bluuebunny/crossref_metadata_2025 huggingface dataset:
Osteoactivin Promotes Breast Cancer Metastasis to Bone
Authors: Rose April A.N. , Pepin François , Russo Caterina , Abou Khalil Jad E. , Hallett Michael , Siegel Peter M.
Published: October 2007

The skeleton is a preferred site of metastasis in patients with disseminated breast cancer. We have used 4T1 mouse mammary carcinoma cells, which metastasize to bone from the mammary fat pads of immunocompetent mice, to identify novel genes involved in this process. In vivo selection of parental cells resulted in the isolation of independent, aggressively bone metastatic breast cancer populations with reduced metastasis to the lung. Gene expression profiling identified osteoactivin as a candidate that is highly and selectively expressed in aggressively bone metastatic breast cancer cells. These cells displayed enhanced migratory and invasive characteristics in vitro, the latter requiring sustained osteoactivin expression. Osteoactivin depletion in these cells, by small interfering RNA, also lead to a loss of matrix metalloproteinase-3 expression, whereas forced osteoactivin expression in parental 4T1 cells was sufficient to elevate matrix metalloproteinase-3 levels, suggesting that this matrix metalloproteinase may be an important mediator of osteoactivin function. Overexpression of osteoactivin in an independent, weakly bone metastatic breast cancer cell model significantly enhanced the formation of osteolytic bone metastases in vivo. Finally, high levels of osteoactivin expression in primary human breast cancers correlate with estrogen receptor–negative status and increasing tumor grade. Thus, we have identified osteoactivin as a protein that is expressed in aggressive human breast cancers and is capable of promoting breast cancer metastasis to bone. (Mol Cancer Res 2007;5(10):1001–14)
Reprogramming Leukemia Cells to Terminal Differentiation and Growth Arrest by RNA Interference of PU.1
Authors: Papetti Michael , Skoultchi Arthur I.
Published: October 2007

Malignant transformation often leads to both loss of normal proliferation control and inhibition of cell differentiation. Some tumor cells can be stimulated to reenter their differentiation program and to undergo terminal growth arrest. The in vitro differentiation of mouse erythroleukemia (MEL) cells is an important example of tumor cell reprogramming. MEL cells are malignant erythroblasts that are blocked from differentiating into mature RBC due to dysregulated expression of the transcription factor PU.1, which binds to and represses GATA-1, the major transcriptional regulator of erythropoiesis. We used RNA interference to ask whether inhibiting PU.1 synthesis was sufficient to cause MEL cells to lose their malignant properties. We report here that transfection of MEL cells with a PU.1-specific short interfering RNA oligonucleotide causes the cells to resume erythroid differentiation, accumulate hemoglobin, and undergo terminal growth arrest. RNA interference directed at specific, aberrantly expressed transcription factors may hold promise for the development of potent antitumor therapies in other hematologic malignancies. (Mol Cancer Res 2007;5(10):1053–62)
Histone Deacetylase Inhibitors: Overview and Perspectives
Authors: Dokmanovic Milos , Clarke Cathy , Marks Paul A.
Published: October 2007

Histone deacetylase inhibitors (HDACi) comprise structurally diverse compounds that are a group of targeted anticancer agents. The first of these new HDACi, vorinostat (suberoylanilide hydroxamic acid), has received Food and Drug Administration approval for treating patients with cutaneous T-cell lymphoma. This review focuses on the activities of the 11 zinc-containing HDACs, their histone and nonhistone protein substrates, and the different pathways by which HDACi induce transformed cell death. A hypothesis is presented to explain the relative resistance of normal cells to HDACi-induced cell death. (Mol Cancer Res 2007;5(10):981–9)
Validity of Current Somatoform Disorder Diagnoses: Perspectives for Classification in DSM-V and ICD-11
Authors: Löwe Bernd , Mundt Christoph , Herzog Wolfgang , Brunner Romuald , Backenstrass Matthias , Kronmüller Klaus , Henningsen Peter
Published: October 2007

Background: The impending revisions of DSM-IV and ICD-10 provide an excellent opportunity to improve the diagnostic accuracy of the current somatoform disorder classification. To prepare for these revisions, this study systematically investigates the validity of the current classification of somatoform disorders. Methods: We searched Medline, Psycinfo and reference lists to investigate convergent, divergent, criterion and predictive validity of the current somatoform disorder classification. Results: Substantial associations of somatoform disorders with functional impairment and elevated health care costs give evidence for the clinical and societal importance of somatoform disorders and for the convergent validity of the current operationalization. The specificity of the current somatoform disorder classification, i.e. their divergent validity, is demonstrated by the fact that functional somatic syndromes and their consequences are only partially explained by association with anxiety and depression. However, the imprecision of the diagnostic criteria, which are not based on positive criteria but on the exclusion of organic disease, largely limits the criterion validity of the current classification systems. Finally, studies investigating the predictive potential of somatoform disorders are lacking, and to date predictive validity has to be considered as low. Conclusions: The insufficient criterion and predictive validity of the present somatoform classification underlines the need to revise the diagnostic criteria. However, an abolishment of the whole category of somatoform disorders would ignore the substantial convergent and divergent validity of the current classification and would exclude patients with somatoform symptoms from the current health care system. A careful revision of the current somatoform disorder diagnoses, based on positive criteria of psychological, biological and social features, has the potential to substantially improve the reproducibility and clinical utility of the existing classification system.
‘Mental Retardation’ or ‘Intellectual Disability’: Time for a Conceptual Change
Authors: Salvador-Carulla Luis , Bertelli Marco
Published: October 2007

Background: The term ‘mental retardation’ (MR) is outdated and has changed to ‘intellectual disability’ (ID). Unfortunately, this decision did not follow a nosology approach. The aim of this overview is twofold: (1) to provide a conceptual background and framing on the ID/MR field to other psychiatrists, and (2) to provide a nosology-based perspective to the debate on the name and concept of MR/ID. Method: This conceptual paper is based on a literature review and on an iterative process of debate within the WPA Section ‘Psychiatry of Mental Retardation’. Results: ID may be regarded not as a disease or as a disability but as a syndrome grouping (metasyndrome) similar to the construct of dementia. It includes a heterogeneous group of clinical conditions, ranging from genetic to nutritional, infectious, metabolic or neurotoxic conditions. The ID metasyndrome is characterized by a deficit in cognitive functioning prior to the acquisition of skills through learning. The intensity of the deficit is such to interfere in a significant way with individual normal functioning as expressed in limitations in activities and restriction in participation (disabilities). Conclusions: The name ‘developmental cognitive impairment’ is here suggested to coexist with ID for naming the metasyndrome previously called MR following a polysemic-polynomious approach.
Evolution Theory: An Overview of Its Applications in Psychiatry
Authors: Baptista Trino , Aldana Elis , Angeles Félix , Beaulieu Serge
Published: October 2007

Objectives: (1) Describe the concept, mechanisms and outcome of evolution; (2) review the current topics in research and clinical psychiatry where evolutionary concepts are explicitly applied. Methods: The authors reviewed relevant textbooks of evolution, evolutionary psychiatry/psychology and articles in scientific journals, and discussed these topics in a college course at McGill University School of Medicine, Montreal, Canada. Results: (1) Most natural scientists agree that evolution has occurred in all living beings. However, the mechanisms and outcomes of evolution are controversial. (2) In the first three quarters of the 20th century, several authors provided theories about human psychology based on ethological concepts. The so-called evolutionary psychology/psychiatry developed more recently, and it explores the adaptive/nonadaptive features of psychopathology and mental disorders. In the 1990s a concept of mental disorder (as a harmful dysfunction) based on evolutionary theory has been developed. Conclusions: Evolution is a pivotal concept in biology with relevant applications in psychiatry. We suggest encouraging the interaction between psychiatric educators and researchers in evolutionary psychiatry and biology in order to improve the education of psychiatric residents in this subject.
Continuous Distribution of Atypical Depressive Symptoms between Major Depressive and Bipolar II Disorders: Dose-Response Relationship with Bipolar Family History
Authors: Akiskal Hagop S. , Benazzi Franco
Published: October 2007

Background: Despite the categorical position of formal diagnostic approaches (i.e. ICD-10 and DSM-IV) to mood disorders, atypical depression (AD) occupies an ambiguous position between major depressive (MDD) and bipolar II (BP-II) disorders. Methods: Three hundred and eighty-nine and 261 consecutive BP-II and MDD patients, respectively, presenting for treatment of depression in an Italian private practice, were interviewed by a mood specialist psychiatrist using the Structured Clinical Interview for DSM-IV Axis I Disorders – Clinician Version as modified by the authors to improve the probing for hypomania. Familial bipolarity was measured by the Family History Screen. AD was defined, according to DSM-IV, as a major depressive episode with the ‘atypical features’ specifier. Results: BP-II, versus MDD, had the usual distinguishing features (i.e. earlier age at onset, higher rate of depressive recurrences, AD symptoms, and bipolar family history). Such categorical distinction notwithstanding, the distribution of the number of AD symptoms between BP-II and MDD depressions, studied by Kernel estimate, was continuous, showing no bimodality. Furthermore, there was a dose-response relationship between such symptoms and bipolar family history. Conclusions: The continuous distribution of a distinct clinical feature (i.e. atypical symptoms) between BP-II and MDD supports a dimensional view of depressive disorders. Our data could also be interpreted as providing further support for the subclassification of AD within the bipolar spectrum.
The Bermond-Vorst Alexithymia Questionnaire Cutoff Scores: A Study in Eating-Disordered and Control Subjects
Authors: Deborde A.-S. , Berthoz S. , Wallier J.M. , Fermanian J. , Falissard B. , Jeammet P. , Corcos M.
Published: October 2007

Background: The evaluation of alexithymic deficits has become increasingly desirable in health and psychopathology research. The purpose of this study was to calculate alexithymia cutoff scores for a recently developed self-report alexithymia questionnaire: the Bermond-Vorst Alexithymia Questionnaire Form B (BVAQ-B). Sampling: Three hundred subjects (47 eating-disordered patients and 253 healthy individuals) completed the BVAQ-B and the 20-item Toronto Alexithymia Scale (TAS-20). Methods: The TAS-20 was used as a gold standard for this research, with its previously established cutoff scores serving as diagnostic criteria for determining the presence or absence of alexithymia. The BVAQ-B cutoff score selection was based on the examination of psychometric data (i.e., the sensitivity and specificity of the BVAQ-B scores and receiver operating characteristic curve analyses) and of clinical data (i.e., BVAQ-B mean score of the control subjects, who were mostly nonalexithymic, and BVAQ-B mean score of a group of patients with eating disorders, the majority of whom were alexithymic). Results: This research found that the most appropriate BVAQ-B cutoff scores for determining the absence and presence of alexithymia were 43 and 53, respectively. Conclusion: In light of these findings, we believe that the BVAQ-B may also lend itself to a categorical evaluation of alexithymia, with these cutoff scores determining its absence or presence.
Hypertension Increases Pro-Oxidant Generation and Decreases Antioxidant Defense in the Kidney in Early Diabetes
Authors: Biswas Subrata K. , Peixoto Elisa B. , Souza Denise S. , Lopes de Faria Jose B.
Published: October 2007

Aims: The combination of hypertension and diabetes exacerbates renal oxidative stress. The aim of the present study was therefore to evaluate the pro-oxidant and antioxidant mechanisms responsible for the induction of renal oxidative stress in the presence of hypertension and diabetes mellitus. Methods: Diabetes was induced in spontaneously hypertensive rats (SHR) and their genetically normotensive control Wistar-Kyoto (WKY) rats by streptozotocin at 12 weeks of age. After 10 days, pro-oxidant, antioxidant and oxidative stress parameters were evaluated in the renal tissue. Results: NADPH oxidase-dependent superoxide generation in the renal cortex was significantly elevated in WKY and SHR diabetic (D) groups compared to the respective control (C) groups (p < 0.005, n = 5). However, the highest level of superoxide generation was observed in the SHR-D group compared to all other groups. The expression of the gp91phox subunit of NADPH oxidase was significantly elevated in the SHR-D (p < 0.05, n = 5), but not in the WKY-D group, compared to the respective control groups. The renal cortical extracellular-superoxide dismutase level was found to be markedly decreased in the SHR groups compared to the WKY groups (p < 0.05, n = 5). The antioxidant glutathione level was found to be lower in the SHR-D (p = 0.03, n = 15), but not in the WKY-D group, compared to the respective control groups. Finally, nitrotyrosine and 8-hydroxy-2′-deoxyguanosine, markers of oxidative stress, were found to be similar in the kidneys of WKY-C and WKY-D, but were elevated in the SHR-D compared to the SHR-C group. Conclusion: We therefore conclude that hypertension increases pro-oxidant generation and decreases antioxidant defense, and thereby induces renal oxidative stress in early diabetes.
Pharmacodynamic Study of the Saltz Regimen for Metastatic Colorectal Cancer in a Hemodialyzed Patient
Authors: Akiyama Shinichiro , Nakayama Hidetsugu , Takami Hiroya , Gotoh Hiromichi , Gotoh Yoshikazu
Published: October 2007

Objective: Combination therapy with irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin is widely used for the treatment of metastatic colorectal cancer. However, little is known about the safety of chemotherapy of malignancies in hemodialysis (HD) patients. We encountered a patient with colorectal carcinoma on HD. We decided to administer combination chemotherapy while monitoring the pharmacodynamics of the patient. Case Report: A 74-year-old male received regular HD 3 times a week because of type 1 diabetes mellitus. He was diagnosed with stage IV colorectal cancer in November 2004. After sigmoidectomy, the patient received chemotherapy: a weekly schedule of CPT-11 (50 mg/m2) was administered followed by l-leucovorin (10 mg/m2) and 5-FU (400 mg/m2) just after HD. During the course, the plasma concentrations of both SN-38, an active metabolite of CPT-11, and 5-FU were not increased compared with those of patients with normal renal function. Our patient presented with grade III hematological toxicity that was easily recovered by granulocyte colony-stimulating factor. Conclusion: These data suggest that the dose-reduced Saltz regimen can be feasible for colorectal cancer patients receiving dialysis as postoperative adjuvant chemotherapy.
High-Dose Platinum Combination Therapy in Pretreated Patients with Disseminated Melanoma
Authors: Hofmann Maja A. , Gabriel Verena , Milling Annett , Kiecker Felix , Sterry Wolfram , Trefzer Uwe
Published: October 2007

Background: There are no accepted second-line therapeutic options in patients with disseminated melanoma. We evaluated toxicity and efficacy of a combination therapy with cisplatin and carboplatin. Methods: Fifty consecutively treated melanoma patients who were progressive after at least one previous chemotherapy received cisplatin 100 mg/m2 intravenously and carboplatin 200 mg/m2 intravenously in a 2-day regimen once every 28 days. Results: As grade 3 and 4 toxicities, leucopenia (14%), thrombopenia (10%), anaemia (22%), nausea (8%), nephrotoxicity (4%), hypomagnesaemia (80%) and hepatotoxicity (2%) were observed. Among 42 patients evaluable for response, 2 (4.7%) had complete remission, 4 (9.5%) had partial remission and 21 (50%) had stable disease. The median progression-free time was 17 weeks (range 0–156) for all patients and 39 weeks (range 17–156) for patients with objective responses. The median overall survival time for all patients from the start of therapy was 32 weeks (range 2–156). Melanoma inhibitory activity levels of <12 ng/ml before therapy were identified to be associated with a favourable survival. Conclusion: Our results indicate that a combination of cisplatin and carboplatin in patients with pretreated disseminated melanoma has an acceptable safety profile, induces objective responses and may prolong survival.
Sonodynamic Antitumor Effect of Protoporphyrin IX Disodium Salt on S180 Solid Tumor
Authors: Liu Quanhong , Wang Xiaobing , Wang Pan , Xiao Lina
Published: October 2007

Background: The sonodynamically induced antitumor effect of protoporphyrin IX (PPIX) disodium salt was studied in mice bearing sarcoma 180 solid tumors. Methods: In order to determine the optimum timing of ultrasound exposure after administration of PPIX, the PPIX concentrations in plasma, skin, muscle and tumor were estimated by measuring the fluorescence intensity of tissue extractions with a fluorescence photometer based on the standard curve. Antitumor effects were estimated by measuring tumor size and calculating the average survival time of tumor-bearing mice after sonodynamic therapy; additionally, the morphological changes of sarcoma 180 cells were evaluated by transmission electron microscope observation in vivo. Results: Our experiments suggested a time of 24 h after the administration of PPIX to be best for ultrasound exposure. At an ultrasound intensity ≧5 W/cm2 and a PPIX dose ≧5 mg/kg, a significant synergistic effect of ultrasound combined with PPIX was observed, reducing tumor volume and increasing average animal survival time; this synergistic effect was obviously stronger than ultrasound treatment alone, while PPIX alone showed no significant effect. Transmission electron microscope observation indicated that changes in cell ultrastructure, such as cell membrane destruction, mitochondria swelling and chromatin condensation, were important factors that inhibited tumor growth and even induced cell death. Conclusion: The results implied that the antitumor effect of ultrasound could be enhanced in the presence of PPIX which might be involved in a sonochemical mechanism.
Nanoparticle-Based Oral Drug Delivery System for an Injectable Antibiotic – Streptomycin
Authors: Pandey Rajesh , Khuller Gopal K.
Published: October 2007

Background: To develop an oral drug delivery system for an injectable antibiotic, streptomycin. Methods: Poly-lactide-co-glycolide (PLG) nanoparticles encapsulating streptomycin were prepared by the multiple emulsion technique and administered orally to mice for biodistribution and chemotherapeutic studies. Results: The mean particle size was 153.12 nm with 32.12 ± 4.08% drug encapsulation and 14.28 ± 2.83% drug loading. Streptomycin levels were maintained for 4 days in the plasma and for 7 days in the organs following a single oral administration of PLG nanoparticles. There was a 21-fold increase in the relative bioavailability of PLG-encapsulated streptomycin compared with intramuscular free drug. In Mycobacterium tuberculosis H37Rv infected mice, eight doses of the oral streptomycin formulation administered weekly were comparable to 24 intramuscular injections of free streptomycin. Further, the nanoparticle formulation did not result in nephrotoxicity as assessed on a biochemical basis. Conclusion: Our results suggest that nanoencapsulation might be useful for developing a suitable oral dosage form for streptomycin and perhaps for other antibiotics that are otherwise injectable.
Second-Line Combination Chemotherapy with Docetaxel for Cisplatin-Pretreated Refractory Metastatic Esophageal Cancer: A Preliminary Report of Initial Experience
Authors: Tanaka Toshiaki , Fujita Hiromasa , Sueyoshi Susumu , Tanaka Yuichi , Sasahara Hiroko , Mori Naoki , Nagano Tsuyoshi , Yamana Hideaki , Shirouzu Kazuo
Published: October 2007

Background and Aims: Patients with esophageal cancer often develop metastatic disease after esophageal resection and generally receive cisplatin-based chemotherapy or chemoradiotherapy. The efficacy and toxicity of the combination of docetaxel, 5-fluorouracil (5-FU) and cisplatin (DFC) as a second-line chemotherapy were evaluated in patients with postoperative metastatic esophageal cancer refractory to cisplatin-based chemotherapy. Patients and Methods: Twenty patients with metastatic esophageal cancer after esophagectomy refractory to cispatin-based therapy were included in this study. The DFC regimen consisted of docetaxel (60 mg/m2) on day 1, 5-FU (500 mg/day) on days 1–5 and cisplatin (10 mg/day) on days 1–5, being repeated every 3 weeks. Results: A total of 49 cycles (median 2, range 1–6) was administered to 20 patients. The median follow-up was 8 months (range 3–24). Of the 20 patients, 1 had a complete response, 6 had a partial response, 6 had stable and 7 had progressive disease. Median time to progression for all patients was 4 months (95% Cl 1.7–5.6). The median overall survival for all patients was 8 months (95% CI 5.7–10.3). The major toxicity was myelosuppression. Neutropenia of grade 3 or more occurred in 13 patients (65%), and thrombocytopenia of grade 3 occurred in 1 patient (5%). Febrile neuropenia was observed in 1 patient (5%). There was no treatment-related mortality. Conclusion: DFC is a feasible and promising regimen as a second-line therapy in metastatic/recurrent esophageal cancer refractory to cisplatin-based chemotherapy.
Inhibition of Integrin-Linked Kinase via a siRNA Expression Plasmid Attenuates Connective Tissue Growth Factor-Induced Human Proximal Tubular Epithelial Cells to Mesenchymal Transition
Authors: Liu Bi-Cheng , Li Min-Xia , Zhang Jian-Dong , Liu Xiao-Cong , Zhang Xiao-Liang , Phillips Aled O.
Published: October 2007

Background: Increasing evidence suggests that connective tissue growth factor (CTGF) is involved in the epithelial-to-mesenchymal transition (EMT). The exact intracellular events that drive this process, however, are not fully understood. In this study, we investigated the role of integrin-linked kinase (ILK) in mediating CTGF-induced EMT. Methods: The expression of α-smooth muscle actin (α-SMA) and E-cadherin upon the stimulation by recombinant human CTGF (rhCTGF) in cultured human tubular epithelial cell line (HK-2) was detected by real-time RT-PCR and Western blot. Subsequently, the role of ILK was determined by using ILK siRNA. Results: rhCTGF increased the mRNA expression of α-SMA significantly in a dose- and time-dependent manner, while E-cadherin mRNA decreased in a dose- and time-dependent manner. α-SMA protein was up-regulated after stimulation by 5 ng/ml CTGF for 96 h, and increased further after stimulation by 50 ng/ml. An immunocytochemical study showed that α-SMA was initially detectable at 48 h, and increased further at 72 h, while there was almost no α-SMA immunostaining observed in the control group at the same time point. E-cadherin protein was also down-regulated in a dose-dependent manner. Transfection of HK-2 cells with ILK-siRNA significantly attenuated rhCTGF-induced α-SMA induction and E-cadherin repression. Conclusion: Our study suggested that ILK mediated the effect of EMT in proximal tubular epithelial cells stimulated by CTGF.
Effects of Dietary Salt on Intrarenal Angiotensin System, NAD(P)H Oxidase, COX-2, MCP-1 and PAI-1 Expressions and NF-κB Activity in Salt-Sensitive and -Resistant Rat Kidneys
Authors: Chandramohan G. , Bai Y. , Norris K. , Rodriguez-Iturbe B. , Vaziri N.D.
Published: October 2007

Background: Chronic consumption of a high-salt diet causes hypertension (HTN) and renal injury in Dahl salt-sensitive (SSR) but not salt-resistant rats (SRR). These events are, in part, mediated by oxidative stress and inflammation in the kidney and vascular tissues. Activation of the angiotensin II type 1 (AT1) receptor plays an important role in the pathogenesis of oxidative stress and inflammation in many hypertensive disorders. However, the systemic renin-angiotensin system (RAS) is typically suppressed in salt-sensitive HTN. This study was designed to test the hypothesis that differential response to a high-salt diet in SSR versus SRR may be related to upregulation of tissue RAS and pathways involved in inflammation and reactive oxygen species (ROS) production. Methods and Results: SSR and SRR were studied 3 weeks after consumption of high- (8%) or low-salt (0.07%) diets. The SSR consuming a low-salt diet exhibited significant increases in AT1 receptor, cyclooxygenase (COX) 2, plasminogen activator inhibitor (PAI) and phospho-IĸB in the kidney as compared to those found in SRR. The high-salt diet resulted in severe HTN and proteinuria (in SSR but not SRR) and marked elevations of renal tissue monocyte chemoattractant protein 1, p22phox, NADPH oxidase subunit 4, angiotensin-II-positive cell count, infiltrating T cells and macrophages and further increases in AT1 receptor, COX-2, PAI-1 and phospho-IĸB in the SSR group. The high-salt diet significantly lowered plasma renin activity (PRA) in SRR but not in the SSR. COX-1 abundance was similar on the low-salt diet and rose equally with the high-salt diet in both groups. Among subgroups of animals fed the low-salt diet, kidney glutathione peroxidase (GPX) abundance was significantly lower in the SSR than SRR. The high-salt diet raised GPX and mitochondrial superoxide dismutase (SOD) abundance in the SRR kidneys but failed to do so in SSR. Cu/Zn-SOD abundance was similar in the subgroups of SSR and SRR fed the low-salt diet. The high-salt diet resulted in downregulation of Cu/Zn-SOD in SSR but not SRR. Conclusions: Salt sensitivity in the SSR is associated with upregulations of the intrarenal angiotensin system, ROS-generating and proinflammatory/profibrotic proteins and an inability to raise antioxidant enzymes and maximally suppress PRA in response to high salt intake. These events can contribute to renal injury with high salt intake in SSR.
Inhibition of CETP by Torcetrapib Attenuates the Atherogenicity of Postprandial TG-Rich Lipoproteins in Type IIB Hyperlipidemia
Authors: Guerin Maryse , Le Goff Wilfried , Duchene Emilie , Julia Zélie , Nguyen Tu , Thuren Tom , Shear Charles L. , Chapman M. John
Published: October 2007

Objective—

The purpose of this study was to evaluate the impact of torcetrapib on atherogenic TG-rich lipoprotein subfractions in the postprandial phase in Type IIB hyperlipidemia.

Methods and Results—

The quantitative and qualitative features of the postprandial profile of TG-rich lipoproteins were determined at baseline, after treatment for 6 weeks with 10 mg/d atorvastatin, and subsequently with an atorvastatin/torcetrapib combination (10/60 mg/d) in Type IIB patients (n=18). After ingestion of a standardized mixed meal, TG-rich lipoprotein subfractions were evaluated over 8 hours after each experimental period. On a background of atorvastatin, torcetrapib significantly attenuated the incremental postprandial area under the curve (iAUC 0 to 8 hours) for VLDL-1 (−40%), and the AUC 0 to 8 hours for VLDL-2 (-53%), with minor effect on chylomicron iAUC (−24%); concomitantly, the CE/TG ratio in both VLDL-1 and VLDL-2 was significantly reduced (−27% to −42%). Such reduction was attributable to torcetrapib-mediated attenuation of postprandial CE transfer to Chylomicrons (−17%) and VLDL-1 (−33%). Marked reduction in postprandial VLDL-1 levels was associated with apoE enrichment.

Conclusions—

On a background of atorvastatin, torcetrapib attenuated the quantitative and qualitative features of the atherogenic postprandial profile of chylomicrons, VLDL-1 and VLDL-2. Such changes reflect the sum of torcetrapib-mediated effects on TG-rich lipoprotein production, intravascular remodeling, and catabolism.
Macrophage β3 Integrin Suppresses Hyperlipidemia-Induced Inflammation by Modulating TNFα Expression
Authors: Schneider Jochen G. , Zhu Yimin , Coleman Trey , Semenkovich Clay F.
Published: October 2007

Objective—

High-fat, cholesterol-containing diets contribute to hyperlipidemia. Both high-fat diets and hyperlipidemia are associated with chronic inflammatory diseases like atherosclerosis. Integrins, heterodimeric mediators of inflammatory cell recruitment, are not generally thought to be affected by diet. However, high-fat feeding promotes inflammation, atherosclerosis, and death in hyperlipidemic mice with β3 integrin deficiency, and treatment of humans from Western populations with oral β3 integrin inhibitors increases mortality. The mechanisms responsible for these β3 integrin-associated events are unknown.

Methods and Results—

Here we show that diet-induced death in β3 integrin-deficient mice is a TNFα-dependent process mediated by bone marrow–derived cells. In 2 different hyperlipidemic models, apoE-null and LDL receptor–null mice, β3-replete animals transplanted with β3-deficient marrow died with Western-type high-fat feeding whereas β3-deficient animals transplanted with β3-replete marrow were rescued from diet-induced death. Transplantation with β3-deficient marrow also increased atherosclerosis. TNFα expression was increased in β3-deficient macrophages and normalized by either retroviral or adenoviral reconstitution of β3 integrin expression. Treatment with the anti-TNFα antibody infliximab rescued β3 integrin–deficient mice from Western diet–induced death, directly implicating TNFα in the pathophysiology triggered by diet-induced hyperlipidemia.

Conclusions—

These findings suggest that macrophage β3 integrin, acting through TNFα, suppresses inflammation caused by hyperlipidemia attributable to high-fat feeding.
Genetic Variation in
ABCA1
Predicts Ischemic Heart Disease in the General Population
Authors: Frikke-Schmidt Ruth , Nordestgaard Børge G. , Jensen Gorm B. , Steffensen Rolf , Tybjærg-Hansen Anne
Published: October 2007

Objective—

We tested the hypothesis that 6 nonsynonymous single nucleotide polymorphisms (SNPs) in
ATP-Binding-Cassette transporter A1 (ABCA1
) affect risk of ischemic heart disease (IHD) in the general population.

Methods and Results—

We genotyped 9259 individuals from the Danish general population followed for 25 years. Two SNPs (V771M and V825I) were previously associated with increases in HDL-C, 1 (R1587K) with decreased HDL-C, whereas 3 (R219K, I883M and E1172D) did not affect HDL-C levels. Despite this, 5 out of 6 SNPs (V771M, V825I, I883M, E1172D, R1587K) predicted increased risk of IHD. Similar results were obtained in a verification sample with 932 IHD cases versus 7999 controls. A stepwise regression approach identified V771M, I883M, and E1172D as the most important predictors of IHD and additive effects on IHD risk were present for V771M/I883M and I883M/E1172D pairs.

Conclusions—

We show that 3 of 6 nonsynonymous SNPs in
ABCA1
predict risk of IHD in the general population.
RhoB Regulates PDGFR-β Trafficking and Signaling in Vascular Smooth Muscle Cells
Authors: Huang Minzhou , DuHadaway James B. , Prendergast George C. , Laury-Kleintop Lisa D.
Published: October 2007

Objective—

RhoB is a small GTPase localized at the plasma membrane and endosomes that participates in the regulation of endocytic trafficking of the epidermal growth factor (EGF) receptor and the nonreceptor kinases Src and Akt. This study was performed to determine whether RhoB plays a critical role in trafficking and signaling by the platelet-derived growth factor receptor-β (PDGFR-β) in vascular smooth muscle cells.

Methods and Results—

Cells derived from RhoB knockout mice failed to proliferate in response to PDGF, and downstream signaling was compromised as reflected by reduced phosphorylation of the effector kinases Akt and ERK1/2. In normal cells, PDGF stimulated trafficking of PDGFR-β into a perinuclear late endosomal compartment and triggered entry of Src, Akt, extracellular signal-regulated kinase (ERK) into the cell nucleus. In contrast, PDGF treatment of RhoB null cells resulted in neither PDGFR-β trafficking to late endosomes nor nuclear localization of Src, Akt, or ERK. In support of an essential function in these processes, restoring expression of RhoB in null cells rescued these defects and restored cell proliferation in response to PDGF.

Conclusion—

Our findings establish RhoB as a critical regulator of PDGFR-β trafficking and signaling in vascular smooth muscle cells.
Cell-Based Therapy of Myocardial Infarction
Authors: Dimmeler Stefanie , Burchfield Jana , Zeiher Andreas M.
Published: October 2007

Cell-based therapy is a promising option for treatment of ischemic diseases. Several cell types have experimentally been shown to increase the functional recovery of the heart after ischemia by physically forming new blood vessels, differentiating to cardiac myocytes and—additionally or alternatively—by providing proangiogenic and antiapoptotic factors promoting tissue repair in a paracrine manner. Clinical studies preferentially used adult bone marrow–derived cells for the treatment of patients with acute myocardial infarction. Most of the studies suggested that cell therapy reduced the infarct size and improved cardiac contractile function. However, cell therapy is in its early stages, and various questions remain. For example, the identification of those patients who benefit most from cell therapy, the optimal cell type and number for patient with acute and chronic diseases, the best time and way of cell delivery, and the mechanisms of action by which cells exhibit beneficial effects, need to be further evaluated. Although no major safety concerns were raised during the initial clinical trials, several potential side effects need to be carefully monitored. The present review article summarizes the results of the clinical studies and discusses the open issues.
Are Serum Carcinoembryonic Antigen Levels Associated With Carotid Atherosclerosis in Japanese Men?
Authors: Ishizaka Nobukazu , Ishizaka Yuko , Toda Ei-Ichi , Koike Kazuhiko , Yamakado Minoru , Nagai Ryozo
Published: October 2007

Objective—

Carcinoembryonic antigen (CEA), a serological marker of malignant tumors, may show a modest increase under some nonmalignant conditions, such as ageing and cigarette smoking. We have investigated whether serum CEA levels are associated with early carotid atherosclerosis.

Methods and Results—

Cross-sectional data from 4181 male individuals who underwent general health screening were analyzed. The interquartile of cutoff values of serum CEA levels were 1.0, 1.6, and 2.5 ng/mL. Cigarette smoking was associated with increased serum CEA levels in a dose- and duration-dependent manner, and this association was more prominent in current than former smokers. Logistic regression analysis adjusted for age, body mass index, serum lipid and glucose profiles, white blood cell count, C-reactive protein, and smoking habits showed that the first, second, third, and fourth CEA quartiles were associated with carotid plaque with an odds ratio of 1 (reference), 1.25 (95% CI 1.03 to 1.52,
P
=0.023), 1.49 (95% CI 1.23 to 1.82
P
<0.001), and 1.34 (95% CI 1.08 to 1.65,
P
=0.007), respectively. Although serum CEA levels were associated with metabolic syndrome, association between serum CEA and carotid plaque was significant in individuals without metabolic syndrome.

Conclusions—

Serum CEA was associated with carotid atherosclerosis independently of atherogenic risk factors and markers of inflammation. Our data suggest that a slight elevation of CEA in current smokers, as well as in never smokers, may not be an innocuous observation from the viewpoint of atherosclerosis.
Histone Deacetylase 7 Silencing Alters Endothelial Cell Migration, a Key Step in Angiogenesis
Authors: Mottet Denis , Bellahcène Akeila , Pirotte Sophie , Waltregny David , Deroanne Christophe , Lamour Virginie , Lidereau Rosette , Castronovo Vincent
Published: October 2007

Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the development of blood vessels. Using small interfering RNAs, we observed that HDAC7 silencing in endothelial cells altered their morphology, their migration, and their capacity to form capillary tube-like structures in vitro but did not affect cell adhesion, proliferation, or apoptosis. Among several factors known to be involved in angiogenesis, platelet-derived growth factor-B (
PDGF-B
) and its receptor (
PDGFR
-β) were the most upregulated genes following HDAC7 silencing. We demonstrated that their increased expression induced by HDAC7 silencing was partially responsible for the inhibition of endothelial cell migration. In addition, we have also shown that treatment of endothelial cells with phorbol 12-myristate 13-acetate resulted in the exportation of HDAC7 out of the nucleus through a protein kinase C/protein kinase D activation pathway and induced, similarly to HDAC7 silencing, an increase in PDGF-B expression, as well as a partial inhibition of endothelial cell migration. Collectively, these data identified HDAC7 as a key modulator of endothelial cell migration and hence angiogenesis, at least in part, by regulating PDGF-B/PDGFR-β gene expression. Because angiogenesis is required for tumor progression, HDAC7 may represent a rational target for therapeutic intervention against cancer.
Identification of Myocardial and Vascular Precursor Cells in Human and Mouse Epicardium
Authors: Limana Federica , Zacheo Antonella , Mocini David , Mangoni Antonella , Borsellino Giovanna , Diamantini Adamo , De Mori Roberta , Battistini Luca , Vigna Elisa , Santini Massimo , Loiaconi Vincenzo , Pompilio Giulio , Germani Antonia , Capogrossi Maurizio C.
Published: October 2007

During cardiac development, the epicardium is the source of multipotent mesenchymal cells, which give rise to endothelial and smooth muscle cells in coronary vessels and also, possibly, to cardiomyocytes. The aim of the present study was to determine whether stem cells are retained in the adult human and murine epicardium and to investigate the regenerative potential of these cells following acute myocardial infarction. We show that c-kit
+
and CD34
+
cells can indeed be detected in human fetal and adult epicardium and that they represent 2 distinct populations. Both subsets of cells were negative for CD45, a cell surface marker that identifies the hematopoietic cell lineage. Immunofluorescence revealed that freshly isolated c-kit
+
and CD34
+
cells expressed early and late cardiac transcription factors and could acquire an endothelial phenotype in vitro. In the murine model of myocardial infarction, there was an increase in the absolute number and proliferation of epicardial c-kit
+
cells 3 days after coronary ligation; at this time point, epicardial c-kit
+
cells were identified in the subepicardial space and expressed GATA4. Furthermore, 1 week after myocardial infarction, cells coexpressing c-kit
+
, together with endothelial or smooth muscle cell markers, were identified in the wall of subepicardial blood vessels. In summary, the postnatal epicardium contains a cell population with stem cell characteristics that retains the ability to give rise to myocardial precursors and vascular cells. These cells may play a role in the regenerative response to cardiac damage.
Targeting Focal Adhesion Kinase With Small Interfering RNA Prevents and Reverses Load-Induced Cardiac Hypertrophy in Mice
Authors: Clemente Carolina F.M.Z. , Tornatore Thais F. , Theizen Thais H. , Deckmann Ana C. , Pereira Tiago C. , Lopes-Cendes Iscia , Souza José Roberto M. , Franchini Kleber G.
Published: October 2007

Hypertrophy is a critical event in the onset of failure in chronically overloaded hearts. Focal adhesion kinase (FAK) has attracted particular attention as a mediator of hypertrophy induced by increased load. Here, we demonstrate increased expression and phosphorylation of FAK in the hypertrophic left ventricles (LVs) of aortic-banded mice. We used an RNA interference strategy to examine whether FAK signaling plays a role in the pathophysiology of load-induced LV hypertrophy and failure. Intrajugular delivery of specific small interfering RNA induced prolonged FAK silencing (≈70%) in both normal and hypertrophic LVs. Myocardial FAK silencing was accompanied by prevention, as well as reversal, of load-induced left ventricular hypertrophy. The function of LVs was preserved and the survival rate was higher in banded mice treated with small interfering RNA targeted to FAK, despite the persistent pressure overload. Studies in cardiac myocytes and fibroblasts harvested from LVs confirmed the ability of the systemically administered specific small interfering RNA to silence FAK in both cell types. Further analysis indicated attenuation of cardiac myocyte hypertrophic growth and of the rise in the expression of β-myosin heavy chain in overloaded LVs. Moreover, FAK silencing was demonstrated to attenuate the rise in the fibrosis, collagen content, and activity of matrix metalloproteinase-2 in overloaded LVs, as well as the rise of matrix metalloproteinase-2 protein expression in fibroblasts harvested from overloaded LVs. This study provides novel evidence that FAK may be involved in multiple aspects of the pathophysiology of cardiac hypertrophy and failure induced by pressure overload.
Isl1
Expression at the Venous Pole Identifies a Novel Role for the Second Heart Field in Cardiac Development
Authors: Snarr Brian S. , O’Neal Jessica L. , Chintalapudi Mastan R. , Wirrig Elaine E. , Phelps Aimee L. , Kubalak Steven W. , Wessels Andy
Published: October 2007

The right ventricle and outflow tract of the developing heart are derived from mesodermal progenitor cells from the second heart field (SHF). SHF cells have been characterized by expression of the transcription factor Islet-1 (
Isl1
). Although
Isl1
expression has also been reported in the venous pole, the specific contribution of the SHF to this part of the heart is unknown. Here we show that
Isl1
is strongly expressed in the dorsal mesenchymal protrusion (DMP), a non–endocardially-derived mesenchymal structure involved in atrioventricular septation. We further demonstrate that abnormal development of the SHF-derived DMP is associated with the pathogenesis of atrioventricular septal defects. These results identify a novel role for the SHF.
When the Worst Headache Becomes the Worst Heartache!
Authors: Hakeem Abdul , Marks Adam D. , Bhatti Sabha , Chang Su Min
Published: October 2007

Background and Purpose—

Although a great deal of literature has been generated regarding left ventricular wall abnormalities, ECG changes and cardiac enzyme leaks associated with subarachnoid hemorrhage (SAH), there have been only a few reports of true transient left ventricular apical ballooning syndrome in patients with SAH. Several pathophysiological mechanisms have been proposed to explain the unusual features of this syndrome, such as multivessel coronary vasospasm, abnormalities in coronary microvascular function, and catecholamine-mediated cardiotoxicity.

Summary of Case—

A previously healthy 64-year-old woman with no history of vascular disease was found unresponsive at home. She was taken to the emergency room where a CT head revealed an SAH due to a ruptured aneurysm of the posterior communicating artery. On admission, an ECG showed deeply inverted T-waves and QT prolongation, typical of SAH. Cardiac troponin was measured at 1.2 ng/mL, and later increased to 3.7 ng/mL. A transthoracic echocardiogram on the next day revealed a large left ventricular wall abnormality, characteristic of apical ballooning with an ejection fraction of 25% to 30%. The patient remained hemodynamically stable and was started on low dose β-blocker and angiotensin-converting enzyme inhibitor. She had an uneventful cardiac recovery within 5 days at which time a repeat transthoracic echocardiogram revealed a normal ejection fraction with no wall motion abnormality.

Conclusions—

This report adds to the growing list of “stressors” for Takotsubo cardiomyopathy. Clinicians should be aware of the existence and the typical clinical manifestations of this syndrome, which is increasingly recognized in various populations. In particular, neurologists should consider this syndrome in the differential diagnosis of ECG changes and apical wall motion abnormalities in patients with SAH. Prognosis is generally very good with full recovery in most patients; however, there may be increased morbidity associated in patients with SAH.
Cystatin C, Associated With Hemorrhagic and Ischemic Stroke, Is a Strong Predictor of the Risk of Cardiovascular Events and Death in Chinese
Authors: Ni Li , Lü Jiagao , Bo Hou Ling , Tao Yan Jiang , Fan Qiao , Hui Rutai , Cianflone Katherine , Wang Wei , Wen Wang Dao
Published: October 2007

Background and Purpose—

Cystatin C, a serum measure of renal function, has been reported as a strong predictor of risk of death and cardiovascular events in elderly people. We investigated the association between cystatin C and first-ever stroke and evaluated the predictive value of cysctatin C in cardiovascular events and death from all causes based on the outcomes of a 5-year follow-up.

Methods—

We recruited 293 stroke patients (199 cases of cerebral infarction, 94 cases of cerebral hemorrhage) and 894 controls. For each measure, the study population was divided into quintiles.

Results—

Total plasma cystatin C levels were significantly higher in patients than controls. Higher cystatin C levels were directly associated with a higher risk of stroke. As compared with the first (lowest) quintile, the hazard ratios (and 95% CIs) for stroke were as follows: second quintile, 1.97 (1.07 to 3.64); third quintile, 2.71 (1.50 to 4.90); fourth quintile, 3.79 (2.12 to 6.75); fifth quintile, 6.38 (3.60 to 11.32). Follow-up of the patients and controls also showed that high cystatin C levels were associated with high prevalence of cardiovascular events or death from all causes.

Conclusions—

Elevated cystatin C levels were independently associated with both ischemic and hemorrhagic stroke, and cystatin C was a strong predictor for the risk of cardiovascular events and death.