bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective evaluation of non-interval- and interval-based exercise training progressions in rodents
Authors: Jendzjowsky Nicholas G. , DeLorey Darren S.
Published: October 2011

Non-interval and interval training progressions were used to determine (i) the mean rate at which treadmill speed could be incremented daily using a non-interval training progression to train rats to run continuously at different intensities and (ii) the number of training days required for rats to run continuously at different exercise intensities with non-interval- and interval-based training progressions to establish methods of progressive overload for rodent exercise training studies. Rats were randomly assigned to mild-intensity (n = 5, 20 m·min–1, 5% grade), moderate-intensity (n = 5, 30 m·min–1, 5% grade), and heavy-intensity non-interval groups (n = 5, 40 m·min–1, 5% grade) or a heavy-intensity interval (n = 5, 40 m·min–1, 5% grade) group and ran 5 days·week–1 for 6 weeks. Non-interval training involved a daily increase of treadmill speed, whereas interval training involved a daily increase of interval time, until the animal could run continuously at a prescribed intensity. In mild-, moderate-, and heavy-intensity non-interval-trained rats, treadmill speed was increased by 0.6 ± 0.7  m·min–1·day–1, 0.6 ± 0.2  m·min–1·day–1, and 0.8 ± 0.1 m·min–1·day–1, respectively. Target training intensity and duration were obtained following 0.4 ± 0.5 days, 17 ± 3 days, and 23 ± 3 training days (p < 0.05) in mild-, moderate-, and heavy-intensity groups, respectively. In contrast, interval-trained rodents required 11 ± 1 training days. These data demonstrate that rodents will tolerate an increase in treadmill speed of ∼0.7 ± 0.1 m·min–1·day–1 and that this progression enables rats to run continuously at moderate and heavy intensities with 3–4 weeks of progressive overload. Interval training significantly reduces the number of training days required to attain a target intensity.
Evidence that the association between exercise intensity and insulin sensitivity is sex dependent
Authors: Hougham Kaitlyn A. , Ross Robert
Published: October 2011

The purpose of this study was to determine if, after adjusting for the contribution of exercise dose, exercise intensity was associated with the improvement of insulin sensitivity. Abdominally obese, sedentary men (n = 16, (mean ± SD) age 45.0 ± 7.5 years, waist circumference 108.6 ± 5.3 cm) and women (n = 18, (mean ± SD) age 42.3 ± 6.2 years, waist circumference 100.1 ± 8.2 cm) performed daily, supervised exercise for 3 and 4 months, respectively. Exercising at a self-selected exercise intensity, men were required to expend 700 kcal per session and women 500 kcal per session. Exercise intensity and dose were determined using heart rate and oxygen consumption data obtained from repeated graded exercise tests. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamp. Insulin sensitivity improved in both men and women (change scores: men 7.2 ± 5.4 mg·(kg skeletal muscle (skm))–1·min–1; women 5.8 ± 7.1 mg·(kg skm)–1·min–1; p < 0.05). Exercise intensity was associated with the improvement of insulin sensitivity in men (unstandardized regression coefficient (β) = 0.43, p = 0.02). Adjusting for exercise dose, total abdominal adipose tissue (AT), or visceral AT did not alter this association (p < 0.05). Exercise intensity was not associated with the improvement of insulin sensitivity in women (β = –0.11, p = 0.7). Adjusting for exercise dose, total abdominal AT, or visceral AT did not change this association in women (p > 0.05). Our findings suggest that exercise intensity is independently associated with the improvement of insulin sensitivity in abdominally obese men but not women.
Force produced by isolated sarcomeres and half-sarcomeres after an imposed stretch
Authors: Rassier Dilson E. , Pavlov Ivan
Published: October 2011

When a stretch is imposed to activated muscles, there is a residual force enhancement that persists after the stretch; the force is higher than that produced during an isometric contraction in the corresponding length. The mechanisms behind the force enhancement remain elusive, and there is disagreement if it represents a sarcomeric property, or if it is associated with length nonuniformities among sarcomeres and half-sarcomeres. The purpose of this study was to investigate the effects of stretch on single sarcomeres and myofibrils with predetermined numbers of sarcomeres ( n = 2, 3. . . , 8) isolated from the rabbit psoas muscle. Sarcomeres were attached between two precalibrated microneedles for force measurements, and images of the preparations were projected onto a linear photodiode array for measurements of half-sarcomere length (SL). Fully activated sarcomeres were subjected to a stretch (5–10% of initial SL, at a speed of 0.3 μm·s−1·SL−1) after which they were maintained isometric for at least 5 s before deactivation. Single sarcomeres showed two patterns: 31 sarcomeres showed a small level of force enhancement after stretch (10.46 ± 0.78%), and 28 sarcomeres did not show force enhancement (−0.54 ± 0.17%). In these preparations, there was not a strong correlation between the force enhancement and half-sarcomere length nonuniformities. When three or more sarcomeres arranged in series were stretched, force enhancement was always observed, and it increased linearly with the degree of half-sarcomere length nonuniformities. The results show that the residual force enhancement has two mechanisms: 1) stretch-induced changes in sarcomeric structure(s); we suggest that titin is responsible for this component, and 2) stretch-induced nonuniformities of half-sarcomere lengths, which significantly increases the level of force enhancement.
KV2.1 and electrically silent KV channel subunits control excitability and contractility of guinea pig detrusor smooth muscle
Authors: Hristov Kiril L. , Chen Muyan , Soder Rupal P. , Parajuli Shankar P. , Cheng Qiuping , Kellett Whitney F. , Petkov Georgi V.
Published: October 2011

Voltage-gated K+ (KV) channels are implicated in detrusor smooth muscle (DSM) function. However, little is known about the functional role of the heterotetrameric KV channels in DSM. In this report, we provide molecular, electrophysiological, and functional evidence for the presence of KV2.1 and electrically silent KV channel subunits in guinea pig DSM. Stromatoxin-1 (ScTx1), a selective inhibitor of the homotetrameric KV2.1, KV2.2, and KV4.2 as well as the heterotetrameric KV2.1/6.3 and KV2.1/9.3 channels, was used to examine the role of these KV channels in DSM function. RT-PCR indicated mRNA expression of KV2.1, KV6.2–6.3, KV8.2, and KV9.1–9.3 subunits in isolated DSM cells. KV2.1 protein expression was confirmed by Western blot and immunocytochemistry. Perforated whole cell patch-clamp experiments revealed that ScTx1 (100 nM) inhibited the amplitude of the KV current in freshly isolated DSM cells. ScTx1 (100 nM) did not significantly change the steady-state activation and inactivation curves for KV current. However, ScTx1 (100 nM) decreased the activation time-constant of the KV current at positive voltages. Although our patch-clamp data could not exclude the presence of the homotetrameric KV2.1 channels, the biophysical characteristics of the ScTx1-sensitive current were consistent with the presence of heterotetrameric KV2.1/silent KV channels. Current-clamp recordings showed that ScTx1 (100 nM) did not change the DSM cell resting membrane potential. ScTx1 (100 nM) increased the spontaneous phasic contraction amplitude, muscle force, and muscle tone as well as the amplitude of the electrical field stimulation-induced contractions of isolated DSM strips. Collectively, our data revealed that KV2.1-containing channels are important physiological regulators of guinea pig DSM excitability and contractility.
Mechanisms of lysophosphatidylcholine-induced hepatocyte lipoapoptosis
Authors: Kakisaka Keisuke , Cazanave Sophie C. , Fingas Christian D. , Guicciardi Maria E. , Bronk Steven F. , Werneburg Nathan W. , Mott Justin L. , Gores Gregory J.
Published: October 2011

Isolated hepatocytes undergo lipoapoptosis, a feature of hepatic lipotoxicity, on treatment with saturated free fatty acids (FFA) such as palmitate (PA). However, it is unknown if palmitate is directly toxic to hepatocytes or if its toxicity is indirect via the generation of lipid metabolites such as lysophosphatidylcholine (LPC). PA-mediated hepatocyte lipoapoptosis is associated with endoplasmic reticulum (ER) stress, c-Jun NH2-terminal kinase (JNK) activation, and a JNK-dependent upregulation of the potent proapoptotic BH3-only protein PUMA (p53 upregulated modulator of apoptosis). Our aim was to determine which of these mechanisms of lipotoxicity are activated by PA-derived LPC. We employed Huh-7 cells and isolated murine and human primary hepatocytes. Intracellular LPC concentrations increase linearly as a function of the exogenous, extracellular PA, stearate, or LPC concentration. Incubation of Huh-7 cells or primary hepatocytes with LPC induced cell death by apoptosis in a concentration-dependent manner. Substituting LPC for PA resulted in caspase-dependent cell death that was accompanied by activating phosphorylation of JNK with c-Jun phosphorylation and an increase in PUMA expression. LPC also induced ER stress as manifest by eIF2α phosphorylation and CAAT/enhancer binding homologous protein (CHOP) induction. LPC cytotoxicity was attenuated by pharmacological inhibition of JNK or glycogen synthase kinase-3 (GSK-3). Similarly, short-hairpin RNA (shRNA)-targeted knockdown of CHOP protected Huh-7 cells against LPC-induced toxicity. The LPC-induced PUMA upregulation was prevented by JNK inhibition or shRNA-targeted knockdown of CHOP. Finally, genetic deficiency of PUMA rendered murine hepatocytes resistant to LPC-induced apoptosis. We concluded that LPC-induced lipoapoptosis is dependent on mechanisms largely indistinguishable from PA. These data suggest that FFA-mediated cytotoxicity is indirect via the generation of the toxic metabolite, LPC.
Inhibition of Mas G-protein signaling improves coronary blood flow, reduces myocardial infarct size, and provides long-term cardioprotection
Authors: Zhang Tong , Li Zhuangjie , Dang Huong , Chen Ruoping , Liaw Chen , Tran Thuy-Anh , Boatman P. Douglas , Connolly Daniel T. , Adams John W.
Published: October 2011

The Mas receptor is a class I G-protein-coupled receptor that is expressed in brain, testis, heart, and kidney. The intracellular signaling pathways activated downstream of Mas are still largely unknown. In the present study, we examined the expression pattern and signaling of Mas in the heart and assessed the participation of Mas in cardiac ischemia-reperfusion injury. Mas mRNA and protein were present in all chambers of human hearts, with cardiomyocytes and coronary arteries being sites of enriched expression. Expression of Mas in either HEK293 cells or cardiac myocytes resulted in constitutive coupling to the Gq protein, which in turn activated phospholipase C and caused inositol phosphate accumulation. To generate chemical tools for use in probing the function of Mas, we performed a library screen and chemistry optimization program to identify potent and selective nonpeptide agonists and inverse agonists. Mas agonists activated Gq signaling in a dose-dependent manner and reduced coronary blood flow in isolated mouse and rat hearts. Conversely, treatment of isolated rat hearts with Mas inverse agonists improved coronary flow, reduced arrhythmias, and provided cardioprotection from ischemia-reperfusion injury, an effect that was due, at least in part, to decreased cardiomyocyte apoptosis. Participation of Mas in ischemia-reperfusion injury was confirmed in Mas knockout mice, which had reduced infarct size relative to mice with normal Mas expression. These results suggest that activation of Mas during myocardial infarction contributes to ischemia-reperfusion injury and further suggest that inhibition of Mas-Gq signaling may provide a new therapeutic strategy directed at cardioprotection.
Life-long consequences of postnatal normoxia exposure in rats raised at high altitude
Authors: Lumbroso Delphine , Lemoine Alexandra , Gonzales Marcelino , Villalpando Gabriela , Seaborn Tommy , Joseph Vincent
Published: October 2011

We tested the hypothesis that exposure of high-altitude (HA) rats to a period of postnatal normoxia has long-term consequences on the ventilatory and hematological acclimatization in adults. Male and female HA rats (3,600 m, Po2≃ 100 Torr; La Paz, Bolivia) were exposed to normal room air [HA control (HACont)] or enriched oxygen (32% O2; Po2≃ 160 Torr) from 1 day before to 15 days after birth [HA postnatal normoxia (HApNorm)]. Hematocrit and hemoglobin values were assessed at 2, 12, and 32 wk of age. Cardiac and lung morphology were assessed at 12 wk by measuring right ventricular hypertrophy (pulmonary hypertension index) and lung air space-to-tissue ratio (indicative of alveolarization). Respiratory parameters under baseline conditions and in response to 32% O2for 10 min (relieving the ambient hypoxic stimulus) were measured by whole body plethysmography at 12 wk. Finally, we performed a survival analysis up to 600 days of age. Compared with HACont, HApNorm rats had reduced hematocrit and hemoglobin levels at all ages (both sexes); reduced right ventricular hypertrophy (both sexes); lower air space-to-tissue ratio in the lungs (males only); reduced CO2production rate, but higher oxygen uptake (males only); and similar respiratory frequency, tidal volume, and minute ventilation. When breathing 32% O2, HApNorm male rats had a stronger decrease of minute ventilation than HACont. HApNorm rats had a marked tendency toward longer survival throughout the study. We conclude that exposure to ambient hypoxia during postnatal development in HA rats has deleterious consequences on acclimatization to hypoxia as adults.
Order-disorder phenomena from X-ray diffraction in FeCo alloys annealed and ground at high energy
Authors: Loureiro J. M. , Batista A. C. , Khomchenko V. A. , Costa B. F. O. , Le Caër G.
Published: October 2011

Order-disorder transformations were studied in annealed and high-energy ball-milled near-equiatomic FeCo alloys. X-ray diffraction with Co Kα radiation enables to follow disordering with milling time because of anomalous dispersion.
Ambient-temperature powder diffraction data for benzocaine hydrochloride and a monoclinic polymorph of benzocaine base
Authors: Rendle D. F. , Rogers K. D. , Beckett S.
Published: October 2011

Powder diffraction data are presented for two compounds of forensic importance: benzocaine hydrochloride and a monoclinic polymorph of benzocaine base. Data were collected at room temperature using nickel-filtered Cu Kα radiation.
A Novel Aldehyde Dehydrogenase-3 Activator Leads to Adult Salivary Stem Cell EnrichmentIn Vivo
Authors: Banh Alice , Xiao Nan , Cao Hongbin , Chen Che-Hong , Kuo Peiwen , Krakow Trevor , Bavan Brindha , Khong Brian , Yao Mike , Ha Chi , Kaplan Michael J. , Sirjani Davud , Jensen Kristin , Kong Christina S. , Mochly-Rosen Daria , Koong Albert C. , Le Quynh-Thu
Published: October 2011

Purpose: To assess aldehyde dehydrogenase (ALDH) expression in adult human and murine submandibular gland (SMG) stem cells and to determine the effect of ALDH3 activation in SMG stem cell enrichment.

Experimental Design: Adult human and murine SMG stem cells were selected by cell surface markers (CD34 for human and c-Kit for mouse) and characterized for various other stem cell surface markers by flow cytometry and ALDH isozymes expression by quantitative reverse transcriptase PCR. Sphere formation and bromodeoxyuridine (BrdUrd) incorporation assays were used on selected cells to confirm their renewal capacity and three-dimensional (3D) collagen matrix culture was applied to observe differentiation. To determine whether ALDH3 activation would increase stem cell yield, adult mice were infused with a novel ALDH3 activator (Alda-89) or with vehicle followed by quantification of c-Kit+/CD90+ SMG stem cells and BrdUrd+ salispheres.

Results: More than 99% of CD34+ huSMG stem cells stained positive for c-Kit, CD90 and 70% colocalized with CD44, Nestin. Similarly, 73.8% c-Kit+ mSMG stem cells colocalized with Sca-1, whereas 80.7% with CD90. Functionally, these cells formed BrdUrd+ salispheres, which differentiated into acinar- and ductal-like structures when cultured in 3D collagen. Both adult human and murine SMG stem cells showed higher expression of ALDH3 than in their non–stem cells and 84% of these cells have measurable ALDH1 activity. Alda-89 infusion in adult mice significantly increased c-Kit+/CD90+ SMG population and BrdUrd+ sphere formation compared with control.

Conclusion: This is the first study to characterize expression of different ALDH isozymes in SMG stem cells. In vivo activation of ALDH3 can increase SMG stem cell yield, thus providing a novel means for SMG stem cell enrichment for future stem cell therapy. Clin Cancer Res; 17(23); 7265–72. ©2011 AACR.
SAR3419: An Anti-CD19-Maytansinoid Immunoconjugate for the Treatment of B-Cell Malignancies
Authors: Blanc Veronique , Bousseau Anne , Caron Anne , Carrez Chantal , Lutz Robert J. , Lambert John M.
Published: October 2011

SAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies. SAR3419 combines the strengths of a high-potency tubulin inhibitor and the exquisite B-cell selectivity of an anti-CD19 antibody. The internalization and processing of SAR3419, following its binding at the surface of CD19-positive human lymphoma cell lines and xenograft models, release active metabolites that trigger cell-cycle arrest and apoptosis, leading to cell death and tumor regression. SAR3419 has also been shown to be active in different lymphoma xenograft models, including aggressive diffuse large B-cell lymphoma, resulting in complete regressions and tumor-free survival. In these models, the activity of SAR3419 compared favorably with rituximab and lymphoma standard of care chemotherapy. Two phase I trials with 2 different schedules of SAR3419 as a single agent were conducted in refractory/relapsed B-cell non-Hodgkin lymphoma. Activity was reported in both schedules, in heavily pretreated patients of both follicular and diffuse large B-cell lymphoma subtypes, with a notable lack of significant hematological toxicity, validating SAR3419 as an effective antibody-drug conjugate and opening opportunities in the future. Numerous B-cell–specific anti-CD19 biologics are available to treat B-cell non-Hodgkin lymphoma, and early phase I results obtained with SAR3419 suggest that it is a promising candidate for further development in this disease. In addition, thanks to the broad expression of CD19, SAR3419 may provide treatment options for B-cell leukemias that are often CD20-negative. Clin Cancer Res; 17(20); 6448–58. ©2011 AACR.
Antibody-Drug Conjugates of Calicheamicin Derivative: Gemtuzumab Ozogamicin and Inotuzumab Ozogamicin
Authors: Ricart Alejandro D.
Published: October 2011

Antibody-drug conjugates (ADC) are an attractive approach for the treatment of acute myeloid leukemia and non-Hodgkin lymphomas, which in most cases, are inherently sensitive to cytotoxic agents. CD33 and CD22 are specific markers of myeloid leukemias and B-cell malignancies, respectively. These endocytic receptors are ideal for an ADC strategy because they can effectively carry the cytotoxic payload into the cell. Gemtuzumab ozogamicin (GO, Mylotarg) and inotuzumab ozogamicin consist of a derivative of calicheamicin (a potent DNA-binding cytotoxic antibiotic) linked to a humanized monoclonal IgG4 antibody directed against CD33 or CD22, respectively. Both of these ADCs have a target-mediated pharmacokinetic disposition. GO was the first drug to prove the ADC concept in the clinic, specifically in phase II studies that included substantial proportions of older patients with relapsed acute myeloid leukemia. In contrast, in phase III studies, it has thus far failed to show clinical benefit in first-line treatment in combination with standard chemotherapy. Inotuzumab ozogamicin has shown remarkable clinical activity in relapsed/refractory B-cell non-Hodgkin lymphoma, and it has started phase III evaluation. The safety profile of these ADCs includes reversible myelosuppression (especially neutropenia and thrombocytopenia), elevated hepatic transaminases, and hyperbilirubinemia. There have been postmarketing reports of hepatotoxicity, especially veno-occlusive disease, associated with GO. The incidence is ∼2%, but patients who undergo hematopoietic stem cell transplantation have an increased risk. As we steadily move toward the goal of personalized medicine, these kinds of agents will provide a unique opportunity to treat selected patient subpopulations based on the expression of their specific tumor targets. Clin Cancer Res; 17(20); 6417–27. ©2011 AACR.
Antibody Fusion Proteins: Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox
Authors: Kreitman Robert J. , Pastan Ira
Published: October 2011

Recombinant immunotoxins are fusion proteins that contain the cytotoxic portion of a protein toxin fused to the Fv portion of an antibody. The Fv binds to an antigen on a target cell and brings the toxin into the cell interior, where it arrests protein synthesis and initiates the apoptotic cascade. Moxetumomab pasudotox, previously called HA22 or CAT-8015, is a recombinant immunotoxin composed of the Fv fragment of an anti-CD22 monoclonal antibody fused to a 38-kDa fragment of Pseudomonas exotoxin A, called PE38. Moxetumomab pasudotox is an improved, more active form of a predecessor recombinant immunotoxin, BL22 (also called CAT-3888), which produced complete remission in relapsed/refractory hairy cell leukemia (HCL), but it had a <20% response rate in chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL), diseases in which the leukemic cells contain much lower numbers of CD22 target sites. Compared with BL22, moxetumomab pasudotox is up to 50-fold more active on lymphoma cell lines and leukemic cells from patients with CLL and HCL. A phase I trial was recently completed in HCL patients, who achieved response rates similar to those obtained with BL22 but without dose-limiting toxicity. In addition to further testing in HCL, moxetumomab pasudotox is being evaluated in phase I trials in patients with CLL, B-cell lymphomas, and childhood ALL. Moreover, protein engineering is being used to increase its activity, decrease nonspecific side effects, and remove B-cell epitopes. Clin Cancer Res; 17(20); 6398–405. ©2011 AACR.
Defective Mismatch Repair Status as a Prognostic Biomarker of Disease-Free Survival in Stage III Colon Cancer Patients Treated with Adjuvant FOLFOX Chemotherapy
Authors: Zaanan Aziz , Fléjou Jean-François , Emile Jean-François , Des Guetz Gaëtan , Cuilliere-Dartigues Peggy , Malka David , Lecaille Cédric , Validire Pierre , Louvet Christophe , Rougier Philippe , de Gramont Aimery , Bonnetain Franck , Praz Françoise , Taïeb Julien
Published: October 2011

Purpose: Adding oxaliplatin to adjuvant 5-fluorouracil (5-FU) chemotherapy improves 3-year disease-free survival (DFS) after resection of stage III colon cancer. Several studies suggest that patients with tumors exhibiting defective mismatch repair (MMR) do not benefit from adjuvant 5-FU chemotherapy, but there are few data on 5-FU–oxaliplatin (FOLFOX) adjuvant chemotherapy in this setting. The aim of this study was to evaluate the prognostic value of MMR status for DFS in patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy.

Experimental Design: MMR status was determined by microsatellite instability testing or immunohistochemistry in 303 unselected patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy in 9 centers. Cox proportional hazards models were used to examine the association between MMR status and 3-year DFS.

Results: The 3-year DFS rate was significantly higher in the 34 patients (11.2% of the study population) with defective MMR tumors (90.5%) than in patients with proficient MMR tumors (73.8%; log-rank test; HR = 2.16; 95% CI, 1.09–4.27; P = 0.027). In multivariate analysis, MMR status remained an independent significant prognostic factor for DFS (HR = 4.48; 95% CI, 1.34–14.99; P = 0.015).

Conclusion: MMR status is an independent prognostic biomarker for DFS in patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy. Clin Cancer Res; 17(23); 7470–8. ©2011 AACR.
GDC-0980 Is a Novel Class I PI3K/mTOR Kinase Inhibitor with Robust Activity in Cancer Models Driven by the PI3K Pathway
Authors: Wallin Jeffrey J. , Edgar Kyle A. , Guan Jane , Berry Megan , Prior Wei Wei , Lee Leslie , Lesnick John D. , Lewis Cristina , Nonomiya Jim , Pang Jodie , Salphati Laurent , Olivero Alan G. , Sutherlin Daniel P. , O'Brien Carol , Spoerke Jill M. , Patel Sonal , Lensun Letitia , Kassees Robert , Ross Leanne , Lackner Mark R. , Sampath Deepak , Belvin Marcia , Friedman Lori S.
Published: October 2011

Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic. Mol Cancer Ther; 10(12); 2426–36. ©2011 AACR.
Stem Cell-Derived Vascular Endothelial Cells and Their Potential Application in Regenerative Medicine
Authors: Chaudhury Hera , Raborn Eric , Goldie Lauren C. , Hirschi Karen K.
Published: October 2011

Although a ‘vascular stem cell’ population has not been identified or generated, vascular endothelial and mural cells (smooth muscle cells and pericytes) can be derived from currently known pluripotent stem cell sources including human embryonic stem cells and induced pluripotent stem cells. We review the vascular potential of these human pluripotent stem cells, the mechanisms by which they are induced to differentiate toward a vascular endothelial cell fate, and their applications in regenerative medicine.
Endoplasmic Reticulum Stress and Glycogen Synthase Kinase-3β Activation in Apolipoprotein E–Deficient Mouse Models of Accelerated Atherosclerosis
Authors: McAlpine Cameron S. , Bowes Anna J. , Khan Mohammad I. , Shi Yuanyuan , Werstuck Geoff H.
Published: October 2011

Objective—

The goal of this study was to examine the role of endoplasmic reticulum (ER) stress signaling and the contribution of glycogen synthase kinase (GSK)-3β activation in hyperglycemic, hyperhomocysteinemic, and high-fat–fed apolipoprotein E–deficient (apoE
−/−
) mouse models of accelerated atherosclerosis.

Methods and Results—

Female apoE
−/−
mice received multiple low-dose injections of streptozotocin (40 μg/kg) to induce hyperglycemia, methionine-supplemented drinking water (0.5% wt/vol) to induce hyperhomocysteinemia, or a high-fat (21% milk fat+0.2% cholesterol) diet to induce relative dyslipidemia. A subset of mice from each group was supplemented with sodium valproate (625 mg/kg), a compound with GSK3 inhibitory activity. At 15 and 24 weeks of age, markers of ER stress, lipid accumulation, GSK3β phosphorylation, and GSK3β activity were analyzed in liver and aorta. Atherosclerotic lesions were examined and quantified. Hyperglycemia, hyperhomocysteinemia, and high-fat diet significantly enhanced GSK3β activity and also increased hepatic steatosis and atherosclerotic lesion volume compared with controls. Valproate supplementation blocked GSK3β activation and attenuated the development of atherosclerosis and the accumulation of hepatic lipids in each of the models examined. The mechanism by which GSK3β activity is regulated in these models likely involves alterations in phosphorylation at serine 9 and tyrosine 216.

Conclusion—

These findings support the existence of a common mechanism of accelerated atherosclerosis involving ER stress signaling through activation of GSK3β. Furthermore, our results suggest that atherosclerosis can be attenuated by modulating GSK3β phosphorylation.
Splice Variant Specific Modulation of Ca
V
1.2 Calcium Channel by Galectin-1 Regulates Arterial Constriction
Authors: Wang Juejin , Thio Sharon S.C. , Yang Sophia S.H. , Yu Dejie , Yu Chye Yun , Wong Yuk Peng , Liao Ping , Li Shengnan , Soong Tuck Wah
Published: October 2011

Rationale:

Ca
V
1.2 channels are essential for excitation–contraction coupling in the cardiovascular system, and alternative splicing optimizes its role. Galectin-1 (Gal-1) has been reported to regulate vascular smooth muscle cell (VSMC) function and play a role in pulmonary hypertension. We have identified Gal-1 multiple times in yeast 2-hybrid assays using the Ca
V
1.2 I–II loop as bait.

Objective:

Our hypothesis is that Gal-1 interacts directly with Ca
V
1.2 channel at the I–II loop to affect arterial constriction.

Methods and Results:

Unexpectedly, Gal-1 was found to selectively bind to the I–II loop only in the absence of alternatively spliced exon 9*. We found that the current densities of Ca
V
1.2
Δ9*
channels were significantly inhibited as a result of decreased functional surface expression due to the binding of Gal-1 at the export signal located on the C-terminus of exon 9. Moreover, the suppression of Gal-1 expression by siRNA in rat A7r5 and isolated VSMCs produced the opposite effect of increased
I
Ca,L
. The physiological significance of Gal-1 mediated splice variant-specific inhibition of Ca
V
1.2 channels was demonstrated in organ bath culture where rat MAs were reversibly permeabilized with Gal-1 siRNA and the arterial wall exhibited increased K
+
-induced constriction.

Conclusion:

The above data indicated that Gal-1 regulates
I
Ca,L
via decreasing the functional surface expression of Ca
V
1.2 channels in a splice variant selective manner and such a mechanism may play a role in modulating vascular constriction.
Effects of Augmented Exercise Therapy on Outcome of Gait and Gait-Related Activities in the First 6 Months After Stroke
Authors: Veerbeek Janne M. , Koolstra Muriel , Ket Johannes C.F. , van Wegen Erwin E.H. , Kwakkel Gert
Published: October 2011

Background and Purpose—

The purpose of this study was to determine the effects of augmented exercise therapy on gait, gait-related activities, and (basic and extended) activities of daily living within the first 6 months poststroke.

Methods—

A systematic literature search in electronic databases from 1990 until October 2010 was performed. Randomized controlled trials were included in which the experimental group spent augmented time in lower-limb exercise therapy compared with the control group. Outcomes were gait, gait-related activities, and (extended) activities of daily living. Results from individual studies were pooled by calculating the summary effect sizes. Subgroup analyses were applied for a treatment contrast of ≥16 hours, timing poststroke, type of control intervention, and methodological quality.

Results—

Fourteen (N=725) of 4966 identified studies were included. Pooling resulted in small to moderate significant summary effect sizes in favor of augmented exercise therapy for walking ability, comfortable and maximum walking speed, and extended activities of daily living. No significant effects were found for basic activities of daily living. Subgroup analysis did not show a significant effect modification.

Conclusions—

Dose–response trials in stroke rehabilitation are heterogeneous. The present meta-analysis suggests that increased time spent on exercise of gait and gait-related activities in the first 6 months poststroke results in significant small to moderate effects in terms of walking ability, walking speed, and extended activities of daily living. High-quality dose–response exercise therapy trials are needed with identical treatment goals but incremental levels of intensity.
Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran
Authors: Zhou Wei , Schwarting Sönke , Illanes Sergio , Liesz Arthur , Middelhoff Moritz , Zorn Markus , Bendszus Martin , Heiland Sabine , van Ryn Joanne , Veltkamp Roland
Published: October 2011

Background and Purpose—

Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth.

Methods—

In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 μL), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later.

Results—

DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent.

Conclusions—

The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.
Vasopressin V
1a
Receptors Mediate Posthemorrhagic Systemic Hypertension Thereby Determining Rebleeding Rate and Outcome After Experimental Subarachnoid Hemorrhage
Authors: Hockel Konstantin , Schöller Karsten , Trabold Raimund , Nussberger Jürg , Plesnila Nikolaus
Published: October 2011

Background and Purpose—

Arginine vasopressin V
1
receptors have been suggested to be involved in the pathophysiology of acute brain injury. Therefore, we aimed to determine the role of arginine vasopressin V
1
receptors after experimental subarachnoid hemorrhage (SAH).

Methods—

Sprague-Dawley rats subjected to SAH by endovascular puncture received either vehicle or a V
1
receptor antagonist intravenously from 1 minute before until 3 hours after SAH. Intracranial pressure, cerebral blood flow, and mean arterial blood pressure were monitored until 60 minutes after SAH. Brain water content was quantified 24 hours after SAH and neurological function and mortality were assessed daily for 7 days after hemorrhage.

Results—

In control rats, SAH induced high intracranial pressure, a brief increase in plasma arginine vasopressin, a subsequent increase in systemic blood pressure (Cushing response), a high rebleeding rate (30%), severe neurological deficits, and a 7-day mortality rate of 50%. V
1
receptor antagonist-treated animals exhibited a far less pronounced Cushing response, a less severe increase of intracranial pressure, did not exhibit rebleedings, had less severe brain edema formation and neurological deficits, and a mortality rate of only 20% (all
P
<0.05 versus vehicle).

Conclusions—

Inhibition of arginine vasopressin V
1a
receptors reduces the severity of SAH and prevents rebleedings by blunting the posthemorrhagic hypertonic response (Cushing reflex), thereby reducing mortality and secondary brain damage after experimental SAH. Because the severity of the initial bleeding and rebleedings are major factors contributing to an unfavorable outcome after SAH, inhibition of V
1a
receptors may represent a novel strategy to treat SAH.
Cardiac Cycle-Related Volume Change in Unruptured Cerebral Aneurysms
Authors: Kuroda Junko , Kinoshita Manabu , Tanaka Hisashi , Nishida Takeo , Nakamura Hajime , Watanabe Yoshiyuki , Tomiyama Noriyuki , Fujinaka Toshiyuki , Yoshimine Toshiki
Published: October 2011

Background and Purpose—

The hemodynamic factors of aneurysms were recently evaluated using computational fluid dynamics in a static vessel model in an effort to understand the mechanisms of initiation and rupture of aneurysms. However, few reports have evaluated the dynamic wall motion of aneurysms due to the cardiac cycle. The objective of this study was to quantify cardiac cycle-related volume changes in aneurysms using 4-dimensional CT angiography.

Methods—

Four-dimensional CT angiography was performed in 18 patients. Image data of 1 cardiac cycle were divided into 10 phases and the volume of the aneurysm was then quantified in each phase. These data were also compared with intracranial vessels of normal appearance.

Results—

The observed cardiac cycle-related volume changes were in good agreement with the sizes of the aneurysms and normal vessels. The cardiac cycle-related volume changes of the intracranial aneurysms and intracranial normal arteries were 5.40%±4.17% and 4.20±2.04%, respectively, but these did not differ statistically (
P
=0.12).

Conclusions—

We successfully quantified the volume change in intracranial aneurysms and intracranial normal arteries in human subjects. The data may indicate that cardiac cycle-related volume changes do not differ between unruptured aneurysms and normal intracranial arteries, suggesting that the global integrity of an unruptured aneurysmal wall is not different from that of normal intracranial arteries.
Carotid Plaque Vulnerability
Authors: Cicha Iwona , Wörner Anja , Urschel Katharina , Beronov Kamen , Goppelt-Struebe Margarete , Verhoeven Eric , Daniel Werner G. , Garlichs Christoph D.
Published: October 2011

Background and Purpose—

Rupture of atherosclerotic plaques is one of the main causes of ischemic strokes. The aim of this study was to investigate carotid plaque vulnerability markers in relation to blood flow direction and the mechanisms leading to plaque rupture at the upstream side of carotid stenoses.

Methods—

Frequency and location of rupture, endothelial erosion, neovascularization, and hemorrhage were determined in longitudinal sections of 80 human carotid specimens. Plaques were immunohistochemically analyzed for markers of vulnerability. Plaque geometry was measured to reconstruct shape profiles of ruptured versus stable plaques and to perform computational fluid dynamics analyses.

Results—

In 86% of ruptured plaques, rupture was observed upstream. In this region, neovascularization and hemorrhage were increased, along with increased immunoreactivity of vascular endothelial and connective tissue growth factor, whereas endothelial erosion was more frequent downstream. Proteolytic enzymes, mast cell chymase and cathepsin L, and the proapoptotic protein Bax showed significantly higher expression upstream as compared with the downstream shoulder of atherosclerotic lesions. Comparison of geometric profiles for ruptured and stable plaques showed increased longitudinal asymmetry of fibrous cap and lipid core thickness in ruptured plaques. The specific geometry of plaques ruptured upstream induced increased levels of shear stress and increased pressure drop between the upstream and the downstream plaque shoulders.

Conclusions—

Vulnerability of the upstream plaque region is associated with enhanced neovascularization, hemorrhage, and cap thinning induced by proteolytic and proapoptotic mechanisms. These processes are reflected in structural plaque characteristics, analyses of which could improve the efficacy of vascular diagnostics and prevention.
A New Support System Using a Mobile Device (Smartphone) for Diagnostic Image Display and Treatment of Stroke
Authors: Takao Hiroyuki , Murayama Yuichi , Ishibashi Toshihiro , Karagiozov Kostadin L. , Abe Toshiaki
Published: October 2011

Background and Purpose—

With the increasing demand for rapid diagnosis and treatment of stroke, the telemedicine role of coordinating timely the efforts of the stroke team became important. We developed a system for rapidly exchanging diagnostic images and clinical and management information.

Methods—

A system was created on the basis of communicating patient data and images between hospital systems and participating staff members in and out of the hospital through their standard, currently used handheld communication devices. The system is able to transfer clinical data, CT, MR, angiographic, intraoperative images, and expert opinion in real time.

Results—

A pilot application of the system in our hospital showed successful information transfer, allowing medical staff to discuss patients' diagnosis and management using a Twitter system.

Conclusions—

The system (i-Stroke) may become a useful tool for acute patient management in the field of neurology and neurosurgery.
Mortality of Cerebral Venous–Sinus Thrombosis in a Large National Sample
Authors: Haghighi Afshin Borhani , Edgell Randall C. , Cruz-Flores Salvador , Feen Eli , Piriyawat Paisith , Vora Nirav , Callison R. Charles , Alshekhlee Amer
Published: October 2011

Background and Purpose—

The purpose of this study was to evaluate the mortality rates associated with cerebral venous–sinus thrombosis in a large national sample.

Methods—

A cohort of patients with cerebral venous–sinus thrombosis was identified from the National Inpatient Sample database for the years 2000 to 2007. According to the International Classification of Diseases, 9th Revision, Clinical Modification codes, cerebral venous–sinus thrombosis is categorized into pyogenic and nonpyogenic groups. Multivariate logistic regression analysis was used to assess covariates associated with hospital mortality.

Results—

Among 3488 patients, the overall mortality rate was 4.39%, which was nonsignificantly higher among the pyogenic group (4.55% versus 3.52%; OR, 0.76; 95% CI, 0.47–1.23). In the pyogenic cerebral venous–sinus thrombosis group, hematologic disorders were the most frequent predisposing condition (16.2%); whereas systemic malignancy followed by hematologic disorders were most common in the nonpyogenic group (14.08% and 10.04%, respectively). Predictors of mortality included age, intracerebral hemorrhage as well as the predisposing conditions of hematologic disorders, systemic malignancy, and central nervous system infection.

Conclusions—

Compared with arterial stroke, CVST harbors a relatively low mortality rate. Death is determined by age, the presence of intracerebral hemorrhage, and certain predisposing conditions.
Dynamics of Interdecadal Climate Variability: A Historical Perspective*
Authors: Liu Zhengyu
Published: October 2011

The emerging interest in decadal climate prediction highlights the importance of understanding the mechanisms of decadal to interdecadal climate variability. The purpose of this paper is to provide a review of our understanding of interdecadal climate variability in the Pacific and Atlantic Oceans. In particular, the dynamics of interdecadal variability in both oceans will be discussed in a unified framework and in light of historical development. General mechanisms responsible for interdecadal variability, including the role of ocean dynamics, are reviewed first. A hierarchy of increasingly complex paradigms is used to explain variability. This hierarchy ranges from a simple red noise model to a complex stochastically driven coupled ocean–atmosphere mode. The review suggests that stochastic forcing is the major driving mechanism for almost all interdecadal variability, while ocean–atmosphere feedback plays a relatively minor role. Interdecadal variability can be generated independently in the tropics or extratropics, and in the Pacific or Atlantic. In the Pacific, decadal–interdecadal variability is associated with changes in the wind-driven upper-ocean circulation. In the North Atlantic, some of the multidecadal variability is associated with changes in the Atlantic meridional overturning circulation (AMOC). In both the Pacific and Atlantic, the time scale of interdecadal variability seems to be determined mainly by Rossby wave propagation in the extratropics; in the Atlantic, the time scale could also be determined by the advection of the returning branch of AMOC in the Atlantic. One significant advancement of the last two decades is the recognition of the stochastic forcing as the dominant generation mechanism for almost all interdecadal variability. Finally, outstanding issues regarding the cause of interdecadal climate variability are discussed. The mechanism that determines the time scale of each interdecadal mode remains one of the key issues not understood. It is suggested that much further understanding can be gained in the future by performing specifically designed sensitivity experiments in coupled ocean–atmosphere general circulation models, by further analysis of observations and cross-model comparisons, and by combining mechanistic studies with decadal prediction studies.
Trends in Daily Solar Radiation and Precipitation Coefficients of Variation since 1984
Authors: Medvigy David , Beaulieu Claudie
Published: October 2011

This study investigates the possibility of changes in daily scale solar radiation and precipitation variability. Coefficients of variation (CVs) were computed for the daily downward surface solar radiation product from the International Satellite Cloud Climatology Project and the daily precipitation product from the Global Precipitation Climatology Project. Regression analysis was used to identify trends in CVs. Statistically significant changes in solar radiation variability were found for 35% of the globe, and particularly large increases were found for tropical Africa and the Maritime Continent. These increases in solar radiation variability were correlated with increases in precipitation variability and increases in deep convective cloud amount. The changes in high-frequency climate variability identified here have consequences for any process depending nonlinearly on climate, including solar energy production and terrestrial ecosystem photosynthesis. To assess these consequences, additional work is needed to understand how high-frequency climate variability will change in the coming decades.