bluuebunny/crossref_metadata_2025 huggingface dataset:
About a switch: how P-glycoprotein (ABCB1) harnesses the energy of ATP binding and hydrolysis to do mechanical work
Authors: Sauna Zuben E. , Ambudkar Suresh V.
Published: January 2007

The efflux of drugs by the multidrug transporter P-glycoprotein (Pgp; ABCB1) is one of the principal means by which cancer cells evade chemotherapy and exhibit multidrug resistance. Mechanistic studies of Pgp-mediated transport, however, transcend the importance of this protein per se as they help us understand the transport pathway of the ATP-binding cassette proteins in general. The ATP-binding cassette proteins comprise one of the largest protein families, are central to cellular physiology, and constitute important drug targets. The functional unit of Pgp consists of two nucleotide-binding domains (NBD) and two transmembrane domains that are involved in the transport of drug substrates. Early studies postulated that conformational changes as a result of ATP hydrolysis were transmitted to the transmembrane domains bringing about drug transport. More recent structural and biochemical studies on the other hand suggested that ATP binds at the interface of the two NBDs and induces the formation of a closed dimer, and it has been hypothesized that this dimerization and subsequent ATP hydrolysis powers transport. Based on the mutational and biochemical work on Pgp and structural studies with isolated NBDs, we review proposed schemes for the catalytic cycle of ATP hydrolysis and the transport pathway. [Mol Cancer Ther 2007;6(1):13–23]
The role of spermidine/spermineN1-acetyltransferase in determining response to chemotherapeutic agents in colorectal cancer cells
Authors: Allen Wendy L. , McLean Estelle G. , Boyer John , McCulla Andrea , Wilson Peter M. , Coyle Vicky , Longley Daniel B. , Casero Robert A. , Johnston Patrick G.
Published: January 2007

Polyamines have been shown to play a role in the growth and survival of several solid tumors, including colorectal cancer. We identified the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT) as being one of the most highly inducible genes in two DNA microarray screens to identify novel determinants of response to chemotherapeutic agents in colorectal cancer. SSAT was shown to be inducible in response to 5-fluorouracil (5-FU) or oxaliplatin in parental and drug-resistant HCT116 cell lines. It was also shown that SSAT mRNA was up-regulated in response to 5-FU or oxaliplatin in a panel of six colorectal cancer cell lines. The polyamine analogue N1,N11-diethylnorspermine (DENSpm) depletes polyamine pools and potently induces SSAT. We evaluated the effect of combining DENSpm with chemotherapeutic agents in HCT116 p53+/+ cells and in HCT116 drug-resistant daughter cell lines. Western blot analyses showed that SSAT protein expression was dramatically enhanced when DENSpm was combined with oxaliplatin or 5-FU in HCT116 p53+/+ cells. Using cell viability assays and flow cytometry, synergistic induction of cell death was observed following cotreatment of HCT116 p53+/+ cells with DENSpm and each chemotherapeutic agent. Of note, this combined therapy increased the chemosensitivity of cells rendered resistant to each of these chemotherapeutic agents. Small interfering RNA–mediated down-regulation of SSAT resulted in loss of synergy between DENSpm and these agents. These results show that SSAT plays an important role in regulating cell death following combined cytotoxic drug and DENSpm treatment. Furthermore, DENSpm sensitizes both sensitive and resistant cells to chemotherapeutic agents. Taken together, these results suggest that SSAT may be an important target for therapeutic intervention in colorectal cancer. [Mol Cancer Ther 2007;6(1):128–37]
Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells
Authors: Park Moon-Taek , Kang Young-Hee , Park In-Chul , Kim Chun-Ho , Lee Yun-Sil , Chung Hee Yong , Lee Su-Jae
Published: January 2007

Resistance to anticancer drugs can sometimes be overcome by combination treatment with other therapeutic drugs. Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As2O3) enhanced cell death of naturally As2O3-resistant human myeloid leukemia cells. The combination treatment induced an increase in intracellular reactive oxygen species level, mitochondrial relocalization of Bax, poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cytochrome c release from the mitochondria. N-acetyl-l-cysteine, a thiol-containing antioxidant, completely blocked Bax relocalization, PARP-1 activation, and cytochrome c release. Pretreatment of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, a PARP-1 inhibitor, or PARP-1/small interfering RNA partially attenuated cytochrome c release, whereas the same treatment did not affect Bax relocalization. The combination treatment induced selective activation of p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK by treatment of SB203580 or expression of dominant-negative forms of p38 MAPK suppressed the combination treatment–induced Bax relocalization but did not affect PARP-1 activation. In addition, antioxidant N-acetyl-l-cysteine completely blocked p38 MAPK activation. These results indicate that phytosphingosine in combination with As2O3 induces synergistic apoptosis in As2O3-resistant leukemia cells through the p38 MAPK–mediated mitochondrial translocation of Bax and the PARP-1 activation, and that p38 MAPK and PARP-1 activations are reactive oxygen species dependent. The molecular mechanism that we elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to As2O3 treatment. [Mol Cancer Ther 2007;6(1):82–92]
Knock-down of Bcl-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis in human PC-3 prostate tumor xenografts
Authors: Anai Satoshi , Goodison Steve , Shiverick Kathleen , Hirao Yoshihiko , Brown Bob D. , Rosser Charles J.
Published: January 2007

Expression of the proto-oncogene Bcl-2 is associated with tumor progression. Bcl-2's broad expression in tumors, coupled with its role in resistance to chemotherapy and radiation therapy–induced apoptosis, makes it a rational target for anticancer therapy. Antisense Bcl-2 oligodeoxynucleotide (ODN) reagents have been shown to be effective in reducing Bcl-2 expression in a number of systems. We investigated whether treating human prostate cancer cells with antisense Bcl-2 ODN (G3139, oblimersen sodium, Genasense) before irradiation would render them more susceptible to radiation effects. Two prostate cancer cell lines expressing Bcl-2 at different levels (PC-3-Bcl-2 and PC-3-Neo) were subjected to antisense Bcl-2 ODN, reverse control (CTL), or mock treatment. Antisense Bcl-2 ODN alone produced no cytotoxic effects and was associated with G1 cell cycle arrest. The combination of antisense Bcl-2 ODN with irradiation sensitized both cell lines to the killing effects of radiation. Both PC-3-Bcl-2 and PC-3-Neo xenografts in mice treated with the combination of antisense Bcl-2 ODN and irradiation were more than three times smaller by volume compared with xenografts in mice treated with reverse CTL alone, antisense Bcl-2 ODN alone, irradiation alone, or reverse CTL plus radiotherapy (P = 0.0001). Specifically, PC-3-Bcl-2 xenograft tumors treated with antisense Bcl-2 ODN and irradiation had increased rates of apoptosis and decreased rates of angiogenesis and proliferation. PC-3-Neo xenograft tumors had decreased proliferation only. This is the first study which shows that therapy directed at Bcl-2 affects tumor vasculature. Together, these findings warrant further study of this novel combination of Bcl-2 reduction and radiation therapy, as well as Bcl-2 reduction and angiogenic therapy. [Mol Cancer Ther 2007;6(1):101–11]
Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling
Authors: Mullen Peter , Cameron David A. , Hasmann Max , Smyth John F. , Langdon Simon P.
Published: January 2007

Pertuzumab (Omnitarg, rhuMab 2C4) is a humanized monoclonal antibody, which inhibits HER2 dimerization. Because it has shown some clinical activity in ovarian cancer, this study sought to identify predictors of response to this agent in a model of ovarian cancer. A panel of 13 ovarian cancer cell lines was treated with heregulin β1 (HRGβ1) or transforming growth factor-α, and cell proliferation was assessed. Both agents increased cell number in the majority of cell lines studied, the response to both being similar (r = 0.83; P = 0.0004, Pearson test). HRGβ1 stimulation could be partially reversed by pertuzumab in 6 of 13 cell lines, with complete reversal in PE04 and PE06 cells. Addition of pertuzumab to transforming growth factor-α−stimulated cells produced growth inhibition in 3 of 13 cell lines (PE01, PE04, and PE06). The magnitude of HRGβ1-driven growth stimulation correlated significantly with an increase in extracellular signal-regulated kinase 2 (P = 0.037) but not Akt (P = 0.99) phosphorylation. Such HRGβ1-driven phosphorylation of extracellular signal-regulated kinase 1/2 and Akt could be reduced with pertuzumab, accompanied by changes in cell cycle distribution. In cell lines responsive to pertuzumab, HRGβ1-enhanced phosphorylation of HER2 (Tyr877) was reduced. Estrogen-stimulated changes in growth, cell cycle distribution, and signaling were reversed by pertuzumab, indicating cross-talk between HER2 and estrogen signaling. These data indicate that there is a subset of ovarian cancer cell lines sensitive to pertuzumab and suggest possible predictors of response to identify patients who could benefit from this therapy. Furthermore, we have identified an interaction between HER2 and estrogen signaling in this disease. [Mol Cancer Ther 2007;6(1):93–100]
Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes
Authors: Yates Melinda S. , Tauchi Masafumi , Katsuoka Fumiki , Flanders Kathleen C. , Liby Karen T. , Honda Tadashi , Gribble Gordon W. , Johnson Delinda A. , Johnson Jeffrey A. , Burton Neal C. , Guilarte Tomás R. , Yamamoto Masayuki , Sporn Michael B. , Kensler Thomas W.
Published: January 2007

Synthetic triterpenoids have been developed, which are potent inducers of cytoprotective enzymes and inhibitors of inflammation, greatly improving on the weak activity of naturally occurring triterpenoids. An imidazolide triterpenoid derivative, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im or TP235), has been previously shown to potently protect against hepatic tumorigenesis, acting in part by inducing cytoprotective genes through Keap1-Nrf2-antioxidant response element (ARE) signaling. In these studies, the pharmacodynamic activity of CDDO-Im is characterized in two distinct lines of ARE reporter mice and by measuring increases in Nqo1 transcript levels as a marker of cytoprotective gene induction. Oral administration of CDDO-Im induces ARE-regulated cytoprotective genes in many tissues in the mouse, including liver, lung, kidney, intestines, brain, heart, thymus, and salivary gland. CDDO-Im induces Nqo1 RNA transcripts in some organs at doses as low as 0.3 μmol/kg body weight (orally). A structure activity evaluation of 15 additional triterpenoids (a) confirmed the importance of Michael acceptor groups on both the A and C rings, (b) showed the requirement for a nitrile group at C-2 of the A ring, and (c) indicated that substituents at C-17 dramatically affected pharmacodynamic action in vivo. In addition to CDDO-Im, other triterpenoids, particularly the methyl ester CDDO-Me (TP155) and the dinitrile TP225, are extremely potent inducers of cytoprotective genes in mouse liver, lung, small intestine mucosa, and cerebral cortex. This pharmacodynamic characterization highlights the chemopreventive promise of several synthetic triterpenoids in multiple target organs. [Mol Cancer Ther 2007;6(1):154–62]
Synergism between vitamin D and secreted protein acidic and rich in cysteine–induced apoptosis and growth inhibition results in increased susceptibility of therapy-resistant colorectal cancer cells to chemotherapy
Authors: Taghizadeh Farnaz , Tang Michelle J. , Tai Isabella T.
Published: January 2007

Patients with advanced colorectal cancer continue to have poor outcomes because of therapy-refractory disease. We previously showed that secreted protein acidic and rich in cysteine (SPARC) gene and protein could function as a chemotherapy sensitizer by enhancing tumor regression in response to radiation and chemotherapy in tumor xenograft models of chemotherapy-resistant tumors. This function of SPARC was gleamed from a microarray analysis that also revealed down-regulation of the vitamin D receptor (VDR) in therapy-refractory colorectal cancer cells. This study examines the potential synergistic effect of SPARC and vitamin D, which up-regulates VDR, in enhancing chemotherapy response in colorectal cancer. Using MIP101 colorectal cancer cell lines and SPARC-overexpressing MIP101 cells, we were able to show that, in the presence of SPARC, exposure to low doses of 1α,25-dihydroxyvitamin D3 significantly reduces cell viability, enhances chemotherapy-induced apoptosis, and inhibits the growth of colorectal cancer cells. Moreover, in tumor xenograft mouse models, up-regulation of VDR was seen in tumors that had the greatest regression following treatment that combined SPARC with chemotherapy. Therefore, our findings reveal a synergistic effect between SPARC and low doses of 1α,25-dihydroxyvitamin D3 that further augments the sensitivity of tumors to chemotherapy. This combination may prove to be a useful adjunct in the treatment of colorectal cancer, especially in those patients with therapy-refractory disease. [Mol Cancer Ther 2007;6(1):309–17]
Endothelin signaling in osteoblasts: global genome view and implication of the calcineurin/NFAT pathway
Authors: Van Sant Charles , Wang Gang , Anderson Mark G. , Trask Oscar J. , Lesniewski Rick , Semizarov Dimitri
Published: January 2007

Patients with prostate cancer develop osteoblastic metastases when tumor cells arrive in the bone and stimulate osteoblasts by secreting growth-promoting factors. Endothelin 1 (ET-1) is believed to be a key factor in promoting osteoblastic metastasis. Selective blockade of the ETA receptor is an established strategy in the development of cancer therapeutics. However, the molecular mechanisms whereby prostate cancer promotes abnormal bone growth are not fully understood. In this study, we have applied genomic approaches to elucidate the molecular mechanism of stimulation of osteoblasts by ET-1. To examine the ET-1 axis, we generated genomic signatures for osteoblasts treated with ET-1, in the presence and absence of a selective ETA antagonist (ABT-627). The ET-1 signature was comprised of several motifs, such as osteoblastic differentiation, invasion, and suppression of apoptosis. The signature also pointed at possible activation of the calcineurin/NFAT pathway. We showed that ET-1 activates calcineurin and causes nuclear translocation of NFATc1, implicating the pathway in the ET-1–mediated stimulation of osteoblasts. We also showed that ET-1 inhibits apoptosis in osteoblasts, implying that the suppression of apoptosis may be an important factor in the promotion of osteoblastic growth by ET-1. [Mol Cancer Ther 2007;6(1):253–61]
The Sympathetic Nervous System of Anamniotes
Authors: Funakoshi Kengo , Nakano Masato
Published: January 2007

The sympathetic nervous system develops as an evolutionary trait with gnathostomes (jawed vertebrates), but not with agnathan fishes (i.e., hagfishes and lampreys). Organization of the sympathetic preganglionic neuronal columns is different in teleosts and anurans. In the teleosts so far examined, the majority of sympathetic preganglionic neurons (SPNs) are located in the dorsal part of the spinal central gray matter. In Tetraodontiformes, the cell column occupies only two rostral spinal segments, which are distinct in their cytoarchitecture and projections. On the other hand, the SPNs of anurans form two cell columns segregated mediolaterally. The lateral and medial columns are also distinct in their cytoarchitecture and projections. The neuroactive substances expressed in the SPNs both in teleosts and anurans are coded to the projections. In anurans, the SPNs containing gonadotrophin-releasing hormone and those containing calcitonin gene-related peptide are involved in the regulation of blood vessels and cutaneous glands, respectively. In the filefish, the SPNs containing galanin project specifically to non-adrenergic non-cholinergic postganglionic neurons in the cranial sympathetic ganglia. Therefore, both anuran and teleost systems have different morphological and chemical-coded patterns for functional variation, although the anuran sympathetic nervous system has more organizational similarity with that of amniotes.
Ocular Melatonin Rhythms in Teleost Fish
Authors: Iigo Masayuki , Furukawa Kiyoshi , Nishi Genjirou , Tabata Mitsuo , Aida Katsumi
Published: January 2007

Melatonin (N-acetyl-5-methoxytryptamine) is synthesized in the pineal organ and the retina of vertebrates. In some teleost species, ocular melatonin levels can exhibit a circadian periodicity with elevated levels during the dark phase under light-dark (LD) cycles and this periodicity can persist even under constant dark (DD) cycles. However, reversed melatonin profiles and an absence of circadian ocular melatonin rhythms have also been reported. In this study, we investigated the daily rhythms of ocular melatonin in 32 teleost species under LD cycles. The melatonin profiles could be classified into three types: (1) normal profiles, with higher melatonin levels during the dark phase than the light phase; (2) reversed profiles, with higher levels during the light phase than the dark phase; (3) no significant differences in melatonin levels. We also studied whether ocular melatonin exhibits circadian rhythms under DD in selected species. Our results showed that ocular melatonin exhibited circadian rhythms in some but not all of the species examined. These results indicate that ocular melatonin rhythms in teleost fish exhibit species-specific variations as a result of the changes in the regulatory mechanisms during the course of evolution.
Relationship between Platelet Indexes and Coronary Angiographic Findings in Patients with Ischemic Heart Disease
Authors: Ihara Akihiro , Kawamoto Toshiharu , Matsumoto Kengo , Shouno Saburou , Hirahara Chiemi , Morimoto Tadao , Noma Yasuharu
Published: January 2007

To understand the mechanisms linking platelets to the risk of coronary artery disease, we investigated the relation between coronary angiographic morphology and platelet indexes – platelet count, mean platelet volume (MPV), platelet-large cell ratio (P-LCR) and platelet distribution width (PDW) – in patients with ischemic heart disease. Eighty-four patients with ischemic heart disease and 120 aged controls (AC) were enrolled in the study. The patients without any signs of acute myocardial infarction and acute coronary syndromes who underwent coronary angiography were divided into two groups, an ‘angiographically negative group’ (group 0) and an ‘angiographically positive group’ (group 1), with positive coronary obstruction depending on the diagnostic criteria in our hospital. Platelet indexes were measured in peripheral venous blood. The mean platelet counts were significantly lower in groups 1 and 0 than in AC (p = 0.0128 and p = 0.0041, respectively). MPV, P-LCR and the PDW were significantly higher in group 0 than in group 1 and AC (p = 0.0352 and 0.0433, p = 0.0059 and 0.0052, p = 0.00461 and 0.0146, respectively). The indexes of group 1 were almost the same compared with AC with respect to MPV, P-LCR and PDW. In conclusion, these findings suggest that the measurement of platelet indexes may reflect the underlying pathophysiological state and subsequent clinical events in the patients. In particular, lower P-LCR seems to identify patients with positive coronary angiography.
Mechanism of the Antithrombotic Effect of Dietary Diacylglycerol in Atherogenic Mice
Authors: Ijiri Yoshinobu , Naemura Aki , Yamashita Tsutomu , Ikarugi Hideo , Meguro Shinichi , Tokimitsu Ichiro , Yamamoto Junichiro
Published: January 2007

Introduction: We have shown earlier that diacylglycerol (DAG) but not triacylglycerol (TAG) inhibited thrombus formation. The aim of the present study was to investigate the mechanism of this antithrombotic effect of DAG. Materials and Methods: Four different diets, the (1) Western-style high-fat diet (HFD) containing 20% lipid and 0.05% cholesterol (w/w), (2) TAG-rich and (3) DAG-rich HFDs containing 20% lipid and 0.05% cholesterol, but all lipid replaced by TAG or DAG oil with very similar fatty acid composition and the (4) Japanese-style low-fat diet (LFD) containing 7% oil but no cholesterol were given to apolipoprotein E and low-density lipoprotein (LDL) receptor double-deficient mice. Atherogenicity was assessed by morphology, mapping the whole aorta and measuring the total area of lipid-stained lesions. Endothelial function was measured by the flow-mediated vasodilation test. Platelet reactivity was assessed from native blood sample by a shear-induced platelet function test (hemostatometry). Serum lipoprotein profile was measured by HPLC. Results: Both the Western-style and the TAG-rich HFDs have accelerated atherosclerosis. In contrast, DAG-rich HFD inhibited the atherosclerotic process to an extent comparable with the Japanese-style LFD. There was no significant difference in platelet and coagulant activity between the studied diet groups. DAG-rich but not the TAG-rich HFD significantly suppressed serum LDL cholesterol level. Conclusions: The present findings suggest that the mechanism of antithrombotic and anti-atherogenic effect of DAG may involve the protection of the vascular endothelium from injury and lowered serum LDL cholesterol.
Relationship between Hemostatic Factors and the Platelet Index in Patients with Ischemic Heart Disease
Authors: Ihara Akihiro , Kawamoto Toshiharu , Matsumoto Kengo , Shouno Saburou , Morimoto Tadao , Noma Yasuharu
Published: January 2007

To understand the heterogeneity of platelets, we investigated the correlation between hemostatic factors and the platelet index [platelet count, mean platelet volume (MPV), platelet-large cell ratio (P-LCR) and platelet distribution width (PDW)] in patients with ischemic heart disease (IHD). Ninety-seven patients with IHD and 120 aged controls (AC) were enrolled in the study. D-dimer, thrombin-antithrombin III complex (TAT), von Willebrand factor antigen (VWF:Ag) and platelet indexes were measured in the peripheral venous blood. The D-dimer and TAT levels in the patients were significantly elevated compared to the AC. VWF:Ag was also elevated, but not significantly so. However, no differences were observed in the platelet index between the patients and the AC. In the patients, the level of VWF:Ag was significantly inversely correlated with the platelet count, but such correlations were not observed in the D-dimer and TAT. TAT was significantly positively correlated with MPV, P-LCR and PDW. VWF:Ag was also correlated, though not significantly, with MPV, P-LCR and PDW. The D-dimer was not correlated with the platelet index. In the AC, the platelet count was inversely correlated with VWF:Ag, but not significantly so. VWF:Ag showed significant positive correlations with MPV, P-LCR and PDW. However, the D-dimer and TAT were not correlated with the platelet index in AC. These findings suggest that VWF:Ag and TAT seem to be profoundly related to platelet volume.
Improving Volitional Competence Is Crucial for the Efficacy of Psychosomatic Therapy: A Controlled Clinical Trial
Authors: Forstmeier Simon , Rueddel Heinz
Published: January 2007

Background: Although skills of will (volitional competences), such as self-motivation or emotion regulation, are particularly necessary for patients with psychiatric and psychosomatic disorders, it is unknown whether volitional deficits can be reduced and thereby the efficacy of psychotherapy increased. We investigated the effect of a group therapy for improving volitional competence in an inpatient rehabilitation program. Methods: In a controlled clinical trial, patients from a rehabilitation clinic participated either in the volition group therapy in addition to the standard cognitive behavioral therapy (volition group, VG) or in the standard cognitive behavioral therapy (standard group, SG). Patients were tested for volitional competence, depressive symptoms, total psychiatric symptomatology, and physical complaints prior to, at the end of inpatient therapy and after 6 months of follow-up (n = 242). Results: At the end of inpatient therapy, better improvement in volitional competence was observed in the VG than in the SG [e.g. self-motivation: effect size (ES) 0.96 vs. 0.39; ANCOVA: F(1, 209) = 16.58; p < 0.001]. Patients with greater volitional improvements had a better rehabilitation outcome. In the VG, depressive symptoms as well as total psychiatric symptomatology decreased significantly more than in the SG [ES: 1.18 vs. 0.87, F(1, 207) = 4.68, p < 0.05, and ES 1.12 vs. 0.73, F(1, 205) = 4.68, p < 0.05, respectively], but not physical complaints [ES: 0.62 vs. 0.48, F(1, 207) = 1.08, n.s.]. Conclusions: Effect size increased in patients with initially low volitional competence and high motivation to participate in a volitional training. These results might lead to a more systematic assessment and training of volitional competence.
Pain Response in Depersonalization: A Functional Imaging Study Using Hypnosis in Healthy Subjects
Authors: Röder Christian H. , Michal Matthias , Overbeck G. , van de Ven Vincent G. , Linden David E.J.
Published: January 2007

Background: Depersonalization (DP) is characterized by persistent or recurrent episodes of detachment from one’s self with reduced pain perception being a common feature. Alterations in the body schema similar to the cortico-limbic disconnection syndrome of pain asymbolia are suggested to be responsible for DP. In this study we used hypnosis to induce DP in healthy subjects and to examine neural patterns of pain perception in the state of DP by means of functional magnetic resonance imaging (fMRI). Methods: Pain perception was investigated in 7 healthy subjects with high susceptibility to hypnosis in three different mental states: waking state (N-W), hypnotic relaxation (H-R) and hypnotic DP (H-DP). Pain was induced with electrical stimulation to the median nerve at the right wrist. fMRI measurements were performed during all states. Results: Nociceptive stimuli led to an activation of the well described pain network including somatosensory and insular regions and the cerebellum. Activation was markedly reduced in the contralateral somatosensory cortex, parietal cortex (Brodmann area 40, BA40), prefrontal cortex (BA9), putamen and the ipsilateral amygdala during H-DP. Subjects also reported a significant decrease in pain intensity from N-W to H-DP. Conclusion: Pain response during H-DP was reduced in sensory and affective pain-related areas, reflecting the diminished intensity of the perceived pain. Moreover, a network of cortical and subcortical areas that have been implicated in the perception of the own body was less responsive during DP, which might point to a specific neural mechanism underlying the ‘out-of-body’ experience. Although the small number of subjects does not allow a generalization of our findings, H-DP seems to be a promising tool for the investigation of psychological and biological mechanisms of self-inflicted injuries as well as the mind-body interplay within the realm of psychosomatic disorders.
Pseudomembranous Colitis following Bortezomib Therapy in a Myeloma Patient
Authors: Moon Sung-Jin , Min Chang-Ki , Lee Dong-Gun , Lee Seok , Lee Jong-Wook , Min Woo-Sung , Kim Chun-Choo , Kim Myungshin , Park Gyeongsin , Kim Younggu
Published: January 2007

The proteasome inhibitor, bortezomib, has antimyeloma activity even in myeloma cells refractory to multiple prior treatments. The most commonly reported adverse events in patients receiving bortezomib are sensory neuropathy, thrombocytopenia and gastrointestinal events. We report a patient with myeloma who developed pseudomembranous colitis after bortezomib treatment. Bortezomib has the boronic acid moiety which improves the specificity of proteasome inhibition and can be used as non-β-lactam-based β-lactamase inhibitors. This case indicates that gastrointestinal toxicities by bortezomib may be caused, in part, as a result of change in the colonization of colonic microflora.
Symptomatic Venous Thromboembolism and Thrombophilic Status in Adult Acute Leukemia: A Single-Center Experience of 114 Patients at Diagnosis
Authors: Melillo Lorella , Grandone Elvira , Colaizzo Donatella , Cappucci Filomena , Valvano Maria Rosa , Cascavilla Nicola
Published: January 2007

Inherited and acquired thrombophilia are associated with venous thromboembolic events (TE). The prevalence of inherited and acquired prothrombotic risk factors and the incidence of symptomatic TE were evaluated in a cohort of 114 adult acute leukemia patients. The most frequent prothrombotic risk factor was hyperhomocysteinemia which occurred in 46.6% of patients. The incidence of TE was 9.6%, mainly in the first month of follow-up. In multivariate analysis, hyperhomocysteinemia was the only risk factor for TE (OR 33.90; 95% CI 1.53–751.33; p = 0.026). The results of this study indicate that measurements of homocysteinemia could be useful in determining the risk of early TE in adult acute leukemia patients, while systematic thrombophilia screening should not be justified.
Further Evidence of Pleiotropy Influencing Speech and Language: Analysis of the DYX8 Region
Authors: Miscimarra L. , Stein C. , Millard C. , Kluge A. , Cartier K. , Freebairn L. , Hansen A. , Shriberg L. , Taylor H.G. , Lewis B. , Iyengar S.K.
Published: January 2007

Background/Aims: Genetic studies have raised the possibility of common bases for cognitive linguistic disorders such as speech sound disorder (SSD), reading disorder (RD) and language impairment (LI). Thus, some of the same genes may jointly influence cognitive components within and between these three disorders. We examined the plausibility of this theory in a sample of families ascertained on the basis of a child with SSD. Methods: Using the method of generalized estimating equations to solve a bivariate family predictive model we obtained measures of comorbidity and familial aggregation of SSD and LI. We then used two methods of multipoint model-free linkage analysis to evaluate SSD and LI psychometric test measures over a region previously implicated in linkage studies of RD, DYX8 region, 1p34-p36. Results: Bivariate phenotypic analyses show evidence of comorbidity and within family aggregation and coaggregation of SSD and LI. In addition, two regions on chromosome 1 show suggestive evidence of linkage. The first region was previously reported in dyslexia studies. Our maximum linkage signal in this region measured articulation (p = 0.0009) in SSD sibling pairs. The second region is characterized by processes involved in language production, with the maximum linkage signal measuring listening comprehension (p = 0.0019) using all sibling pairs. Conclusion: We conclude that the DYX8 region could bear genes controlling pleiotropic effects on SSD, LI and RD.
Pregnancy-Associated Plasma Protein A and Soluble Receptor for Advanced Glycation End Products after Kidney Transplantation
Authors: Kalousová Marta , Bartošová Kateřina , Zima Tomáš , Skibová Jelena , Teplan Vladimír , Viklický Ondřej
Published: January 2007

Background: Pregnancy-associated plasma protein A (PAPP-A) and soluble receptor for advanced glycation end products (sRAGE) are new markers related to vascular damage. Methods: Thirty-one patients who had undergone kidney transplantation (TX) in the year 2005 under tacrolimus-based immunosuppression were included in this prospective single-center study. PAPP-A and sRAGE were determined before TX and 2 and 6 weeks and 3 months after TX. The results were correlated with the 3-month protocol kidney graft biopsy findings. Results: Both PAPP-A and sRAGE decreased after TX (mean values in serum: PAPP-A 20.8, 13.7, 12.1, and 10.7 mIU/l, respectively, before and 2 and 6 weeks and 3 months after TX, p < 0.001; sRAGE 4,403.4, 2,512.7, 1,909.0, and 1,817.6 pg/ml, respectively, before and 2 and 6 weeks and 3 months after TX, p < 0.001) and were correlated with the graft function (PAPP-A vs. modification of diet in renal disease formula r = –0.52, p < 0.001; sRAGE vs. modification of diet in renal disease formula r = –0.54, p < 0.001). Additionally, the PAPP-A levels correlated with interstitial inflammation (r = 0.57, p < 0.05) and vascular intimal thickening (r = 0.47, p < 0.05), while sRAGE correlated with arteriolar hyalinosis (r = 0.49, p < 0.05). Conclusions: Our study demonstrates the role of the kidney in the metabolism and/or the removal of PAPP-A and sRAGE. After successful TX, these substances decrease, and, on the contrary, early chronic vascular changes in the kidney TX are associated with elevation of their serum levels.
Long-Term Prevention of Hypertension and End-Organ Damage in Ren-2 Transgenic Rats Is Achieved Only with Persistent but Not Transient AT1 Receptor Blockade
Authors: Vaněčková Ivana , Kopkan Libor , Husková Zuzana , Vaňourková Zdenka , Schejbalová Stanislava , Červenka Luděk , Kramer Herbert J.
Published: January 2007

The aim of this study was first to evaluate the effects of persistent or transient blockade of the angiotensin II (ANG II) receptor AT1 on the development of hypertension and end-organ damage in hypertensive Ren-2 transgenic rats (TGR), and second to assess the potential role of AT2 receptors in the control of blood pressure (BP) in this monogenetic model of hypertension. Male heterozygous TGR and Hannover Sprague-Dawley (HanSD) rats fed a normal salt diet were treated from day 32 of age either persistently until the end of the experiment (day 100 of age) or transiently until day 56 of age with the selective AT1 receptor antagonist candesartan or with the combination of candesartan and the AT2 receptor antagonist PD 123319. Persistent treatment with candesartan completely prevented the rise in BP, proteinuria and the increase in left ventricular weight/body weight ratio, whereas transient treatment with candesartan was effective only as long as the drug was administered. In the presence of candesartan, PD 123319 was without effect. Our results show that in male heterozygous TGR persistent candesartan treatment completely prevented hypertension and end-organ damage as long as the drug was administered, whereas transient AT1 receptor blockade had no long-term effects.
Calcitriol (1,25-Dihydroxycholecalciferol) Selectively Inhibits Proliferation of Freshly Isolated Tumor-Derived Endothelial Cells and Induces Apoptosis
Authors: Flynn Geraldine , Chung Ivy , Yu Wei-Dong , Romano Michelle , Modzelewski Ruth A. , Johnson Candace S. , Trump Donald L.
Published: January 2007

Calcitriol (1,25-dihydroxycholecalciferol) has antiproliferative and/or proapoptotic effects on many cell types and the glucocorticoid dexamethasone enhances these effects. We have shown that calcitriol modulates several key signaling proteins involved in differentiation, proliferation and apoptosis in tumor-derived murine endothelial cells (TDEC) and that these effects were not seen with endothelial cells isolated similarly from normal tissues. In the present study, TDEC and mouse embryonic yolk sac endothelial cells (MYSEC) were treated with calcitriol and followed over time for an effect. MYSEC were utilized as ‘normal’ control endothelial cells because they were more primitive, being isolated from a highly neovascular tissue, and had a similar morphology without the stimulus of the tumor microenvironment. The vitamin D receptor (VDR) is present in TDEC and MYSEC, and was upregulated in calcitriol-treated TDEC and MYSEC; dexamethasone further increased VDR expression following 48 h of treatment. The modulatory effects on signaling proteins were maximal by treatment for 48 h; phospho-Erk, phospho-Akt, p21 and bcl-2 were decreased in treated TDEC with the induction of p27 but there were no effects on MYSEC. After 48 h increased apoptosis was seen in treated TDEC by annexin V labeling with caspase-3 cleavage and decreased levels of poly(ADP-ribose) polymerase, but no effects were seen in MYSEC. Cell cycle analysis showed increased G₀/G1 arrest and an increase in the apoptotic sub-G1 peak in treated TDEC but similar effects were not seen in MYSEC following 48-hour treatment. Proliferation assays were utilized and TDEC demonstrated decreased proliferation compared to normal endothelial cells at 48 h. To determine whether or not the VDR signaling was impaired in MYSEC, we performed the 24-hydroxylase (CYP24) promoter-luciferase reporter assay. CYP24 is a key enzyme involved in the breakdown of vitamin D. VDR signaling was intact in both cell types and calcitriol induced CYP24 mRNA expression in MYSEC but not in TDEC. Taken together, despite similar levels of VDR expression and intact signaling in both cell types, calcitriol selectively inhibits proliferation and induces apoptosis in TDEC with no effect on MYSEC. Thus calcitriol exerts differential effects on TDEC compared to normal cells.
Exercise Training Restores Coronary Arteriolar Dilation to NOS Activation Distal to Coronary Artery Occlusion
Authors: Thengchaisri Naris , Shipley Robert , Ren Yi , Parker Janet , Kuo Lih
Published: January 2007

Objective—

Exercise training has been shown to restore vasodilation to nitric oxide synthase (NOS) activation in arterioles distal to coronary artery occlusion. Because reactive oxygen species are generated during NOS uncoupling and the production of vasodilator H
2
O
2
is increased during exercise in patients with coronary disease, we proposed that H
2
O
2
may contribute to the restoration of vasodilation in porcine coronary occlusion model.

Methods and Results—

Left circumflex (LCX) coronary artery of miniature swine was progressively occluded for 8 weeks followed by exercise training (EX; 5 days/wk treadmill) or sedentary (SED) protocols for 12 weeks. Arterioles were isolated from distal LCX and nonoccluded left anterior descending (LAD) artery for in vitro study. Vasodilation to NOS activators adenosine and ionomycin was impaired in SED LCX, but not LAD, arterioles. This impairment was restored by L-arginine. NO production induced by adenosine was also reduced in SED LCX arterioles. EX had no effect on LAD arterioles but improved NO production and restored dilation of LCX arterioles. NOS blockade (L-NAME) inhibited vasodilation to NOS activators in LAD (SED & EX) arterioles but was ineffective in SED LCX arterioles. In EX LCX arterioles, vasodilation to NOS activators was slightly inhibited by L-NAME but abolished by catalase. H
2
O
2
production was markedly increased by adenosine in EX LCX arterioles.

Conclusions—

This study demonstrates that endothelium-dependent NO-mediated dilation is impaired in SED LCX arterioles and that EX training restores the impaired function. It appears that H
2
O
2
, in addition to NO, contributes significantly to EX-induced restoration of endothelium-dependent dilation of coronary arterioles distal to occlusion.
MicroRNAs Play an Essential Role in the Development of Cardiac Hypertrophy
Authors: Sayed Danish , Hong Chull , Chen Ieng-Yi , Lypowy Jacqueline , Abdellatif Maha
Published: January 2007

MicroRNAs are naturally existing, small, noncoding RNA molecules that downregulate posttranscriptional gene expression. Their expression pattern and function in the heart remain unknown. Here we report an array of microRNAs that are differentially and temporally regulated during cardiac hypertrophy. Significantly, the muscle-specific microRNA-1 (miR-1) was singularly downregulated as early as day 1 (0.56±0.036), persisting through day 7 (0.29±0.14), after aortic constriction–induced hypertrophy in a mouse model. Overexpression experiments showed that miR-1 inhibited its in silico–predicted, growth-related targets, including Ras GTPase–activating protein (RasGAP), cyclin-dependent kinase 9 (Cdk9), fibronectin, and Ras homolog enriched in brain (Rheb), in addition to protein synthesis and cell size. Thus, we propose that microRNAs play an essential regulatory role in the development of cardiac hypertrophy, wherein downregulation of miR-1 is necessary for the relief of growth-related target genes from its repressive influence and induction of hypertrophy.
Intracranial Hemorrhage Associated With Revascularization Therapies
Authors: Khatri Pooja , Wechsler Lawrence R. , Broderick Joseph P.
Published: January 2007

Background and Purpose—

This review discusses the state of our current knowledge on hemorrhagic transformation (HT) and summarizes key factors to be considered when comparing risk associated with various approaches to revascularization.

Summary of Review—

HT is a common and natural consequence of infarction, likely related to matrix metalloproteinases and free radical pathways disrupting permeability barriers between blood and brain during ischemia and reperfusion. Symptomatic HT rates within 24 to 36 hours of stroke are increased in the setting of revascularization therapy regardless of modality. HT incidence rates must be considered in the context of the timing of imaging, the period of the study, the definition of clinically significant HT, and other key predictors of HT. The most consistently identified predictors of clinically significant HT in acute revascularization trials have been thrombolytic therapy, dose of lytic agents, edema or mass effect on head CT, stroke severity, and age. Other risk factors may be hyperglycemia, concurrent heparin use, timing of therapy, and timing of successful recanalization. Future predictors may also include imaging parameters, serological markers, variables related to intra-arterial technique, and arterial lesion location.

Conclusions—

Understanding how baseline and treatment variables impact HT rates after acute stroke is critical for those designing and interpreting acute stroke trials. Future trials should consider the use of PH-2 as a standardized safety end point, putting hemorrhagic changes in the context of overall clinical outcome, and developing strategies to reduce the rates of clinically significant intracranial hemorrhage.
Confirmation of tPA Treatment Effect by Baseline Severity-Adjusted End Point Reanalysis of the NINDS-tPA Stroke Trials
Authors: Saver Jeffrey L. , Yafeh Banafsheh
Published: January 2007

Background and Purpose—

Baseline severity-adjusted end point analysis, an emerging approach to the evaluation of primary end points in acute stroke trials, offers a novel means of adjusting trial analysis for baseline imbalances in presenting stroke severity among treatment groups, a factor that has complicated interpretation and reception of the results of the pivotal National Institute of Neurological Disorders and Stroke tissue plasminogen activator (NINDS-tPA) trials.

Methods—

The sliding scale dichotomy end point responder analysis applied in recent acute ischemic stroke clinical trials was used to analyze NINDS-tPA stroke trials 1 and 2. Good outcomes were: 3-month Rankin scale=0 if pretreatment NIHSS scores were 1 to 7; 3-month Rankin scale=0 to 1 if pretreatment NIHSS scores were 8 to 14; 3-month Rankin scale=0 to 2 if pretreatment NIHSS scores were >14.

Results—

Both of the NINDS-tPA stroke trials showed a statistically significant beneficial treatment effect of tPA. In unadjusted analyses, in trial 1, good outcomes in tPA versus placebo patients were 39.6% versus 28.6% (odds ratio 1.64,
P
=0.049); in trial 2, 35.7% versus 24.2% (odds ratio 1.74,
P
=0.024). Among all 624 patients in trials 1 and 2 combined, good outcomes occurred in 37.5% versus 26.3% patients (odds ratio 1.68,
P
=0.0034). In the 91- to 180-minute onset to treatment time subgroup of patients among whom baseline severity imbalance was particularly severe, good outcomes were noted in 36.1% versus 24.0% (odds ratio 1.80,
P
=0.021). Odds ratios favoring tPA generally further increased after adjustment for 12 additional covariates known to predict acute stroke outcome.

Conclusion—

Baseline-adjusted severity end point reanalysis of the NINDS Stroke tPA trials confirms a beneficial treatment effect of intravenous tPA.
Disparities in Outcomes Among Patients With Stroke Associated With Insurance Status
Authors: Shen Jay J. , Washington Elmer L.
Published: January 2007

Background and Purpose—

Despite well-documented discrepancies in many clinical conditions across insurance groups, limited research has examined insurance-related disparities for patients with stroke. This study examined the relationship between insurance status and hospital care for patients with stroke.

Methods—

Discharges with intracerebral hemorrhage and acute ischemic stroke were abstracted from the 2002 National Inpatient Sample. Neurologic impairment status and mortality were examined.

Results—

Compared with privately insured patients, uninsured patients had a higher level of neurologic impairment, a longer average length of hospital stay, and higher mortality risk. For patients with intracerebral hemorrhage and acute ischemic stroke, mortality risk of uninsured patients was approximately 24% and 56% higher, respectively, than that of their privately insured peers.

Conclusions—

Policy should promote access to outpatient and preventive care for uninsured patients so risk factors such as hypertension can be detected and treated during early, asymptomatic stages. Further research is needed to evaluate the extent to which differences in outcomes are attributable to differences in severity level on admission.
Evolution of Dipole-Type Blocking Life Cycles: Analytical Diagnoses and Observations
Authors: Huang Fei , Tang Xiaoyan , Lou S. Y. , Lu Cuihua
Published: January 2007

A variable coefficient Korteweg–de Vries (VCKdV) system is derived by considering the time-dependent background flow and boundary conditions from a nonlinear, inviscid, nondissipative, and equivalent barotropic vorticity equation in a beta plane. One analytical solution obtained from the VCKdV equation can be successfully used to explain the evolution of atmospheric dipole-type blocking (DB) life cycles. Analytical diagnoses show that the background mean westerlies have great influence on evolution of DB during its life cycle. A weak westerly is necessary for blocking development and the blocking life period shortens, accompanied with the enhanced westerlies. The shear of the background westerlies also plays an important role in the evolution of blocking. The cyclonic shear is preferable for the development of blocking but when the cyclonic shear increases, the intensity of blocking decreases and the life period of DB becomes shorter. Weak anticyclonic shear below a critical threshold is also favorable for DB formation. Time-dependent background westerly (TDW) in the life cycle of DB has some modulations on the blocking life period and intensity due to the behavior of the mean westerlies. Statistical analysis regarding the climatological features of observed DB is also investigated. Observational results show that the Pacific is a preferred region for DB, especially at high latitudes. These features may associate with the weakest westerlies and the particular westerly shear structure over the northwestern Pacific.