to catalytic inhibition, displayed impaired anticoagulation compared to free ATH, and the magnitude of this effect increased significantly as anticoagulant concentration increased. Kinetic experiments indicated that the rate of reaction of AT with IIa is lower when catalysed by ATH versus UFH. In conclusion, at low anti-Xa doses catalytic inhibition is the primary mechanism of ATH anticoagulation, and the catalytic potential of ATH is reduced relative to UFH. However, the direct inhibitory activity of ATH is comparable to noncovalent AT+UFH, and at high anti-Xa doses the direct inhibitory activity of ATH may play a larger role in anticoagulation.
The potential for circular dichroism as an additional facile and sensitive method of monitoring low-molecular-weight heparins and heparinoids
Authors: Guimond Scott , Holman Joseph , Turnbull Jeremy , Lauder Robert , Fernig David , Rudd Timothy , Skidmore Mark , Yates Edwin 
Published: May 2009

SummaryThe ultraviolet circular dichroism (CD) spectra of commercial low-molecular-weight heparins, heparinoids and other anticoagulant preparations have been recorded between 180 and 260 nm. Principal component analysis of the spectra allowed their differentiation into a number of groups related to the means of their production reflecting the structural changes introduced by each process. The findings suggest that CD provides a complementary technique for the rapid analysis of heparin preparations.
The multi-functionality of CD40L and its receptor CD40 in atherosclerosis
Authors: Lievens Dirk , Eijgelaar Wouter , Biessen Erik , Daemen Mat , Lutgens Esther 
Published: May 2009

SummaryDisrupting the CD40-CD40L co-stimulatory pathway reduces atherosclerosis and induces a stable atherosclerotic plaque phenotype that is low in inflammation and high in fibrosis. Therefore, inhibition of the CD40-CD40L pathway is an attractive therapeutic target to reduce clinical complications of atherosclerosis. The CD40-CD40L dyad is known to interact with other costimulatory molecules, to activate antigen-presenting cells (APC) and to contribute to T-cell priming and B-cell isotype switching. Besides their presence on T-cells and APCs, CD40 and CD40L are also present on macrophages, endothelial cells and vascular smooth muscle cells in the plaque, where they can exert pro-atherogenic functions. Moreover, recent progress indicates the involvement of neutrophil CD40, platelet CD40L and dendritic cell CD40 in atherogenesis. Since systemic CD40-CD40L modulation compromises host defense, more targeted interventions are needed to develop superior treatment strategies for atherosclerosis. We believe that by unravelling the cell-cell CD40-CD40L interactions, inhibition of cell-type specific (signalling components of) CD40(L) that do not compromise the patient’s immune system, will become possible. In this review, we highlight the cell-type specific multi-functionality of CD40-CD40L signalling in atherosclerosis.
Lack of extended venous thromboembolism prophylaxis in high-risk patients undergoing major orthopaedic or major cancer surgery
Authors: Siebenrock Klaus-Arno , Metzger Urs , Tuor Philipp , Sterzing Daniel , Oehy Kurt , Wondberg Daniela , Mouhsine El Yazid , Gautier Emanuel , Kalka Christoph , Spirk David , Kucher Nils 
Published: May 2009

SummaryExtended pharmacological venous thromboembolism (VTE) prophylaxis beyond discharge is recommended for patients undergoing high-risk surgery. We prospectively investigated prophylaxis in 1,046 consecutive patients undergoing major orthopaedic (70%) or major cancer surgery (30%) in 14 Swiss hospitals. Appropriate in-hospital prophylaxis was used in 1,003 (96%) patients. At discharge, 638 (61%) patients received prescription for extended pharmacological prophylaxis: 564 (77%) after orthopaedic surgery, and 74 (23%) after cancer surgery (p <0.001). Patients with knee replacement (94%), hip replacement (81%), major trauma (80%), and curative arthroscopy (73%) had the highest prescription rates for extended VTE prophylaxis; the lowest rates were found in patients undergoing major surgery for thoracic (7%),gastrointestinal (19%),and hepatobiliary (33%) cancer. The median duration of prescribed extended prophylax is was longer in patients with orthopaedic surgery (32 days, interquartile range 14–40 days) than in patients with cancer surgery (23 days, interquartile range 11–30 days; p<0.001).Among the 278 patients with an extended prophylaxis order after hip replacement, knee replacement, or hip fracture surgery, 120 (43%) received a prescription for at least 35 days, and among the 74 patients with an extended prophylaxis order after major cancer surgery, 20 (27%) received a prescription for at least 28 days. In conclusion, approximately one quarter of the patients with major orthopaedic surgery and more than three quarters of the patients with major cancer surgery did not receive prescription for extended VTE prophylaxis. Future effort should focus on the improvement of extended VTE prophylaxis, particularly in patients undergoing major cancer surgery.