bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction between the stent strut and thrombus characterized by contrast-enhanced high-resolution cone beam CT during deployment of the Solitaire stent retriever
Authors: Tsumoto Tomoyuki , Tsurusaki Yuichiro , Tokunaga So
Published: August 2016

Background

The mechanism by which a stent retriever removes intraluminal thrombus from an occluded vessel in humans has not previously been studied. This study performed contrast-enhanced high-resolution cone beam CT (CE-HRCBCT) during deployment of the stent retriever to observe the interaction between the strut and intraluminal thrombus intraoperatively. We also discuss the mechanism by which the thrombus is retrieved.

Methods

In 11 patients, mechanical thrombectomy was performed with a Solitaire stent retriever. The presence or absence of flow restoration (FR) was evaluated immediately and at least 5 min after deployment. Stent retriever findings on CE-HRCBCT were divided into two groups: (1) complete expansion; and (2) incomplete expansion.

Results

FR was observed in all 11 cases (100%) immediately after deployment of the Solitaire stent retriever. Complete expansion was observed in only one case and incomplete expansion was observed in 10 cases. The thrombus was observed mainly near to or outside the strut of the stent retriever by CE-HRCBCT. Loss of FR was seen in only one of the 11 cases. Regardless of this, successful recanalization was achieved with only the stent retriever in nine cases.

Conclusions

CE-HRCBCT showed that the Solitaire stent retriever rarely expanded fully and the thrombus was mainly near to or outside the strut. It may not be necessary to wait a long time to allow the stent to expand fully into the thrombus because the main capture mechanism seems to be engagement of the clot between the crossings of the struts of the Solitaire.
The modified ‘no touch’ technique in the antegrade endovascular approach for left common carotid artery ostial stenosis stenting
Authors: Tang Xiaobin , Long Whitney Annie , Hu Chang , Tang Feng , Wang Qian , Li Lei
Published: August 2016

Background

Open surgery and the retrograde endovascular approach via the distal left common carotid artery (LCCA) have some limitations in LCCA ostial stenosis treatment. The ‘no touch’ technique used in the renal artery was modified for this situation.

Methods

Fifteen selective LCCA stenosis patients were treated by the modified ‘no touch’ technique in the antegrade endovascular approach from March 2013 to March 2016. Thirteen underwent the transfemoral approach and the other two had the transbrachial approach due to a ‘bovine aortic arch’. Distal embolic protection devices were used in all cases. Follow-up included a neurological examination, carotid duplex scan, and office interview. Mean follow-up time was 18.2±11.5 months.

Results

The initial technical success rate was 100%. The average procedure time was 84.0±16.3 min. There were no procedure-related deaths. No clinical neurological complications occurred during the in-hospital stay. No incidence of death or major stroke occurred during the follow-up period; 6.7% (1/15) of patients had a contralateral minor stroke, 66.7% (4/6) of symptomatic patients were relieved of initial symptoms, and the rest showed improvement. No patient developed new ipsilateral neurological symptoms and no in-stent restenosis occurred during the follow-up period. These results were confirmed by ultrasound.

Conclusions

The modified ‘no touch’ antegrade endovascular technique is a feasible method for treating LCCA ostial lesions with a satisfactory initial success rate, acceptable procedure time, and comparable mid- and long-term results. This technique could be considered as a complementary option for LCCA ostial stenosis in addition to open surgery and the retrograde endovascular approach.
Prognostic indicators and generation of novel risk equations for estimation of 10-year and 20-year mortality following acute coronary syndrome
Authors: Magri Caroline J , Debono Roberto , Calleja Neville , Galea Joseph , Fava Stephen
Published: August 2016

Objectives

Although risk assessment is an integral part of management, there are currently no risk calculators of long-term mortality after acute coronary syndrome (ACS). The aim was to provide risk equations for 10-year and 20-year mortality following ACS.

Methods

Patients hospitalised with ACS from December 1990 to June 1994 were recruited and followed up through 31 December 2012.

Results

The study followed 881 patients for 10 years and 712 patients for 20 years. Using Cox regression analysis, 20-year all-cause mortality was associated with myocardial infarction (MI) in the index admission, age and diabetes mellitus (DM). Twenty-year cardiovascular disease (CVD) and cardiac mortality were both associated with MI in the index admission, age, DM and female gender. 10-year all-cause mortality was associated with age and total cholesterol levels; age, DM and total cholesterol levels were found to be independent predictors of 10-year CVD and cardiac mortality. Risk equations were consequently generated for 10-year and 20-year cardiac, cardiovascular and all-cause mortality, with age and DM emerging as the strongest and most consistent predictors of all outcomes studied.

Conclusions

Novel risk equations for all-cause, cardiovascular and cardiac mortality at 10 and 20 years were generated using follow-up data in a large patient population.
Return of function in a feline thoracic limb after suspected traumatic brachial plexus injury with loss of nociception
Authors: Santifort Koen Maurits
Published: August 2016

A two‐year‐old cat was presented after a suspected traumatic incident with loss of motor function and sensation in the right thoracic limb. Nociception was absent and, therefore, prognosis for return of function was considered guarded. However, after two weeks the cat showed signs of motor function in the limb, and upon clinical examination six weeks post incident, nociception and motor function had returned.
Characterisation of antimicrobial usage in cats and dogs attending UK primary care companion animal veterinary practices
Authors: Buckland E. L. , O'Neill D. , Summers J. , Mateus A. , Church D. , Redmond L. , Brodbelt D.
Published: August 2016

There is scant evidence describing antimicrobial (AM) usage in companion animal primary care veterinary practices in the UK. The use of AMs in dogs and cats was quantified using data extracted from 374 veterinary practices participating in VetCompass. The frequency and quantity of systemic antibiotic usage was described.

Overall, 25 per cent of 963,463 dogs and 21 per cent of 594,812 cats seen at veterinary practices received at least one AM over a two‐year period (2012–2014) and 42 per cent of these animals were given repeated AMs. The main agents used were aminopenicillin types and cephalosporins. Of the AM events, 60 per cent in dogs and 81 per cent in cats were AMs classified as critically important (CIAs) to human health by the World Health Organisation. CIAs of highest importance (fluoroquinolones, macrolides, third‐generation cephalosporins) accounted for just over 6 per cent and 34 per cent of AMs in dogs and cats, respectively. The total quantity of AMs used within the study population was estimated to be 1473 kg for dogs and 58 kg for cats.

This study has identified a high frequency of AM usage in companion animal practice and for certain agents classified as of critical importance in human medicine. The study highlights the usefulness of veterinary practice electronic health records for studying AM usage.
Energies and radiative transitions (E1, E2, and M1) for hydrogen-like thorium
Authors: Ürer G.
Published: August 2016

Hydrogen-like ions with high Z present unique opportunities to promote the understanding of atomic structure. On the other hand, determining the atomic structure of hydrogen-like atoms provides us the test of relativistic effects as well as accurate values of the spectral characteristics required for many applications. For this reason we have calculated level energies of hydrogen like thorium (Th89+, Z = 90) with both multiconfiguration Hartree–Fock (MCHF) and multiconfiguration Dirac–Fock (MCDF) methods. These calculations have contained the Breit–Pauli relativistic corrections in MCHF calculation and quantum electrodynamics effects in MCDF calculations besides electron correlations. The wavelengths, λ, weighted oscillator strengths, gf-value, and transition probabilities, Aki, have been also represented for allowed (E1) and forbidden (E2 and M1) transitions. We have compared our results with only theoretical work results because there is no available experimental data for Th89+.
Lexical Categories: Legacy, Lacuna, and Opportunity for Functionalists and Formalists
Authors: Baker Mark , Croft William
Published: August 2016

The fundamental importance of lexical categories is uncontroversial within both formal and functional approaches to grammatical analysis. But despite the familiarity of this topic and its foundational nature for grammatical description and analysis, it is paradoxically not among the best-studied or -understood topics from either the functionalist or formalist perspective. Both schools of linguistic theory have inherited their basic assumptions and instincts about lexical categories from the structuralist practice of distributional analysis. We briefly survey approaches to the various lexical categories. We then comment on a few issues of strategic value that arise from these approaches, including the importance of clearly distinguishing roots, stems, words, and syntactic units when it comes to issues of lexical categories; the importance of recognizing when distributional tests are similar across languages in principled ways; and the need for the choice of distributional tests to be informed by theoretical hypotheses.
Crosslinguistic Variation in Sign Language Syntax
Authors: Fischer Susan D.
Published: August 2016

This review introduces and compares syntactic structures in a variety of sign languages. I first examine ways in which sign languages function like spoken languages, and ways in which they differ. I then briefly discuss what sign languages have in common in the syntactic realm; the rest of the article focuses on how they can differ. Because the level of the simple sentence has been documented extensively, this review emphasizes complex sentences, such as sentential complementation, relative clauses, adverbial clauses, embedded questions, and conditionals.
Venice and I: How a City Can Determine the Fate of a Career
Authors: Malanotte-Rizzoli Paola
Published: August 2016

Quoting the ancient Romans: Audentes Fortuna iuvat. Being in the right place at the right time is useless if you do not grasp your Fortuna and build upon it. In this article, I expound on the milestones of my multiform research career, which over more than 40 years brought me from Venice to California to MIT; from the Venice problem to highly nonlinear, coherent structures in the ocean and atmosphere; and from the mare nostrum (the Mediterranean Sea), a laboratory for global processes, to the tropical ocean-atmosphere systems and regional coupled climate models of the Maritime Continent. The climate system, with its daunting complexity, is arguably the greatest challenge for, and the future of, the entirety of the earth sciences. Finally, living in and working for Venice has been the privilege and Fortuna of my life.
CNS Target Identification and Validation: Avoiding the Valley of Death or Naive Optimism?
Authors: Hutson P.H. , Clark J.A. , Cross A.J.
Published: August 2016

There are many challenges along the path to the approval of new drugs to treat CNS disorders, one of the greatest areas of unmet medical need with a large societal burden and health-care impact. Unfortunately, over the past two decades, few CNS drug approvals have succeeded, leading many pharmaceutical companies to deprioritize this therapeutic area. The reasons for the failures in CNS drug discovery are likely to be multifactorial. However, selecting the most biologically plausible molecular targets that are relevant to the disorder is a critical first step to improve the probability of success. In this review, we outline previous methods for identifying and validating novel targets for CNS drug discovery, and, cognizant of previous failures, we discuss potential new strategies that may improve the probability of success of developing novel treatments for CNS disorders.
3D Displays
Authors: Banks Martin S. , Hoffman David M. , Kim Joohwan , Wetzstein Gordon
Published: August 2016

Creating realistic three-dimensional (3D) experiences has been a very active area of research and development, and this article describes progress and what remains to be solved. A very active area of technical development has been to build displays that create the correct relationship between viewing parameters and triangulation depth cues: stereo, motion, and focus. Several disciplines are involved in the design, construction, evaluation, and use of 3D displays, but an understanding of human vision is crucial to this enterprise because in the end, the goal is to provide the desired perceptual experience for the viewer. In this article, we review research and development concerning displays that create 3D experiences. And we highlight areas in which further research and development is needed.
Interstitial pneumonia induced by bleomycin treatment is exacerbated inAngptl2-deficient mice
Authors: Motokawa Ikuyo , Endo Motoyoshi , Terada Kazutoyo , Horiguchi Haruki , Miyata Keishi , Kadomatsu Tsuyoshi , Morinaga Jun , Sugizaki Taichi , Ito Takaaki , Araki Kimi , Morioka Masaki Suimye , Manabe Ichiro , Samukawa Takuya , Watanabe Masaki , Inoue Hiromasa , Oike Yuichi
Published: August 2016

Angiopoietin-like protein 2 (ANGPTL2) is a chronic inflammatory mediator that, when deregulated, is associated with various pathologies. However, little is known about its activity in lung. To assess a possible lung function, we generated a rabbit monoclonal antibody that specifically recognizes mouse ANGPTL2 and then evaluated protein expression in mouse lung tissue. We observed abundant ANGPTL2 expression in both alveolar epithelial type I and type II cells and in resident alveolar macrophages under normal conditions. To assess ANGPTL2 function, we compared lung phenotypes in Angptl2 knockout (KO) and wild-type mice but observed no overt changes. We then generated a bleomycin-induced interstitial pneumonia model using wild-type and Angptl2 KO mice. Bleomycin-treated wild-type mice showed specifically upregulated ANGPTL2 expression in areas of severe fibrosing interstitial pneumonia, while Angptl2 KO mice developed more severe lung fibrosis than did comparably treated wild-type mice. Lung fibrosis seen following bone marrow transplant was comparable in wild-type or Angptl2 KO mice treated with bleomycin, suggesting that Angptl2 loss in myeloid cells does not underlie fibrotic phenotypes. We conclude that Angptl2 deficiency in lung epithelial cells and resident alveolar macrophages causes severe lung fibrosis seen following bleomycin treatment, suggesting that ANGPTL2 derived from these cell types plays a protective role against fibrosis in lung.
2-Aminoethyldiphenylborinate modifies the pulmonary circulation in pulmonary hypertensive newborn lambs partially gestated at high altitude
Authors: Castillo-Galán S. , Quezada S. , Moraga F. , Ebensperger G. , Herrera E. A. , Beñaldo F. , Hernández I. , Ebensperger R. , Ramírez S. , Llanos A. J. , Reyes R. V.
Published: August 2016

Calcium signaling through store-operated channels (SOC) is involved in hypoxic pulmonary hypertension. We determined whether a treatment with 2-aminoethyldiphenylborinate (2-APB), a compound with SOC blocker activity, reduces pulmonary hypertension and vascular remodeling. Twelve newborn lambs exposed to perinatal chronic hypoxia were studied, six of them received a 2-APB treatment and the other six received vehicle treatment for 10 days in both cases. Throughout this period, we recorded cardiopulmonary variables and on day 11 we evaluated the response to an acute hypoxic challenge. Additionally, we assessed the vasoconstrictor and vasodilator function in isolated pulmonary arteries as well as their remodeling in lung slices. 2-APB reduced pulmonary arterial pressure between the 3rd and 10th days, cardiac output between the 4th and 8th days, and pulmonary vascular resistance at the 10th day of treatment. The pulmonary vasoconstrictor response to acute hypoxia was reduced by the end of treatment. 2-APB also decreased maximal vasoconstrictor response to the thromboxane mimetic U46619 and endothelin-1 and increased maximal relaxation to 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP). The maximal relaxation and potency to phosphodiesterase-5 and Rho-kinase inhibition with sildenafil and fasudil, respectively, were also increased. Finally, 2-APB reduced the medial and adventitial layers' thickness, the expression of α-actin, and the percentage of Ki67-positive nuclei of small pulmonary arteries. Taken together, our results indicate that 2-APB reduces pulmonary hypertension, vasoconstrictor responses, and pathological remodeling in pulmonary hypertensive lambs. We conclude that SOC targeting may be a useful strategy for the treatment of neonatal pulmonary hypertension; however, further testing of specific blockers is needed.
Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma
Authors: Li Huaibiao , Frappart Lucien , Moll Jürgen , Winkler Anne , Kroll Torsten , Hamann Jana , Kufferath Iris , Groth Marco , Taudien Stefan , Schütte Moritz , Yaspo Marie-Laure , Heuer Heike , Lange Bodo M.H. , Platzer Matthias , Zatloukal Kurt , Herrlich Peter , Ploubidou Aspasia
Published: August 2016

Hypofertility is a risk factor for the development of testicular germ cell tumors (TGCT), but the initiating event linking these pathologies is unknown. We hypothesized that excessive planar division of undifferentiated germ cells promotes their self-renewal and TGCT development. However, our results obtained from mouse models and seminoma patients demonstrated the opposite. Defective planar divisions of undifferentiated germ cells caused their premature exit from the seminiferous tubule niche, resulting in germ cell depletion, hypofertility, intratubular germ cell neoplasias, and seminoma development. Oriented divisions of germ cells, which determine their fate, were regulated by spindle-associated RHAMM—a function we found to be abolished in 96% of human seminomas. Mechanistically, RHAMM expression is regulated by the testis-specific polyadenylation protein CFIm25, which is downregulated in the human seminomas. These results suggested that spindle misorientation is oncogenic, not by promoting self-renewing germ cell divisions within the niche, but by prematurely displacing proliferating cells from their normal epithelial milieu. Furthermore, they suggested RHAMM loss-of-function and spindle misorientation as an initiating event underlying both hypofertility and TGCT initiation. These findings identify spindle-associated RHAMM as an intrinsic regulator of male germ cell fate and as a gatekeeper preventing initiation of TGCTs. Cancer Res; 76(21); 6382–95. ©2016 AACR.
Parents' Support for School-Entry Requirements for Human Papillomavirus Vaccination: A National Study
Authors: Calo William A. , Gilkey Melissa B. , Shah Parth D. , Moss Jennifer L. , Brewer Noel T.
Published: August 2016

Background: The number of states proposing school-entry requirements for human papillomavirus (HPV) vaccination has increased over the last decade. However, data are currently limited regarding parents' support of such laws. We sought to obtain the first national estimates of parents' support of HPV vaccination school-entry requirements.

Methods: A national sample of 1,501 parents of 11- to 17-year-old children completed a web-based survey between November 2014 and January 2015. Analyses used multivariable logistic regression to assess correlates of support for school-entry requirements for HPV vaccination.

Results: Overall, 21% of parents agreed that laws requiring HPV vaccination for school attendance “are a good idea,” and 54% disagreed. If school-entry requirements included opt-out provisions, agreement increased to 57%, and only 21% disagreed. Parents more often agreed with requirements without opt-out provisions if they were Hispanic [OR = 1.53; 95% confidence interval (CI), 1.05–2.22], believed HPV vaccine was as or more important than other adolescent vaccines (OR = 2.76; 95% CI, 1.98–3.83), or believed HPV vaccine was effective for preventing cervical cancer (OR = 2.55; 95% CI, 1.93–3.37). Parents less often agreed if they resided in Midwest states or believed that HPV vaccine was being pushed to make money for drug companies (both P < 0.05).

Conclusion: Opt-out provisions almost tripled parents' support for HPV vaccine school-entry requirements. Our findings suggest that race/ethnicity, attitudes about HPV vaccine, and region of residence may influence support for requirements without opt-out provisions.

Impact: Opt-out provisions greatly increase parent support of school-entry requirements for HPV vaccination but may make them ineffective. Cancer Epidemiol Biomarkers Prev; 25(9); 1317–25. ©2016 AACR.
Comparison of Collection Methods for Fecal Samples for Discovery Metabolomics in Epidemiologic Studies
Authors: Loftfield Erikka , Vogtmann Emily , Sampson Joshua N. , Moore Steven C. , Nelson Heidi , Knight Rob , Chia Nicholas , Sinha Rashmi
Published: August 2016

Background: The gut metabolome may be associated with the incidence and progression of numerous diseases. The composition of the gut metabolome can be captured by measuring metabolite levels in the feces. However, there are little data describing the effect of fecal sample collection methods on metabolomic measures.

Methods: We collected fecal samples from 18 volunteers using four methods: no solution, 95% ethanol, fecal occult blood test (FOBT) cards, and fecal immunochemical test (FIT). One set of samples was frozen after collection (day 0), and for 95% ethanol, FOBT, and FIT, a second set was frozen after 96 hours at room temperature. We evaluated (i) technical reproducibility within sample replicates, (ii) stability after 96 hours at room temperature for 95% ethanol, FOBT, and FIT, and (iii) concordance of metabolite measures with the putative “gold standard,” day 0 samples without solution.

Results: Intraclass correlation coefficients (ICC) estimating technical reproducibility were high for replicate samples for each collection method. ICCs estimating stability at room temperature were high for 95% ethanol and FOBT (median ICC > 0.87) but not FIT (median ICC = 0.52). Similarly, Spearman correlation coefficients (rs) estimating metabolite concordance with the “gold standard” were higher for 95% ethanol (median rs = 0.82) and FOBT (median rs = 0.70) than for FIT (median rs = 0.40).

Conclusions: Metabolomic measurements appear reproducible and stable in fecal samples collected with 95% ethanol or FOBT. Concordance with the “gold standard” is highest with 95% ethanol and acceptable with FOBT.

Impact: Future epidemiologic studies should collect feces using 95% ethanol or FOBT if interested in studying fecal metabolomics. Cancer Epidemiol Biomarkers Prev; 25(11); 1483–90. ©2016 AACR.
Survival and Proliferation of Neural Progenitor–Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism
Authors: Calinescu Anda-Alexandra , Yadav Viveka Nand , Carballo Erica , Kadiyala Padma , Tran Dustin , Zamler Daniel B. , Doherty Robert , Srikanth Maithreyi , Lowenstein Pedro Ricardo , Castro Maria Graciela
Published: August 2016

Purpose: One likely cause of treatment failure in glioblastoma is the persistence of glioma stem-like cells (GSLCs) which are highly resistant to therapies currently employed. We found that CXCL12 has highest expression in glioma cells derived from neural progenitor cells (NPC). The development and molecular signature of NPC-derived glioblastomas were analyzed and the therapeutic effect of blocking CXCL12 was tested.

Experimental Design: Tumors were induced by injecting DNA into the lateral ventricle of neonatal mice, using the Sleeping Beauty transposase method. Histology and expression of GSLC markers were analyzed during disease progression. Survival upon treatment with pharmacologic (plerixafor) or genetic inhibition of CXCR4 was analyzed. Primary neurospheres were generated and analyzed for proliferation, apoptosis, and expression of proteins regulating survival and cell-cycle progression.

Results: Tumors induced from NPCs display histologic features of human glioblastoma and express markers of GSLC. In vivo, inhibiting the CXCL12/CXCR4 signaling axis results in increased survival of tumor-bearing animals. In vitro, CXCR4 blockade induces apoptosis and inhibits cell-cycle progression, downregulates molecules regulating survival and proliferation, and also blocks the hypoxic induction of HIF-1α and CXCL12. Exogenous administration of CXCL12 rescues the drug-induced decrease in proliferation.

Conclusions: This study demonstrates that the CXCL12/CXCR4 axis operates in glioblastoma cells under hypoxic stress via an autocrine-positive feedback mechanism, which promotes survival and cell-cycle progression. Our study brings new mechanistic insight and encourages further exploration of the use of drugs blocking CXCL12 as adjuvant agents to target hypoxia-induced glioblastoma progression, prevent resistance to treatment, and recurrence of the disease. Clin Cancer Res; 23(5); 1250–62. ©2016 AACR.
Safety and Pharmacodynamics of the PDE4 Inhibitor Roflumilast in Advanced B-cell Malignancies
Authors: Kelly Kevin , Mejia Alex , Suhasini Avvaru N. , Lin An-Ping , Kuhn John , Karnad Anand B. , Weitman Steven , Aguiar Ricardo C.T.
Published: August 2016

Purpose: In this study, we aimed to validate our extensive preclinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics, and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential antitumor activity of the PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B-cell malignancies.

Experimental Design: Single-center, exploratory phase Ib open-label, nonrandomized study. Roflumilast (500 mcg PO) was given daily for 21 days with prednisone on days 8 to 14. Additional 21-day cycles were started if patients tolerated cycle 1 and had at least stable disease.

Results: Ten patients, median age 65 years with an average of three prior therapies, were enrolled. The median number of cycles administered was 4 (range, 1–13). Treatment was well tolerated; the most common ≥grade 2 treatment-related adverse events were fatigue, anorexia (≥25%), and transient ≥ grade 2 neutropenia (30%). Treatment with roflumilast as a single agent significantly suppressed PI3K activity in the 77% of patients evaluated; on average, patients with PI3K/AKT suppression stayed in trial for 156 days (49–315) versus 91 days (28–139 days) for those without this biomarker response. Six of the nine evaluable patients (66%) had partial response or stable disease. The median number of days in trial was 105 days (range, 28–315).

Conclusions: Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is safe, suppresses the oncogenic PI3K/AKT kinases, and may be clinically active. Clin Cancer Res; 23(5); 1186–92. ©2016 AACR.
A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas
Authors: Infante Jeffrey R. , Cassier Philippe A. , Gerecitano John F. , Witteveen Petronella O. , Chugh Rashmi , Ribrag Vincent , Chakraborty Abhijit , Matano Alessandro , Dobson Jason R. , Crystal Adam S. , Parasuraman Sudha , Shapiro Geoffrey I.
Published: August 2016

Purpose: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas.

Experimental Design: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle.

Results: Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months.

Conclusions: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I–III studies of ribociclib are under way in various indications. Clin Cancer Res; 22(23); 5696–705. ©2016 AACR.
Correlation of PD-L1 Surface Expression on Leukemia Cells with the Ratio of PD-L1 mRNA Variants and with Electrophoretic Mobility
Authors: Brodská Barbora , Otevřelová Petra , Kuželová Kateřina
Published: August 2016

The expression on the surface of tumor cells of ligands for the PD-1 inhibitory receptor prevents the antitumor immune response and is considered to be a negative prognostic factor in a variety of solid tumors as well as in hematologic malignancies. To determine if it were possible to analyze PD-L1 with PCR-based methods, we assessed the expression of PD-L1 in primary samples from patients with acute myeloid leukemia, in healthy donors, and in a panel of cell lines, by means of flow cytometry, RT-PCR, and Western blotting. Although the surface density of the protein was not correlated with the amount of expressed full-length mRNA, we found a statistically significant positive correlation between PD-L1 surface density and the ratio of two transcript variants (variant 1/variant 2). Our PCR-based method allows for retrospective examination of PD-L1 surface expression from frozen cDNA samples, without the need for a reference gene. Our results also suggest that variant 2, which is produced by alternative splicing, negatively regulates PD-L1 protein expression on the cell surface. In addition, PD-L1 exposition on the cell surface is clearly associated with a shift of electrophoretic mobility, observed on Western blots. This finding can explain the relatively large variability in PD-L1 apparent molecular weight reported in the literature and offers an alternate means for the assessment of PD-L1 surface expression. Cancer Immunol Res; 4(10); 815–9. ©2016 AACR.
MicroRNA-21 Lowers Blood Pressure in Spontaneous Hypertensive Rats by Upregulating Mitochondrial Translation
Authors: Li Huaping , Zhang Xiaorong , Wang Feng , Zhou Ling , Yin Zhongwei , Fan Jiahui , Nie Xiang , Wang Peihua , Fu Xiang-Dong , Chen Chen , Wang Dao Wen
Published: August 2016

BACKGROUND:

Excessive reactive oxygen species generated in mitochondria has been implicated as a causal event in hypertensive cardiomyopathy. Multiple recent studies suggest that microRNAs (miRNAs) are able to translocate to mitochondria to modulate mitochondrial activities, but the medical significance of such a new miRNA function has remained unclear. Here, we characterized spontaneous hypertensive rats (SHRs) in comparison with Wistar rats, finding that micro RNA-21 (miR-21) was dramatically induced in SHRs relative to Wistar rats. We designed a series of experiments to determine whether miR-21 is involved in regulating reactive oxygen species generation in mitochondria, and if so, how induced miR-21 may either contribute to hypertensive cardiomyopathy or represent a compensatory response.

METHODS:

Western blotting was used to compare the expression of key nuclear genome (nDNA)–encoded and mitochondrial genome (mtDNA)–encoded genes involved in reactive oxygen species production in SHRs and Wistar rats. Bioinformatics was used to predict miRNA targets followed by biochemical validation using quantitative real-time polymerase chain reaction and Ago2 immunoprecipitation. The direct role of miRNA in mitochondria was determined by GW182 dependence, which is required for miRNA to function in the cytoplasm, but not in mitochondria. Recombinant adeno-associated virus (type 9) was used to deliver miRNA mimic to rats via tail vein, and blood pressure was monitored with a photoelectric tail-cuff system. Cardiac structure and functions were assessed by echocardiography and catheter manometer system.

RESULTS:

We observed a marked reduction of mtDNA-encoded cytochrome b (mt-Cytb) in the heart of SHRs. Downregulation of mt-Cytb by small interfering RNA in mitochondria recapitulates some key disease features, including elevated reactive oxygen species production. Computational prediction coupled with biochemical analysis revealed that miR-21 directly targeted mt-Cytb to positively modulate mt-Cytb translation in mitochondria. Circulating miR-21 levels in hypertensive patients were significantly higher than those in controls, showing a positive correlation between miR-21 expression and blood pressure. Remarkably, recombinant adeno-associated virus–mediated delivery of miR-21 was sufficient to reduce blood pressure and attenuate cardiac hypertrophy in SHRs.

CONCLUSIONS:

Our findings reveal a positive function of miR-21 in mitochondrial translation, which is sufficient to reduce blood pressure and alleviate cardiac hypertrophy in SHRs. This observation indicates that induced miR-21 is part of the compensatory program and suggests a novel theoretical ground for developing miRNA-based therapeutics against hypertension.
2013 ACC/AHA Cholesterol Guideline Versus 2004 NCEP ATP III Guideline in the Prediction of Coronary Artery Calcification Progression in a Korean Population
Authors: Cho Yun Kyung , Jung Chang Hee , Kang Yu Mi , Hwang Jenie Yoonoo , Kim Eun Hee , Yang Dong Hyun , Kang Joon‐Won , Park Joong‐Yeol , Kim Hong‐Kyu , Lee Woo Je
Published: August 2016

Background

Since the release of the 2013 American College of Cardiology/American Heart Association (
ACC
/
AHA)
guidelines, significant controversy has surrounded the applicability of the new cholesterol guidelines and the Pooled Cohort Equations. In this present study, we investigated whether eligibility for statin therapy determined by the 2013
ACC
/
AHA
guidelines on the management of blood cholesterol is better aligned with the progression of coronary artery calcification (
CAC
) detected by coronary computed tomography angiography (
CCTA
) than the previously recommended 2004 National Cholesterol Education Program (
NCEP
) Adult Treatment Panel (
ATP
)
III
guidelines.

Methods and Results

We enrolled 1246 asymptomatic participants who underwent repeated
CAC
score measurement during routine health examinations. The
CAC
score progression was defined as either incident
CAC
in a population free of
CAC
at baseline or increase ≥2.5 units between the baseline and final square root of
CAC
scores participants who had detectable
CAC
at baseline examination. Application of the
ACC
/
AHA
guidelines to the study population increased the proportion of statin‐eligible subjects from 20.5% (according to
ATP III
) to 54.7%. Statin‐eligible subjects, as defined by
ACC
/
AHA
guidelines, showed a higher odds ratio for
CAC
score progression than those considered statin eligible according to
ATP III
guidelines (2.73 [95% CI, 2.07–3.61] vs 2.00 [95% CI, 1.49–2.68]).

Conclusions

Compared with the
ATP III
guidelines, the new
ACC
/
AHA
guidelines result in better discrimination of subjects with cardiovascular risk detected by
CAC
score progression in an Asian population.
2013 ACC/AHA Cholesterol Guideline and Implications for Healthy People 2020 Cardiovascular Disease Prevention Goals
Authors: Egan Brent M. , Li Jiexiang , White Kellee , Fleming Douglas O. , Connell Kenneth , Hernandez German T. , Jones Daniel W. , Ferdinand Keith C. , Sinopoli Angelo
Published: August 2016

Background

Healthy People 2020 aim to reduce fatal atherosclerotic cardiovascular disease (
ASCVD
) by 20%, which translates into 310 000 fewer events annually assuming proportional reduction in fatal and nonfatal
ASCVD
. We estimated preventable
ASCVD
events by implementing the American College of Cardiology/American Heart Association (
ACC
/
AHA
) 2013 Cholesterol Guideline in all statin‐eligible adults. Absolute risk reduction (
ARR
) and number needed‐to‐treat (
NNT
) were calculated.

Methods and Results

National Health and Nutrition Examination Survey data for 2007–2012 were analyzed for adults aged 21 to 79 years and extrapolated to the US population. Literature‐guided assumptions were used including (1) low‐density lipoprotein cholesterol falls 33% with moderate‐intensity statins and 51% with high‐intensity statins; (2) for each 39 mg/dL decline in low‐density lipoprotein cholesterol, 10‐year
ASCVD
10
risk would fall 21% when
ASCVD
10
risk was ≥20% and 33% when
ASCVD
10
risk was <20%; and (3) either all statin‐eligible untreated adults or all with
ASCVD
10
risk ≥7.5% would receive statins. Of 175.9 million adults aged 21 to 79 years not taking statins, 44.8 million (25.5%) were statin eligible. Treating all statin‐eligible adults would prevent an estimated 243 589
ASCVD
events annually (
ARR
5.4%, 10‐year
NNT
18). Treating all statin‐eligible adults with
ASCVD
10
risk ≥7.5% reduces the number treated to 32.2 million (28.2% fewer), whereas
ASCVD
events prevented annually fall only 10.5% to 217 974 (6.8%
ARR
,
NNT
15).

Conclusions

Implementing the
ACC
/
AHA
2013 Cholesterol Guideline in all untreated, statin‐eligible adults could achieve ≈78% of the Healthy People 2020
ASCVD
prevention goal. Most of the benefit is attained by individuals with 10‐year
ASCVD
risk ≥7.5%.
Obstructive Sleep Apnea and Circulating Potassium Channel Levels
Authors: Jiang Ning , Zhou Anyu , Prasad Bharati , Zhou Li , Doumit Jimmy , Shi Guangbin , Imran Hafiz , Kaseer Bahaa , Millman Richard , Dudley Samuel C.
Published: August 2016

Background

Cardiac arrhythmias and sudden cardiac death are more frequent in patients with obstructive sleep apnea (
OSA
).
OSA
is associated with
QT
prolongation, and
QT
prolongation is an independent risk factor for sudden cardiac death. Because
QT
prolongation can be mediated by potassium channel loss of function, we tested whether
OSA
or continuous positive airway pressure therapy altered
mRNA
expression of circulating white blood cell potassium channels.

Methods and Results

In total, 28 patients with OSA newly diagnosed by polysomnogram and 6 participants without
OSA
were enrolled. Potassium channel levels in white blood cells at baseline and at a 4‐week follow‐up visit were compared. There was a significant inverse correlation between the severity of the
OSA
stratified by apnea–hypopnea index and
mRNA
expression of the main potassium channels assessed:
KCNQ
1 (
r
=−0.486,
P
=0.007),
KCNH
2 (
r
=−0.437,
P
=0.016),
KCNE
1 (
r
=−0.567,
P
=0.001),
KCNJ
2 (
r
=−0.442,
P
=0.015), and
KCNA
5 (
r
=−0.468,
P
=0.009). In addition,
KCNQ
1,
KCNH
2, and
KCNE
1 inversely correlated with the oxygen desaturation index 4. After 4 weeks of continuous positive airway pressure therapy, circulating
KCNQ
1 and
KCNJ
2 were increased 1.4±0.4‐fold (
P
=0.040) and 2.1±1.4‐fold (
P
=0.046) in the moderate
OSA
group. Compared with patients with mild or moderate
OSA
, patients with severe
OSA
had a persistently higher apnea–hypopnea index (mild 2.0±1.8, moderate 1.0±0.9, severe 5.8±5.6;
P
=0.015), perhaps explaining why the potassium channel changes were not seen in the severe
OSA
group.

Conclusions

The
mRNA
expression of most potassium channels inversely correlates with the severity of
OSA
and hypoxemia. Continuous positive airway pressure therapy improves circulating
KCNQ
1 and
KCNJ
2 in patients with moderate
OSA
.
Diagnostic Performance of Treadmill Exercise Cardiac Magnetic Resonance: The Prospective, Multicenter Exercise CMR's Accuracy for Cardiovascular Stress Testing (EXACT) Trial
Authors: Raman Subha V. , Dickerson Jennifer A. , Mazur Wojciech , Wong Timothy C. , Schelbert Erik B. , Min James K. , Scandling Debbie , Bartone Cheryl , Craft Jason T. , Thavendiranathan Paaladinesh , Mazzaferri Ernest L. , Arnold John W. , Gilkeson Robert , Simonetti Orlando P.
Published: August 2016

Background

Stress cardiac magnetic resonance (
CMR
) has typically involved pharmacologic agents. Treadmill
CMR
has shown utility in single‐center studies but has not undergone multicenter evaluation.

Methods and Results

Patients referred for treadmill stress nuclear imaging (
SPECT
) were prospectively enrolled across 4 centers. After rest
99m
Tc
SPECT
, patients underwent resting cine
CMR
. In‐room stress was then performed using an
MR
‐compatible treadmill with continuous 12‐lead electrocardiogram monitoring. At peak stress,
99m
Tc was injected, and patients rapidly returned to the
MR
scanner isocenter for real‐time, free‐breathing stress cine and perfusion imaging. After recovery, cine and rest perfusion followed by late gadolinium enhancement acquisitions concluded
CMR
imaging. Stress
SPECT
was then acquired in adjacent nuclear laboratories. A subset of patients not referred for invasive coronary angiography within 2 weeks of stress underwent coronary computed tomography angiography. Angiographic data available in 94 patients showed sensitivity of 79%, specificity of 99% for exercise
CMR
with positive predictive value of 92% and negative predictive value of 96%. Agreement between treadmill stress
CMR
and angiography was strong (κ=0.82), and moderate between
SPECT
and angiography (κ=0.46) and
CMR
versus
SPECT
(κ=0.48).

Conclusions

The multicenter
EXACT
trial indicates excellent diagnostic value of treadmill stress
CMR
in typical patients referred for exercise
SPECT
.
Niche partitioning along the diet axis in a colour polymorphic population of Eastern Red-backed Salamanders, Plethodon cinereus
Authors: Stuczka Angela , Hickerson Cari-Ann , Anthony Carl
Published: August 2016

Eastern Red-backed Salamanders are colour polymorphic and have become a model system for examining ecological separation and the mechanisms for potential divergence in sympatry. Morphs of this species are differentiated along several niche axes including temperature optima, territorial behaviour, and response to predators. We were interested in whether temporal variation in ecological conditions would affect foraging behavior and ultimately diet. The goal of our study was to compare the diets of striped and unstripedP. cinereusover a range of seasonal conditions to better understand if the reported differences observed in the fall season at our field site remain consistent through the active season of this species. Diet differences between the two morphs were greatest during spring and fall when salamanders are most abundant at the surface. These diet differences were driven largely by two prey categories. In the spring, striped salamanders ate more oribatid mites and in the fall they consumed more entomobryomorph Collembola. Trade-offs associated with territory acquisition coupled with physiological and morphological differences may explain the observed seasonal niche partitioning related to the diet in this population.
“Alcohol Controls and Russian Politics, 1863–1876”
Authors: Abbott Robert J.
Published: August 2016

After abolishing monopolies in alcohol production and sales in 1863, Russian officials struggled to reverse the increased drunkenness and crime perceived to have resulted from the rapid spread of taverns while protecting alcohol taxes. The key actors did so in ways that reflected their differing missions and relationships with the new institutions of local self-government. Responsible for public order and viewing local governments as means of improving rural administration, for a time the Ministry of Internal Affairs sponsored a campaign to replace private taverns with a smaller number of community-owned establishments, winning the support of local authorities and journalists of various political stripes. Responsible for revenues and distrusting resource-poor local governments, the Ministry of Finance successfully opposed this approach on fiscal grounds, an approach that was popular with liberal intellectuals, tavern operators, and their suppliers. In its place, the Finance Ministry favored increasing alcohol taxes to limit consumption while maintaining overall revenues. The Internal Affairs Ministry responded by encouraging and manipulating a tavern-closing temperance campaign that deprived local governments of a revenue source and that journalists exposed as a sham. It did, however, persuade the Finance Ministry to compromise. In 1876 it agreed to share control over the number of taverns in the major cities with the Internal Affairs Ministry’s chiefs of police. This concluded a cycle that illustrated both the potential vitality and the limitations of Russian politics during the Age of the Great Reforms.
The Reception of J.S. Mill’s Feminist Thought in Imperial Russia
Authors: Berest Julia
Published: August 2016

The essay explores the publication and reception of J. S. Mill’s The Subjection of Women in Imperial Russia. Translated in 1869, the same year that the book came out in Britain, The Subjection of Women found a wide audience in Russia, attracting both feminist and conservative readers, many of whom had already been familiar with Mill’s name after the publication of his Principles of Political Economy in Russia nine years earlier. Until the end of Imperial period, the book was published in four translations and six editions, some of which were accompanied by extensive editorial introductions and followed by reviews in the leading Russian journals. The essay analyzes conservative and feminist responses to Mill’s ideas in the context of Russian intellectual and socio-political developments in the second half of the nineteenth century. It also highlights the similarities and differences in the reception of Mill’s feminist thought in Russia and in England.
Patterns of Prejudice from Henri Massis to Walter Bedell Smith
Authors: Platon Mircea
Published: August 2016

Astolphe de Custine’s collection of letters La Russie en 1839, first published in France in 1843, was rediscovered by Henri Massis in 1946. Massis re-introduced Custine’s by then long forgotten letters on Russia to the French public. Once American Cold Warriors such as George Kennan and General Walter Bedell-Smith discovered the book, they promptly promoted it to the status of the most prophetic book on the “Russian soul.” Denounced as “fictional,” by many nineteenth-century writers and by a host of twentieth-century scholars, Custine’s book was accepted as canonical by a large reading public and, more importantly, by successive generations of us policy makers. This article contributes to the historiography of Cold War propaganda by looking first at the context in which the book was initially resurrected by Massis, and then by analyzing the ways in which Cold War propaganda constructed its “relevance,” “actuality” and “prophetic” character. The article begins by taking a look at the way in which Massis, the first popularizer of the book, fitted it into his own ideological pattern. In a second movement, the article analyzes the ways in which the book functioned in the post-wwii ideological context, seeking to discover if the alleged relevance of the book had anything to do with the survival into the postwar world of the European Right’s interwar tangle of received ideas and patterns of prejudice.