bluuebunny/crossref_metadata_2025 huggingface dataset:
Histone Deacetylase Inhibitor Romidepsin Has Differential Activity in Core Binding Factor Acute Myeloid Leukemia
Authors: Odenike Olatoyosi M. , Alkan Serhan , Sher Dorie , Godwin John E. , Huo Dezheng , Brandt Stephen J. , Green Margaret , Xie Jingping , Zhang Yanming , Vesole David H. , Stiff Patrick , Wright John , Larson Richard A. , Stock Wendy
Published: November 2008

Purpose: Recruitment of histone deacetylases (HDAC) is a mechanism of transcriptional repression implicated in the differentiation block in acute myeloid leukemia (AML). We hypothesized that the HDAC inhibitor romidepsin could cause transcriptional derepression, up-regulation of specific target genes in AML, and differentiation of the leukemic clone. The primary objectives of the study were to evaluate the safety and efficacy of romidepsin in advanced AML.

Experimental Design: Twenty patients were stratified into cohort A or B based on the absence or presence of chromosomal abnormalities known to recruit HDACs, including those involving core binding factor (CBF). Romidepsin was administered i.v. at 13 mg/m2/d on days 1, 8, and 15 of a 28-day cycle. Pharmacodynamic endpoints were evaluated at serial time points.

Results: Common adverse effects noted were grade 1 to 2 nausea, anorexia, and fatigue. No objective evidence of antileukemic activity was seen in cohort A. In cohort B, although there were no clinical responses by standard criteria, antileukemic activity was observed in 5 of 7 patients. Two patients had clearance of bone marrow blasts and 3 patients had a >50% decrease in bone marrow blasts. Furthermore, in cohort B, at 24 h, there was a significant increase in MDR1 (P = 0.005), p15 (P = 0.01), and p14 (P < 0.0001) expression. In cohort A, although there was a trend toward up-regulation of MDR1, p15, and p14 expression, these changes were not statistically significant.

Conclusion: Romidepsin has differential antileukemic and molecular activity in CBF AML. Development of this agent in CBF AML should focus on combinations that target related mechanisms of gene silencing such as DNA methylation.
Regulation of Pancreatic Tumor Cell Proliferation and Chemoresistance by the Histone Methyltransferase Enhancer of Zeste Homologue 2
Authors: Ougolkov Andrei V. , Bilim Vladimir N. , Billadeau Daniel D.
Published: November 2008

Purpose: Enhancer of zeste homologue 2 (EZH2), a histone methyltransferase, plays a key role in transcriptional repression through chromatin remodeling. Our objectives were to determine the expression pattern of EZH2 and to assess the anticancer effect of EZH2 depletion in pancreatic cancer cells.

Experimental Design: Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the expression pattern of EZH2 in normal pancreas and human pancreatic tumors. We used RNA interference, Western blotting, reverse transcription-PCR, and chromatin immunoprecipitation to study the effect of EZH2 depletion on pancreatic cancer cell proliferation and survival.

Results: We detected nuclear overexpression of EZH2 in pancreatic cancer cell lines and in 71 of 104 (68%) cases of human pancreatic adenocarcinomas. EZH2 nuclear accumulation was more frequent in poorly differentiated pancreatic adenocarcinomas (31 of 34 cases; P < 0.001). We found that genetic depletion of EZH2 results in reexpression of p27Kip1 and decreased pancreatic cancer cell proliferation. Moreover, we showed that EZH2 depletion sensitized pancreatic cancer cells to doxorubicin and gemcitabine, which leads to a significant induction of apoptosis, suggesting that the combination of EZH2 inhibitors and standard chemotherapy could be a superior potential treatment for pancreatic cancer.

Conclusions: Our results show nuclear accumulation of EZH2 as a hallmark of poorly differentiated pancreatic adenocarcinoma; identify the tumor suppressor p27Kip1 as a new target gene of EZH2; show that EZH2 nuclear overexpression contributes to pancreatic cancer cell proliferation; and suggest EZH2 as a potential therapeutic target for the treatment of pancreatic cancer.
A Phase II Study of Gefitinib, 5-Fluorouracil, Leucovorin, and Oxaliplatin in Previously Untreated Patients with Metastatic Colorectal Cancer
Authors: Fisher George A. , Kuo Timothy , Ramsey Meghan , Schwartz Erich , Rouse Robert V. , Cho Cheryl D. , Halsey Joanne , Sikic Branimir I.
Published: November 2008

Purpose: We investigated the gefitinib, 5-fluorouracil (5-FU), leucovorin and oxaliplatin (IFOX) regimen as first-line therapy in patients with metastatic colorectal cancer.

Experimental Design: Eligible patients had stage IV colorectal adenocarcinoma, and had not received prior chemotherapy for metastatic disease. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin, leucovorin, and 5-FU (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg orally daily throughout the 14-day cycle.

Results: Forty-five patients were enrolled and were assessable for toxicity. Forty-three patients were assessable for response. Thirty-one of the 43 patients (72%) had either a complete or partial response by the Response Evaluation Criteria in Solid Tumors. Median overall survival was 20.5 months. Median time to progression was 9.3 months. Commonly encountered grade 3 or 4 toxicities included diarrhea in 67% of patients and neutropenia in 60%. Grade 2 acneiform skin rash typical of gefitinib occurred in 60% of patients.

Conclusions: IFOX is an active first-line regimen in patients with metastatic colorectal adenocarcinoma, showing higher response rates but also increased toxicities compared with FOLFOX-4 alone in a similar patient population.
CD44 is of Functional Importance for Colorectal Cancer Stem Cells
Authors: Du Lei , Wang Hongyi , He Leya , Zhang Jingyu , Ni Biyun , Wang Xiaohui , Jin Haijing , Cahuzac Nathalie , Mehrpour Maryam , Lu Youyong , Chen Quan
Published: November 2008

Purpose: Both CD44 and CD133 were reported as putative markers for isolating colorectal cancer stem cells (CSC). It remains to be resolved if both of these markers are of functional importance for colorectal CSC.

Experimental Design: The expression of CD44 and CD133 in normal colonic tissues and primary colorectal cancer was assessed by immunohistochemistry in a series of 60 patients on tissue microarray sections. Both in vitro clonogenic and in vivo tumorigenic assay were applied to measure CSC activities from the cells isolated from patients. Lentiviral RNA interference was used to stably knock down CD44 or CD133 in colorectal cancer cells from patients.

Results: We found that CD44+ cells displayed clustered growth and they did not colocalize with CD133+ cells within colorectal cancer. As few as 100 CD44+ cells from a patients' tumor initiated a xenograft tumor in vivo. A single CD44+ cell from a tumor could form a sphere in vitro which has characteristic stem cell properties and was able to generate a xenograft tumor resembling the properties of the primary tumor. Knockdown of CD44, but not CD133, strongly prevented clonal formation and inhibited tumorigenicity in xenograft model.

Conclusions: These results indicate that CD44 is a robust marker and is of functional importance for colorectal CSC for cancer initiation.
Reciprocal CD4+ T-Cell Balance of Effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ Regulatory T Cells in Small Cell Lung Cancer Reflects Disease Stage
Authors: Koyama Kenichi , Kagamu Hiroshi , Miura Satoru , Hiura Toru , Miyabayashi Takahiro , Itoh Ryo , Kuriyama Hideyuki , Tanaka Hiroshi , Tanaka Junta , Yoshizawa Hirohisa , Nakata Koh , Gejyo Fumitake
Published: November 2008

Purpose: Small cell lung cancer (SCLC) possesses high tendency to disseminate. However, SCLC patients with paraneoplastic syndrome mediated by immunity against onconeural antigens remain in limited-stage disease (LD) without distant metastases. Cumulative evidence regulates that a balance between immune and regulatory T (Treg) cells determines the magnitude of immune responses to not only self-antigens but also tumor-associated antigens. The purpose of this study was to elucidate the immunologic balance induced in SCLC patients.

Experimental Design: We analyzed T cells in the peripheral blood of 35 consecutive SCLC patients, 8 long-term survivors, and 19 healthy volunteers.

Results: Purified CD4+ T cells with down-regulated expression of CD62L (CD62Llow) produced IFN-γ, interleukin (IL)-4, and IL-17, thus considered to be immune effector T cells (Teff). Significantly more Teff cell numbers were detected in LD-SCLC patients than that of extended-stage SCLC (ED-SCLC). By contrast, induction of CD62LhighCD25+ CD4+ Treg cells was significantly higher in ED-SCLC patients. Long-term survivors of SCLC maintained a high Teff to Treg cell ratio, whereas patients with recurrent disease exhibited a low Teff to Treg cell ratio. Teff cells in LD-SCLC patients included more IL-17–producing CD4+ T cells (Th17). Moreover, dendritic cells derived from CD14+ cells of LD-SCLC patients secreted more IL-23.

Conclusion: These results show that CD4+ T-cell balance may be a biomarker that distinguishes ED-SCLC from LD-SCLC and predicts recurrence. This study also suggests the importance of inducing Teff cells, particularly Th17 cells, while eliminating Treg cells to control systemic dissemination of SCLC.
Systematic Review and Meta-analysis of Ovarian Cancers: Estimation of Microsatellite-High Frequency and Characterization of Mismatch Repair Deficient Tumor Histology
Authors: Pal Tuya , Permuth-Wey Jenny , Kumar Ambuj , Sellers Thomas A.
Published: November 2008

Purpose: A meta-analytic approach was used to estimate the frequency of: (a) microsatellite instability-high (MSI-H) phenotype in unselected ovarian cancers and (b) various histologic subtypes of mismatch repair (MMR)-deficient epithelial ovarian cancers.

Methods: A systematic search of the Medline electronic database was conducted to identify articles published between January 1, 1966, and December 31, 2007, that examined MMR deficiency in ovarian cancers. Data were extracted on the study population, sample size, MSI-H frequency, and histology of MMR-deficient ovarian tumors.

Results: The pooled proportion of MSI-H ovarian cancers was 0.12 [95% confidence interval (CI), 0.08-0.17] from 18 studies with 977 cases. The proportion of histologic subtypes in the pooled analysis from 15 studies with 159 cases was serous at 0.32 (95% CI, 0.20-0.44), mucinous at 0.19 (95% CI, 0.12-0.27), endometrioid at 0.29 (95% CI, 0.22-0.36), clear cell at 0.18 (95% CI, 0.09-0.28), and mixed at 0.24 (95% CI, 0.07-0.47). There was significant heterogeneity between studies.

Conclusions: The frequency of the MSI-H phenotype in unselected ovarian cancers approximates 12%. MMR-deficient ovarian cancers also seem to be characterized by an overrepresentation of nonserous histologic subtypes. Knowledge of histologic subtype may aid clinicians in identifying the relatively large proportion of ovarian cancers due to MMR defects; such knowledge has potential implications for medical management.
Effects of Erlotinib in EGFR Mutated Non-Small Cell Lung Cancers with Resistance to Gefitinib
Authors: Costa Daniel B. , Nguyen Kim-Son H. , Cho Byoung C. , Sequist Lecia V. , Jackman David M. , Riely Gregory J. , Yeap Beow Y. , Halmos Balázs , Kim Joo H. , Jänne Pasi A. , Huberman Mark S. , Pao William , Tenen Daniel G. , Kobayashi Susumu
Published: November 2008

Purpose: Most lung cancers with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib; however, resistance to this tyrosine kinase inhibitor (TKI) invariably ensues. The T790M mutation occurs in 50% and MET amplification in 20% of TKI-resistant tumors. Other secondary mutations (D761Y and L747S) are rare. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated patients resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib.

Experimental Design: Retrospective review of 18 EGFR mutated (exon 19 deletions, L858R, and L861Q) patients that were given gefitinib and subsequently erlotinib. Seven patients had tumor resampling after TKI therapy and were analyzed for secondary EGFR mutations and MET amplification.

Results: Most patients (14 of 18) responded to gefitinib with median progression-free survival of 11 months (95% confidence interval, 4-16). After gefitinib resistance (de novo or acquired), 78% (14 of 18) of these patients displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). Six of 7 resampled patients acquired the T790M mutation, and 0 of 3 had MET amplification. Only 1 gefitinib-resistant patient with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib.

Conclusions: In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most patients. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.
Multiple Myeloma with Myelomatous Pleural Effusion: A Case Report and Review of the Literature
Authors: Kim Yu Jin , Kim Su Jin , Min Kwangseon , Kim Ho Young , Kim Hyo Jung , Lee Young Kyung , Zang Dae Young
Published: November 2008

Multiple myeloma (MM) is a malignant neoplasm of plasma cell origin. Pleural effusion may develop in the setting of MM due to various reasons, but myelomatous pleural effusion (MPE) is rare. We report a case of MPE in a patient with advanced MM. A 76-year-old woman with MM was admitted to hospital because of dyspnea. Chest X-ray showed right-sided pleural effusion. Protein electrophoresis of the pleural fluid showed monoclonal protein, and cytology demonstrated monoclonal plasma cells. Hospice care was implemented, and the patient died one month later. We present an analysis of the clinical characteristics of 57 MPE cases reported in the English literature. Our review revealed that MPE patients had poor overall survival irrespective of whether MPE develops in the course of their disease or presents as the initial manifestation of MM. Based on this analysis, MPE is a poor prognostic factor, and aggressive treatment should be considered, especially for patients with early-onset MPE.
Incidental Unruptured Intracranial Aneurysms in Patients with Acute Ischemic Stroke
Authors: Oh Yoon-Sang , Lee Seung-Jae , Shon Young-Min , Yang Dong Won , Kim Beum Saeng , Cho A-Hyun
Published: November 2008

Background: The management and clinical prognosis of incidental intracranial aneurysms in acute ischemic stroke patients have been understudied. We investigated the clinical outcome of acute ischemic stroke subjects with incidentally found intracranial aneurysms. Methods: We consecutively included acute ischemic stroke patients within 7 days of onset. Their demographics, risk factors, stroke subtypes, antithrombotics use and modified Rankin scale (mRS) at 3 months after stroke were obtained. CT or MR angiography was used to diagnose the intracranial aneurysms. The development of an aneurysmal rupture was checked during the following 3 months. Results: Incidental intracranial aneurysms were found in 17 (6.6%) of the 258 patients. The female sex and old age were associated with the presence of incidental intracranial aneurysms (p = 0.001, 0.032). The most common site of aneurysm was at the distal internal carotid artery (n = 9), followed by the middle cerebral artery (n = 6). The diameters of the aneurysms ranged from 2.09 to 8.06 mm. All the participants except 1 who had cancer were taking antiplatelet agents. No aneurysmal rupture or subarachnoid hemorrhage happened until 3 months after stroke.There was no significant difference in excellent outcome (3-month mRS = 0, 1) between the patients with an aneurysm and those without (28.6 vs. 53.4%, p = 0.097). Conclusion: There was no rupture of the incidentally found aneurysms in the patients with acute ischemic stroke during their first 3 months. The 3-month mRS was not affected by the presence of incidental intracranial aneurysm. A large cohort study and long-term follow-up are required.
Perinatal Findings of Seckel Syndrome: A Case Report of a Fetus Showing Primordial Dwarfism and Severe Microcephaly
Authors: Takikawa Keiko Miyachi , Kikuchi Akihiko , Yokoyama Akiko , Ono Kyoko , Iwasawa Yuki , Sunagawa Sorahiro , Takagi Kimiyo , Kawame Hiroshi , Nakamura Tomohiko
Published: November 2008

Objective/Methods: Seckel syndrome is a rare form of primordial dwarfism and most of the previous reports have been limited to postnatal findings. We report on a fetus showing severe microcephaly, intrauterine growth restriction and a few gyri with shallow sulci on the fetal brain suggesting cortical dysplasia, followed by ultrasound and magnetic resonance imaging in the prenatal period. Results: Cardiotocograph revealed a reassuring fetal status throughout the whole pregnancy period. A male infant weighing 1,556 g was delivered at 39 weeks’ gestation, and a diagnosis of Seckel syndrome was made based on postnatal typical findings. Although previous reports on prenatal findings of Seckel syndrome are quite limited, we think that our case presents typical features of a fetus affected by this syndrome. Conclusions: When prenatal ultrasound shows severe microcephaly and intrauterine growth restriction, this rare syndrome should be included in the differential diagnosis. Moreover, magnetic resonance imaging of the affected fetal brain provides further diagnostic clues.
Agalsidase Alfa Slows the Decline in Renal Function in Patients with Fabry Disease
Authors: Feriozzi Sandro , Schwarting Andreas , Sunder-Plassmann Gere , West Michael , Cybulla Markus
Published: November 2008

The aim of this study was to determine the effects of enzyme replacement therapy with agalsidase α on renal function in patients with Fabry nephropathy. Serum creatinine data were collected from 165 adult patients during 3 years of treatment. Serum creatinine increased in all men whereas it was stable in women, except in stage II renal disease (Kidney Disease Outcomes Quality Initiative). The estimated glomerular filtration rate (eGFR) declined in males with stage I and II (from 115.0 ± 22.2 to 98.3 ± 27.3 and from 76.5 ± 8.1 to 66.3 ±21.6 ml/min/1.73 m2, respectively; both p < 0.01), whereas eGFR was stable in stage III. In females, eGFR was stable in stages I and III, and decreased in stage II (from 72.5 ± 8.3 to 67.3 ± 13.6 ml/min/1.73 m2; p = 0.01). The 24-hour proteinuria was <1 g in all patients, and most patients (96%) were treated with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors. Agalsidase α in combination with ACE inhibitors/ARB may be effective in slowing the deterioration in renal function in Fabry nephropathy.
Antiplatelet Therapy Use After Discharge Among Acute Myocardial Infarction Patients With In-Hospital Bleeding
Authors: Wang Tracy Y. , Xiao Lan , Alexander Karen P. , Rao Sunil V. , Kosiborod Mikhail N. , Rumsfeld John S. , Spertus John A. , Peterson Eric D.
Published: November 2008

Background—

Bleeding among patients with acute myocardial infarction (AMI) is associated with worse long-term outcomes. Although the mechanism underlying this association is unclear, a potential explanation is that withholding antiplatelet therapies long beyond resolution of the bleeding event may contribute to recurrent events.

Methods and Results—

We examined medication use at discharge, 1, 6, and 12 months after AMI among 2498 patients in the Prospective Registry Evaluating Myocardial Infarction: Events and Recovery (PREMIER) registry. Bleeding was defined as non–coronary artery bypass graft–related Thrombolysis of Myocardial Infarction major/minor bleeding or transfusion among patients with baseline hematocrit ≥28%. Logistic regression was used to evaluate the association between bleeding during the index AMI hospitalization and medication use. In-hospital bleeding occurred in 301 patients (12%) with AMI. Patients with in-hospital bleeding were less likely to be discharged on aspirin or thienopyridine (adjusted odds ratio=0.45; 95% CI, 0.31 to 0.64; and odds ratio=0.62; 95% CI, 0.42 to 0.91, respectively). At 1 month after discharge, although patients with in-hospital bleeding remained significantly less likely to receive aspirin (odds ratio=0.68; 95% CI, 0.50 to 0.92), use of thienopyridines in the 2 groups started to become similar. By 1 year, antiplatelet therapy use was similar among patients with and without bleeding. Postdischarge cardiology follow-up was associated with greater antiplatelet therapy use than either primary care or no clinical follow-up.

Conclusions—

Patients whose index AMI is complicated by bleeding are less likely to be treated with antiplatelet therapies during the first 6 months after discharge. Early reassessment of antiplatelet eligibility may represent an opportunity to reduce the long-term risk of adverse outcomes associated with bleeding.
Transcriptional Regulation of Bim by FOXO3a and Akt Mediates Scleroderma Serum–Induced Apoptosis in Endothelial Progenitor Cells
Authors: Zhu Shoukang , Evans Sarah , Yan Bin , Povsic Thomas J. , Tapson Victor , Goldschmidt-Clermont Pascal J. , Dong Chunming
Published: November 2008

Background—

Endothelial progenitor cells (EPCs) contribute to vascular regeneration/repair and thus may protect against scleroderma vasculopathy. We aimed to determine whether circulating EPCs were reduced in scleroderma, whether scleroderma sera could induce EPC apoptosis, and, if so, what the underlying apoptotic signaling pathway was.

Methods and Results—

Circulating EPC levels were quantified in 54 patients with scleroderma and 18 healthy control subjects by colony-forming unit assay and flow cytometry, which revealed markedly decreased EPC levels in scleroderma patients relative to healthy subjects. Substantial apoptosis was detected in EPCs after culturing in the presence of scleroderma sera compared with normal sera. Intriguingly, depletion of the IgG fraction from scleroderma sera completely abolished the apoptotic effects. Furthermore, scleroderma sera inhibited the activation/phosphorylation of Akt, which in turn suppressed the phosphorylation and degradation of forkhead transcription factor FKHRL1 (FOXO3a), resulting in the upregulation of apoptotic protein Bim. siRNA-mediated FOXO3a and Bim knockdown substantially reduced scleroderma serum–induced EPC apoptosis. Importantly, Bim expression and baseline apoptosis were increased in EPCs freshly isolated from scleroderma patients relative to that obtained from healthy subjects.

Conclusion—

Scleroderma serum–induced EPC apoptosis is mediated chiefly by the Akt-FOXO3a-Bim pathway, which may account, at least in part, for the decreased circulating EPC levels in scleroderma patients.
Inhibition of Protein Kinase Cβ Prevents Foam Cell Formation by Reducing Scavenger Receptor A Expression in Human Macrophages
Authors: Osto Elena , Kouroedov Alexei , Mocharla Pavani , Akhmedov Alexander , Besler Christian , Rohrer Lucia , von Eckardstein Arnold , Iliceto Sabino , Volpe Massimo , Lüscher Thomas F. , Cosentino Francesco
Published: November 2008

Background—

Low-density lipoprotein (LDL) uptake by monocyte-derived macrophages is a crucial step in foam cell formation and early atherosclerotic lesion. Increasing evidence supports the theory that activation of protein kinase Cβ (PKCβ) is involved in many mechanisms promoting atherosclerosis. Thus, we investigated whether inhibition of PKCβ prevents foam cell formation.

Methods and Results—

The differentiation of human primary monocytes or the monocytic THP-1 cell line into monocyte-derived macrophages was induced by phorbol 12-myristate 13-acetate (PMA; 0.1 mmol/L), a potent activator of PKC. Incubation of monocyte-derived macrophages with DiI-modified LDL (acetylated LDL and oxidized LDL, 10 μg/mL) led to lipoprotein uptake. Interestingly enough, the nonselective inhibitor of PKCβ
1
and PKCβ
2
, LY379196 (5×10
−7
to 10
−5
mol/L), blunted LDL uptake in monocyte-derived macrophages as shown by flow cytometry. Specific siRNA-mediated knockdown of PKCβ exerted a similar effect. Furthermore, PMA alone and in the presence of modified LDL induced scavenger receptor A mRNA and protein expression, which was abolished by LY379196. CGP53353, a selective inhibitor of PKCβ
2
, did not affect LDL uptake, nor did it prevent scavenger receptor A upregulation. Incubation of monocyte-derived macrophages with PMA/LDL increased PKCβ
1
phosphorylation at the Thr-642 residue, which was blunted by LY379196. However, the expression of CD68, a marker of activated macrophages, was not affected by LY379196. Moreover, LY379196 did not affect lipopolysaccharide-induced CD14 degradation, tumor necrosis factor-α release, or superoxide anion production, ruling out any effect of PKCβ inhibition on innate immunity.

Conclusions—

Nonspecific inhibition of PKCβ prevents LDL uptake in macrophages. These findings suggest that PKCβ inhibitors may represent a novel class of antiatherosclerotic drugs.
Increased Vascular Senescence and Impaired Endothelial Progenitor Cell Function Mediated by Mutation of Circadian Gene
Per2
Authors: Wang Chao-Yung , Wen Ming-Shien , Wang Hong-Wei , Hsieh I-Chang , Li Yuxin , Liu Ping-Yen , Lin Fun-Chung , Liao James K.
Published: November 2008

Background—

Alteration of the circadian rhythm and increased vascular senescence are linked to cardiovascular disease.
Per2
, a circadian gene, is known to regulate endothelium-dependent vasomotion. However, the mechanism by which
Per2
affects endothelial function is unknown. We hypothesize that endothelial dysfunction in
Per2
mutant (Per2
m/m
) mice is mediated in part by increased vascular senescence and impaired endothelial progenitor cell (EPC) function.

Methods and Results—

Endothelial cells from Per2
m/m
mice exhibit increased protein kinase Akt signaling, greater senescence, and impaired vascular network formation and proliferation. Indeed, Per2
m/m
mice have impaired blood flow recovery and developed autoamputation of the distal limb when subjected to hind-limb ischemia. Furthermore, matrigel implantation into Per2
m/m
mice resulted in less neovascularization. Because EPCs contribute to angiogenesis, we studied the role of
Per2
in these cells using bone marrow transplantation. Basal EPC levels were similar between wild-type and Per2
m/m
mice. However, compared with wild-type bone marrow transplantation mice, EPC mobilization was impaired in Per2
m/m
bone marrow transplantation mice in response to ischemia or VEGF stimulation. Bone marrow transplantation or infusion of wild-type EPC restored blood flow recovery and prevented autoamputation in Per2
m/m
mice.

Conclusion—

These findings indicate that mutation of
Per2
causes Akt-dependent senescence and impairs ischemia-induced revascularization through the alteration of EPC function.
Hypertension in Response to Chronic Reductions in Uterine Perfusion in Pregnant Rats
Authors: LaMarca Babbette , Speed Josh , Fournier Lillian , Babcock Sara A. , Berry Hunter , Cockrell Kathy , Granger Joey P.
Published: November 2008

Reductions in uterine perfusion pressure (RUPP) in pregnant rats is associated with increased tumor necrosis factor-α (TNF-α). This study was designed to determine the role of endogenous TNF-α in mediating changes in arterial pressure and endothelin-1 (ET-1) in RUPP rats. To achieve this goal we examined the effect of RUPP in the presence and absence of a TNF-α-soluble receptor, etanerecept (0.4 mg/kg). Mean arterial pressure increased from 102±1 mm Hg in normal pregnant (NP) rats to 134±3 mm Hg (
P
<0.05) in RUPP rats. Serum TNF-α increased to 40±7.6 pg/mL in RUPP rats (n=24) versus 14.8±3.3 pg/mL (n=16;
P
<0.05) in NP rats. Administration of etanerecept decreased TNF-α in RUPP rats (n=20) to 17.2±3 pg/mL and mean arterial pressure to 118±2 mm Hg (
P
<0.05). Tissue ET-1 decreased in etanerecept-treated RUPP rats compared with control RUPP rats. The direct effect of TNF-α blockade on endothelial activation in response to placental ischemia was examined in human umbilical vein endothelial cells. ET-1 secreted from human umbilical vein endothelial cells treated with RUPP serum was 59.2+16 pg/mg and decreased when etanerecept was added to the medium with RUPP serum (7.60±0.77 pg/mg), as well as in response to serum from etanerecept-treated RUPP rats (7.30±0.55 pg/mg;
P
<0.001). ET-1 secreted from human umbilical vein endothelial cells was 15.6±2 pg/mg when treated with NP serum. These data support the hypothesis that endogenous TNF-α is an important stimulus for ET-1 in response to placental ischemia and is important in mediating endothelial cell activation and hypertension during pregnancy.
Prenegotiation and Mediation: Anglo-Argentine Diplomacy After the Falklands/Malvinas War, 1983–1989
Authors: Corbacho Alejandro Luis
Published: November 2008

This paper studies the process of prenegotiation and the role of mediators between the Argentine and British governments concerning the sovereignty dispute of the Falkland/Malvinas Islands between 1982 and 1990. During this period, the relationship between both governments evolved from rupture and norelations to an agreement on the conditions to negotiate the renewal of full diplomatic relations which was concluded in early 1990. In a preliminary process of prenegotiation, the governments of Switzerland, initially, and the United States played a role in helping to reach an agreement. The former failed when the talks ended abruptly in July 1984. The latter succeeded in getting both parties to the table and keeping them there, thus avoiding a potential rupture until the two parties reached an agreement in principle. During the prenegotiation stage, the principal parties were able to reduce the risks of escalation; they defined and narrowed the boundaries of the dispute, clearly identified the trade-offs, and structured the agenda of formal negotiations. Consequently, the likelihood of successful negotiation improves significantly when the parties reach an agreement during prenegotiation on what will be discussed later. This case also illustrate that sometimes, when negotiations reach a point of stalemate, a mediator can help to find a “zone of agreement.” When this situation occurs, the degree of involvement and the resources of the mediator are particularly important. Finally, this case confirms the assertions that effective mediation is more a matter of leverage and influence than a matter of impartiality.
Drop Size Distributions and the Lack of Small Drops in RICO Rain Shafts
Authors: Baker Brad , Mo Qixu , Lawson R. Paul , O’Connor Darren , Korolev Alexei
Published: November 2008

Data from the new two-dimensional stereo (2D-S) probe are used to evaluate drop size distributions in rain shafts observed during the Rain in Shallow Cumulus over the Ocean (RICO) experiment. The 2D-S takes images of both precipitation drops and cloud droplets with 10-μm resolution. These are the first reported measurements of rain to include sizes smaller than 100 μm. The primary result is that there are almost no hydrometeors smaller than about 100 μm in these rain shafts. The measured low concentration of small hydrometeors implies that their rate of production is slow relative to their removal rate. Algorithms for removing the spurious effects of splashing precipitation and noisy photodiodes on 2D probes are also described.
Regionalization of Climate Change Simulations over the Eastern Mediterranean
Authors: Önol Bariş , H. M. Semazzi Fredrick
Published: November 2008

In this study, the potential role of global warming in modulating the future climate over the eastern Mediterranean (EM) region has been investigated. The primary vehicle of this investigation is the Abdus Salam International Centre for Theoretical Physics Regional Climate Model version 3 (ICTP-RegCM3), which was used to downscale the present and future climate scenario simulations generated by the NASA’s finite-volume GCM (fvGCM). The present-day (1961–90; RF) simulations and the future climate change projections (2071–2100; A2) are based on the Intergovernmental Panel on Climate Change (IPCC) greenhouse gas (GHG) emissions. During the Northern Hemispheric winter season, the general increase in precipitation over the northern sector of the EM region is present both in the fvGCM and RegCM3 model simulations. The regional model simulations reveal a significant increase (10%–50%) in winter precipitation over the Carpathian Mountains and along the east coast of the Black Sea, over the Kackar Mountains, and over the Caucasus Mountains. The large decrease in precipitation over the southeastern Turkey region that recharges the Euphrates and Tigris River basins could become a major source of concern for the countries downstream of this region. The model results also indicate that the autumn rains, which are primarily confined over Turkey for the current climate, will expand into Syria and Iraq in the future, which is consistent with the corresponding changes in the circulation pattern. The climate change over EM tends to manifest itself in terms of the modulation of North Atlantic Oscillation. During summer, temperature increase is as large as 7°C over the Balkan countries while changes for the rest of the region are in the range of 3°–4°C. Overall the temperature increase in summer is much greater than the corresponding changes during winter. Presentation of the climate change projections in terms of individual country averages is highly advantageous for the practical interpretation of the results. The consistence of the country averages for the RF RegCM3 projections with the corresponding averaged station data is compelling evidence of the added value of regional climate model downscaling.
Nonnormal Multidecadal Response of the Thermohaline Circulation Induced by Optimal Surface Salinity Perturbations
Authors: Sévellec Florian , Huck Thierry , Ben Jelloul Mahdi , Vialard Jérôme
Published: November 2008

Optimal perturbations of sea surface salinity are obtained for an idealized North Atlantic basin using a 3D planetary geostrophic model—optimality is defined with respect to the intensity of the meridional overturning circulation. Both optimal initial and stochastic perturbations are computed in two experiments corresponding to two different formulations of the surface boundary conditions: the first experiment uses mixed boundary conditions (i.e., restoring surface temperature and prescribed freshwater flux), whereas the second experiment uses flux boundary conditions for both temperature and salinity. The latter reveals greater responses to both initial and stochastic perturbations that are related to the existence of a weakly damped oscillatory eigenmode of the Jacobian matrix, the optimal perturbations being closely related to its biorthogonal. The optimal initial perturbation induces a transient modification of the circulation after 24 yr. The spectral response to the optimal stochastic perturbation reveals a strong peak at 35 yr, corresponding to the period of this oscillatory eigenmode. This study provides an upper bound of the meridional overturning response at multidecadal time scales to freshwater flux perturbation: for typical amplitudes of Great Salinity Anomalies, initial perturbations can alter the circulation by +2.25 Sv (1 Sv ≡ 106 m3 s−1; i.e., 12.5% of the mean circulation) at most; stochastic perturbations with amplitudes typical of the interannual variability of the freshwater flux in midlatitudes induce a circulation variability with a standard deviation of 1 Sv (i.e., 5.5% of the mean circulation) at most.
Sampling Errors in Ensemble Kalman Filtering. Part II: Application to a Barotropic Model
Authors: Sacher William , Bartello Peter
Published: November 2008

In the current study, the authors are concerned with the comparison of the average performance of stochastic versions of the ensemble Kalman filter with and without covariance inflation, as well as the double ensemble Kalman filter. The theoretical results obtained in Part I of this study are confronted with idealized simulations performed with a perfect barotropic quasigeostrophic model. Results obtained are very consistent with the analytic expressions found in Part I. It is also shown that both the double ensemble Kalman filter and covariance inflation techniques can avoid filter divergence. Nevertheless, covariance inflation gives efficient results in terms of accuracy and reliability for a much lower computational cost than the double ensemble Kalman filter and for smaller ensemble sizes.
Dynamical Extended-Range Prediction of Early Monsoon Rainfall over India
Authors: Vitart Frédéric , Molteni Franco
Published: November 2008

The 15-member ensembles of 46-day dynamical forecasts starting on each 15 May from 1991 to 2007 have been produced, using the ECMWF Variable Resolution Ensemble Prediction System monthly forecasting system (VarEPS-monthy). The dynamical model simulates a realistic interannual variability of Indian precipitation averaged over the month of June. It also displays some skill to predict Indian precipitation averaged over pentads up to a lead time of about 30 days. This skill exceeds the skill of the ECMWF seasonal forecasting System 3 starting on 1 June. Sensitivity experiments indicate that this is likely due to the higher horizontal resolution of VarEPS-monthly. Another series of sensitivity experiments suggests that the ocean–atmosphere coupling has an important impact on the skill of the monthly forecasting system to predict June rainfall over India.
Medium-Range Quantitative Precipitation Forecasts from Canada’s New 33-km Deterministic Global Operational System
Authors: Bélair Stéphane , Roch Michel , Leduc Anne-Marie , Vaillancourt Paul A. , Laroche Stéphane , Mailhot Jocelyn
Published: November 2008

The Meteorological Service of Canada (MSC) recently implemented a 33-km version of the Global Environmental Multiscale (GEM) model, with improved physics, for medium-range weather forecasts. Quantitative precipitation forecasts (QPFs) from this new system were compared with those from the previous global operational system (100-km grid size) and with those from MSC’s short-range (48 h) regional system (15-km grid size). The evaluation is based on performance measures that evaluate bias, accuracy, and the value of the QPFs.

Results presented in this article consistently show, for these three aspects of the evaluation, that the new global forecast system (GLBNEW) agrees more closely with observations, relative to the performance of the previous global system (GLBOLD). The biases are noticeably smaller with GLBNEW compared with GLBOLD, which severely overpredicts (underpredicts) the frequencies and total amounts associated with weak (strong) precipitation intensities. The accuracy and value scores reveal gains of at least 12 h and even up to 72 h for medium-range QPFs (i.e., day 3 to day 5 predictions). The new global system even performs slightly better than MSC’s operational regional 15-km system for short-range QPFs.

In a more absolute manner, results suggest that QPFs from the new global system may still have accuracy and value even at the medium range. This seems to be true at least for the smallest precipitation threshold, related to precipitation occurrence, for which the positive area under curves of relative economic value remains important, even for day 5 QPFs.
Projecting Prison Populations Starting With Projected Admissions
Authors: Martinez Pablo E.
Published: November 2008

In this article, a methodology is presented to apply the laws and policies regulating releases from prison and to project the prison population that results from offenders newly admitted into the prison system. The model is a disaggregated flow simulation model that uses Microsoft Excel but can be set up in any electronic worksheet system. Offenders are grouped into unique categories that share common release laws, based on offense categories and sentence lengths. Survival tables are calculated using recently released offenders from prison to estimate future releases. The resulting projected population is only part of the entire population. To calculate the total projected population, the number of offenders resulting from admissions to prison is added to the population that remains in prison from those who are incarcerated at the time the projection begins.
Parental Substance Abuse and Child Well-Being
Authors: Osborne Cynthia , Berger Lawrence M.
Published: November 2008

Parental substance abuse is associated with adverse health and developmental outcomes for children. Existing research, however, has not fully explored the relative magnitude of the associations between maternal, paternal, and both parents' substance abuse and child outcomes, nor has it examined these associations in regard to substance abuse among nonresident fathers. We use data from the Fragile Families and Child Wellbeing Study ( N = 3,027) to explore these issues among a cohort of 3-year-old children. We find that children living with a substance-abusing parent are at considerable risk for poor health and behavior outcomes, that such risk is not moderated by parent gender, and that it is substantially larger when both parents have substance abuse problems. Moreover, children with substance-abusing fathers are at a potentially higher risk of health and behavior problems when their fathers live with them, although this risk is still substantial when they do not.
Nonclinical Safety Evaluation of Sunitinib: A Potent Inhibitor of VEGF, PDGF, KIT, FLT3, and RET Receptors
Authors: Patyna Shem , Arrigoni Claudio , Terron Andrea , Kim Tae-Won , Heward Joyce K. , Vonderfecht Steven L. , Denlinger Robert , Turnquist Susan E. , Evering Winston
Published: November 2008

Sunitinib malate (SUTENT) is a multitargeted receptor tyrosine kinase (RTK) inhibitor that is approved multinationally for the treatment of imatinib-resistant/-intolerant gastrointestinal stromal tumor and advanced renal cell carcinoma. This paper characterizes the organ toxicity of sunitinib in Sprague-Dawley rats and cynomolgus monkeys, and the reversibility of any treatment-induced effects. Rats and monkeys received sunitinib (0–15 and 0–20 mg/kg/day, respectively) orally on a consecutive daily dosing schedule for thirteen weeks or on an intermittent daily dosing schedule for up to nine months. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. In rats, sunitinib was generally tolerated at 0.3 and 1.5 mg/kg/day, and findings were reversible. In monkeys, the level at which there were no observed adverse effects was 1.5 mg/kg/day, and findings were similarly reversible (except for uterine/ovarian weight changes and skin pallor). Data suggest that inhibition of multiple RTK pathways may induce pharmacologic effects on organ systems in nonclinical species. Key pharmacologic effects of sunitinib included reversible inhibition of neovascularization into the epiphyseal growth plate, and impaired corpora lutea formation and uterine development during estrus. Similar observations have been noted with this class of RTK signaling inhibitors and are consistent with pharmacologic perturbations of physiologic/angiogenic processes associated with the intended molecular targets.
Cancer Patients Versus Cancer Survivors
Authors: Mosher Catherine E. , Danoff-Burg Sharon
Published: November 2008

Two studies examined the social and emotional implications of different linguistic classifications of individuals with cancer. Undergraduates were randomly assigned to rate their reactions to either cancer patients or cancer survivors. Across studies, participants held more favorable perceptions of the character of cancer survivors relative to cancer patients and displayed more positive attitudes toward the former group. In addition, participants in Study 1 reported greater willingness to interact with cancer survivors compared with cancer patients. Positive perceptions of prognosis did not appear to account for favorable attitudes toward cancer survivors; most participants in Study 2 did not assume that cancer survivors were beyond the treatment phase of their illness or cured of their disease. Findings point to a potentially powerful effect of word choice on reactions to individuals with cancer.
Possible Pathogenic Link Between Migraine and Urotensin-II
Authors: Bicak Ugur , Karabiber Hamza , Ozerol Halil I. , Aslan Mehmet , Ilhan Atilla , Yakinci Cengiz
Published: November 2008

Our aim was to determine the levels of human urotensin-II (hU-II) in the plasma of migraine patients and controls, to ascertain if there were a difference in the pathogenesis of migraine. A total of 27 patients who suffer from migraines and 27 controls were included in the study. Venous blood samples were drawn twice both from migraine patients and controls to measure hU-II plasma levels. The average levels of hU-II during migraine episode, between episodes, and controls were found to be 0.483, 0.493, and 0.737 pg/mL, respectively. The levels of hU-II in the controls were higher significantly. When comparisons were made according to sex, age groups, and types and durations of migraine, there was no significant difference in the levels of hU-II in the patients. The low levels of hU-II in the plasma of migraine patients compared with controls may be an indicator of its role in the pathogenesis.
Circumstances Surrounding Male Sexual Assault and Rape
Authors: Light David , Monk-Turner Elizabeth
Published: November 2008

Much work in the area of male sexual assault and rape relies on small clinical samples. From these samples, researchers reported that most male victims were physically injured during the attack and that penetration occurred. This work rests on a subsample of 219 men from the 1994-1996 Violence and Threats of Violence Against Women and Men in the United States Survey. Findings from the National Violence Against Women Survey (NVAW) show that the vast majority of male sexual assault victims reported that they were not physically injured during the assault, that a weapon was not used, that there was no substance use at the time of the assault, and that penetration did not occur. Only 29% of male respondents in the NVAW sought medical or psychological help after the assault. Prior work may have overrepresented men who reported being physically injured and/or penetrated. An analysis is presented of how those who presented for help in the NVAW differ from the whole sample. Results show that men who presented for help were more likely to have reported being physically injured during the assault and that penetration occurred. Thus, findings from prior work make sense; however, they may not be representative of male assault victims as a whole.
Science-Media Interface
Authors: Peters Hans Peter , Brossard Dominique , de Cheveigné Suzanne , Dunwoody Sharon , Kallfass Monika , Miller Steve , Tsuchida Shoji
Published: November 2008

An international mail survey of 1,354 biomedical researchers in five countries has revealed that interaction with the media is widespread among this group and that this interaction is largely perceived in a positive light. Possible reasons are offered as to why the perception persists that the scientist-journalist relationship remains troubled, despite the apparent reality. This reality may have negative as well as positive implications; the potential for too much control by the scientific community of media coverage about it, as well as that for too much media influence on inner-scientific processes, are also addressed.
The State of Science Communication Programs at Universities Around the World
Authors: Mulder Henk A. J. , Longnecker Nancy , Davis Lloyd S.
Published: November 2008

Building on discussions at two workshops held at the recent 10th International Conference on the Public Communication of Science and Technology during June 2008 in Malmö, Sweden, this article proposes specific steps toward achieving a common understanding of the essential elements for academic programs in science communication. About 40 academics, science communication professionals, and students from at least 16 countries participated in this process.