bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proximal to distal approach in the treatment of tandem occlusions causing an acute stroke
Authors: Spiotta Alejandro M , Lena Jonathan , Vargas Jan , Hawk Harris , Turner Raymond D , Chaudry M Imran , Turk Aquilla S 
Published: February 2014

IntroductionA tandem occlusion is a rare presentation of acute stroke that involves an occlusion of the internal carotid artery at the bifurcation with an intracranial middle cerebral artery occlusion. This study describes the experience at our institution in treating tandem occlusions with a proximal to distal approach in the acute stroke setting.MethodsA retrospective review of acute strokes caused by tandem occlusions requiring thrombectomy were performed.Results16 cases were identified with a mean National Institutes of Health Stroke Scale score at presentation of 13.1±3.9. The proximal occlusion was crossed initially with a microwire in all cases. All carotid occlusions were treated with stenting, and intracranial vessel thrombectomy was performed with a variety of devices. Procedure related complications occurred in two (12.5%) patients. Eight patients (50%) achieved a good outcome (modified Rankin Scale score of 0–2).ConclusionsA tandem occlusion of the carotid artery at the bifurcation with a concomitant intracranial occlusion is a relatively rare and complex presentation of acute stroke. We have found that addressing the proximal lesion first and covering it with a stent prior to performing distal thrombectomy appears to be a safe and effective option in the treatment algorithm.
Are terrestrial plumes from motionless plates analogues to Martian plumes feeding the giant shield volcanoes?
Authors: Meyzen Christine M. , Massironi Matteo , Pozzobon Riccardo , Zilio Luca Dal 
Published: February 2014

Abstract
On Earth, most tectonic plates are regenerated and recycled through convection. However, the Nubian and Antarctic plates could be considered as poorly mobile surfaces of various thicknesses that are acting as conductive lids on top of Earth's deeper convective system. Here, volcanoes do not show any linear age progression, at least not for the last 30 myr, but constitute the sites of persistent, focused, long-term magmatic activity rather than a chain of volcanoes, as observed in fast-moving plate plume environments. The melt products vertically accrete into huge accumulations. The residual depleted roots left behind by melting processes cannot be dragged away from the melting loci underlying the volcanoes, which may contribute to producing an unusually shallow depth of oceanic swells. The persistence of a stationary thick depleted lid slows down the efficiency of melting processes at shallow depths. Numerous characteristics of these volcanoes located on motionless plates may be shared by those of the giant volcanoes of the Tharsis province, as Mars is a one-plate planet. The aim of this chapter is to undertake a first inventory of these common features, in order to improve our knowledge of the construction processes of Martian volcanoes.
A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors
Authors: Angevin Eric , Tabernero Josep , Elez Elena , Cohen Steven J. , Bahleda Rastilav , van Laethem Jean-Luc , Ottensmeier Christian , Lopez-Martin Jose A. , Clive Sally , Joly Florence , Ray-Coquard Isabelle , Dirix Luc , Machiels Jean-Pascal , Steven Neil , Reddy Manjula , Hall Brett , Puchalski Thomas A. , Bandekar Rajesh , van de Velde Helgi , Tromp Brenda , Vermeulen Jessica , Kurzrock Razelle 
Published: February 2014

Abstract
Purpose: This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors.
Experimental Design: In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non–small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease &gt;6 weeks.
Results: Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1–45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade ≥3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade ≥3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade ≥3 reported in &gt;1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease &gt;6 weeks. Hemoglobin increased ≥1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein suppression was observed.
Conclusions: Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers. The recommended phase II doses were 11 and 15 mg/kg every 3 weeks. Clin Cancer Res; 20(8); 2192–204. ©2014 AACR.
The Phosphoinositide 3-Kinase α Selective Inhibitor BYL719 Enhances the Effect of the Protein Kinase C Inhibitor AEB071 in GNAQ/GNA11-Mutant Uveal Melanoma Cells
Authors: Musi Elgilda , Ambrosini Grazia , de Stanchina Elisa , Schwartz Gary K. 
Published: February 2014

Abstract
G-protein mutations are one of the most common mutations occurring in uveal melanoma activating the protein kinase C (PKC)/mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K)/AKT pathways. In this study, we described the effect of dual pathway inhibition in uveal melanoma harboring GNAQ and GNA11 mutations via PKC inhibition with AEB071 (sotrastaurin) and PI3K/AKT inhibition with BYL719, a selective PI3Kα inhibitor. Growth inhibition was observed in GNAQ/GNA11-mutant cells with AEB071 versus no activity in wild-type cells. In the GNAQ-mutant cells, AEB071 decreased phosphorylation of myristoylated alanine-rich C-kinase substrate, a substrate of PKC, along with ERK1/2 and ribosomal S6, but persistent AKT activation was present. BYL719 had minimal antiproliferative activity in all uveal melanoma cell lines, and inhibited phosphorylation of AKT in most cell lines. In the GNA11-mutant cell line, similar effects were observed with ERK1/2 inhibition, mostly inhibited by BYL719. With the combination treatment, both GNAQ- and GNA11-mutant cell lines showed synergistic inhibition of cell proliferation and apoptotic cell death. In vivo studies correlated with in vitro findings showing reduced xenograft tumor growth with the combination therapy in a GNAQ-mutant model. These findings suggest a new therapy treatment option for G-protein–mutant uveal melanoma with a focus on specific targeting of multiple downstream pathways as part of combination therapy. Mol Cancer Ther; 13(5); 1044–53. ©2014 AACR.
Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma
Authors: Knutson Sarah K. , Kawano Satoshi , Minoshima Yukinori , Warholic Natalie M. , Huang Kuan-Chun , Xiao Yonghong , Kadowaki Tadashi , Uesugi Mai , Kuznetsov Galina , Kumar Namita , Wigle Tim J. , Klaus Christine R. , Allain Christina J. , Raimondi Alejandra , Waters Nigel J. , Smith Jesse J. , Porter-Scott Margaret , Chesworth Richard , Moyer Mikel P. , Copeland Robert A. , Richon Victoria M. , Uenaka Toshimitsu , Pollock Roy M. , Kuntz Kevin W. , Yokoi Akira , Keilhack Heike 
Published: February 2014

Abstract
Mutations within the catalytic domain of the histone methyltransferase EZH2 have been identified in subsets of patients with non-Hodgkin lymphoma (NHL). These genetic alterations are hypothesized to confer an oncogenic dependency on EZH2 enzymatic activity in these cancers. We have previously reported the discovery of EPZ005678 and EPZ-6438, potent and selective S-adenosyl-methionine-competitive small molecule inhibitors of EZH2. Although both compounds are similar with respect to their mechanism of action and selectivity, EPZ-6438 possesses superior potency and drug-like properties, including good oral bioavailability in animals. Here, we characterize the activity of EPZ-6438 in preclinical models of NHL. EPZ-6438 selectively inhibits intracellular lysine 27 of histone H3 (H3K27) methylation in a concentration- and time-dependent manner in both EZH2 wild-type and mutant lymphoma cells. Inhibition of H3K27 trimethylation (H3K27Me3) leads to selective cell killing of human lymphoma cell lines bearing EZH2 catalytic domain point mutations. Treatment of EZH2-mutant NHL xenograft-bearing mice with EPZ-6438 causes dose-dependent tumor growth inhibition, including complete and sustained tumor regressions with correlative diminution of H3K27Me3 levels in tumors and selected normal tissues. Mice dosed orally with EPZ-6438 for 28 days remained tumor free for up to 63 days after stopping compound treatment in two EZH2-mutant xenograft models. These data confirm the dependency of EZH2-mutant NHL on EZH2 activity and portend the utility of EPZ-6438 as a potential treatment for these genetically defined cancers. Mol Cancer Ther; 13(4); 842–54. ©2014 AACR.
Birinapant (TL32711), a Bivalent SMAC Mimetic, Targets TRAF2-Associated cIAPs, Abrogates TNF-Induced NF-κB Activation, and Is Active in Patient-Derived Xenograft Models
Authors: Benetatos Christopher A. , Mitsuuchi Yasuhiro , Burns Jennifer M. , Neiman Eric M. , Condon Stephen M. , Yu Guangyao , Seipel Martin E. , Kapoor Gurpreet S. , LaPorte Matthew G. , Rippin Susan R. , Deng Yijun , Hendi Mukta S. , Tirunahari Pavan K. , Lee Yu-Hua , Haimowitz Thomas , Alexander Matthew D. , Graham Martin A. , Weng David , Shi Yigong , McKinlay Mark A. , Chunduru Srinivas K. 
Published: February 2014

Abstract
The acquisition of apoptosis resistance is a fundamental event in cancer development. Among the mechanisms used by cancer cells to evade apoptosis is the dysregulation of inhibitor of apoptosis (IAP) proteins. The activity of the IAPs is regulated by endogenous IAP antagonists such as SMAC (also termed DIABLO). Antagonism of IAP proteins by SMAC occurs via binding of the N-terminal tetrapeptide (AVPI) of SMAC to selected BIR domains of the IAPs. Small molecule compounds that mimic the AVPI motif of SMAC have been designed to overcome IAP-mediated apoptosis resistance of cancer cells. Here, we report the preclinical characterization of birinapant (TL32711), a bivalent SMAC-mimetic compound currently in clinical trials for the treatment of cancer. Birinapant bound to the BIR3 domains of cIAP1, cIAP2, XIAP, and the BIR domain of ML-IAP in vitro and induced the autoubiquitylation and proteasomal degradation of cIAP1 and cIAP2 in intact cells, which resulted in formation of a RIPK1:caspase-8 complex, caspase-8 activation, and induction of tumor cell death. Birinapant preferentially targeted the TRAF2-associated cIAP1 and cIAP2 with subsequent inhibition of TNF-induced NF-κB activation. The activity of a variety of chemotherapeutic cancer drugs was potentiated by birinapant both in a TNF-dependent or TNF-independent manner. Tumor growth in multiple primary patient–derived xenotransplant models was inhibited by birinapant at well-tolerated doses. These results support the therapeutic combination of birinapant with multiple chemotherapies, in particular, those therapies that can induce TNF secretion. Mol Cancer Ther; 13(4); 867–79. ©2014 AACR.
Aurora Kinase Inhibition Induces PUMA via NF-κB to Kill Colon Cancer Cells
Authors: Sun Jing , Knickelbein Kyle , He Kan , Chen Dongshi , Dudgeon Crissy , Shu Yongqian , Yu Jian , Zhang Lin 
Published: February 2014

Abstract
Aurora kinases play a key role in mitosis and are frequently overexpressed in a variety of tumor cells. Inhibition of aurora kinases results in mitotic arrest and death of cancer cells, and has been explored as an anticancer strategy. However, how aurora inhibition kills cancer cells is poorly understood. In this study, we found that inhibition of aurora kinases by siRNA or small-molecule inhibitors led to induction of p53 upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, in colorectal cancer cells irrespective of p53 status. Deficiency in PUMA increased polyploidy, improved cell survival, and abrogated mitochondria-mediated apoptosis induced by aurora kinase inhibitors. In response to aurora kinase inhibition, PUMA was directly activated by p65 through the canonical NF-κB pathway following AKT inhibition. Furthermore, PUMA was necessary for the chemosensitization and in vivo antitumor effects of aurora kinase inhibitors in colon cancer cells. These results suggest that PUMA induction mediates the apoptotic response to mitotic arrest imposed by aurora kinase inhibition, and may be a useful indicator for the anticancer activity of aurora kinase inhibitors. Mol Cancer Ther; 13(5); 1298–308. ©2014 AACR.
Streptavidin: A Novel Immunostimulant for the Selection and Delivery of Autologous and Syngeneic Tumor Vaccines
Authors: Weir Chris , Hudson Amanda L. , Moon Elizabeth , Ross Angus , Alexander Miles , Peters Lyndsay , Langova Veronika , Clarke Stephen J. , Pavlakis Nick , Davey Ross , Howell Viive M. 
Published: February 2014

Abstract
Induction of antitumor immunity using autologous tumor proteins is an attractive approach to cancer therapy. However, better methods and stimulants to present these autologous proteins back to the immune system are needed. Here, we identify streptavidin as a novel carrier protein and stimulant, and test the efficacy of both syngeneic (rat) and autologous vaccines (dogs) using streptavidin in combination with reduced soluble tumor proteins. Initial syngeneic vaccine studies in the 9L rat glioma model were used to optimize vaccine dose and selectivity. Cytokine and blood analysis was used to monitor the response. Rats receiving two vaccinations of syngeneic tumor vaccine demonstrated a statistically significant (P &lt; 0.05) survival advantage compared with controls (adjuvant only). Notably, vaccination also led to remission rates of between 30% and 60% in the aggressive 9L glioma model. Antibodies to streptavidin were detected in the serum of vaccinated rats; however, antibody levels did not correlate with the response. The cytokine TNF-α was upregulated in vaccine-treated rats, whereas ICAM1 was downregulated. After engraftment, vaccinated rats maintained CD4+, CD8+ T cells, and total lymphocyte levels closer to normal baseline than those in the controls. Twenty-five dogs treated with autologous vaccine preparations using streptavidin as a stimulant showed no adverse reactions, irrespective of additional chemotherapy and other medications. In this study, we developed a novel method for producing syngeneic and autologous vaccines using streptavidin selectivity and immunogenicity. These vaccines show efficacy in the 9L glioma rat model. Safety was also demonstrated in canine patients presenting with cancer treated with autologous vaccine. Cancer Immunol Res; 2(5); 469–79. ©2014 AACR.
Reproductive Fitness and Genetic Transmission of Tetralogy of Fallot in the Molecular Age
Authors: Chin-Yee Nicolas J. , Costain Gregory , Swaby Jodi-Ann , Silversides Candice K. , Bassett Anne S. 
Published: February 2014

Background—
Individuals with tetralogy of Fallot (TOF) now routinely survive to reproductive age and beyond. Reproductive fitness of adults with TOF and recurrence risks to offspring are of increasing interest in the modern era, especially given recent molecular genetic discoveries.

Methods and Results—

After excluding individuals with known genetic syndromes, 543 unrelated adults with TOF underwent a detailed family history assessment and molecular characterization for rare copy number variations using high-resolution genome-wide microarrays. Men and women with TOF had significantly fewer offspring compared with an age-matched comparison group without congenital heart disease (CHD;
P
=0.0004). No aspect of rare copy number variation burden was a predictor of decreased reproductive fitness. Corresponding with the advent of modern surgical repairs, reproductive fitness of women began to exceed that of men (
P
=0.0490). Recurrence risk for CHD in offspring was 4.8%, with no significant differences between men and women with TOF. The risk of severe CHD in offspring (2.3%) far exceeded population expectations (relative risk, 15.6; 95% confidence interval, 7.9–31.0). Most cases of vertical transmission of CHD were not explained by the transmission of a large rare copy number variation. Although conotruncal lesions (31.5%) were the most commonly reported CHD in relatives, the familial spectrum of disease included many anatomically discordant lesions.

Conclusions—
Men and women with TOF have reduced reproductive fitness. Their offspring are at significantly elevated risk for severe CHD. These results support the importance of genetic counseling for both men and women with complex CHD. Many inherited genetic variants remain to be discovered.
Comparative Survival and Cost-Effectiveness of Advanced Therapies for End-Stage Heart Failure
Authors: Long Elisa F. , Swain Gary W. , Mangi Abeel A. 
Published: February 2014

Background—
Treatment options for end-stage heart failure include inotrope-dependent medical therapy, orthotopic heart transplantation (OHT), left ventricular assist device (LVAD) as destination therapy or bridge to transplant.

Methods and Results—
We developed a state-transition model to simulate 4 treatment options and associated morbidity and mortality. Transition probabilities, costs, and utilities were estimated from published sources. Calculated outcomes included survival, quality-adjusted life-years, and incremental cost-effectiveness. Sensitivity analyses were performed on model parameters to test robustness. Average life expectancy for OHT-eligible patients is estimated at 1.1 years, with 39% surviving to 1 year. OHT with a median wait time of 5.6 months is estimated to increase life expectancy to 8.5 years, and costs <$100 000/quality-adjusted life-year gained, relative to inotrope-dependent medical therapy. Bridge to transplant-LVAD followed by OHT further is estimated to increase life expectancy to 12.3 years, for $226 000/quality-adjusted life-year gained versus OHT. Among OHT-ineligible patients, mean life expectancy with inotrope-dependent medical therapy is estimated at 9.4 months, with 26% surviving to 1 year. Patients who instead received destination therapy-LVAD are estimated to live 4.4 years on average from extrapolation of recent constant hazard rates beyond the first year. This strategy costs $202 000/quality-adjusted life-year gained, relative to inotrope-dependent medical therapy. Patient’s age, time on wait list, and costs associated with care influence outcomes.

Conclusions—
Under most scenarios, OHT prolongs life and is cost effective in eligible patients. Bridge to transplant-LVAD is estimated to offer >3.8 additional life-years for patients waiting ≥6 months, but does not meet conventional cost-effectiveness thresholds. Destination therapy-LVAD significantly improves life expectancy in OHT-ineligible patients. However, further reductions in adverse events or improved quality of life are needed for destination therapy-LVAD to be cost effective.
Long-Term Functional and Clinical Follow-Up of Patients With Heart Failure With Recovered Left Ventricular Ejection Fraction After β-Blocker Therapy
Authors: de Groote Pascal , Fertin Marie , Duva Pentiah Anju , Goéminne Céline , Lamblin Nicolas , Bauters Christophe 
Published: February 2014

Background—
Some patients with left ventricular systolic dysfunction (LVSD) have a dramatic improvement in left ventricular ejection fraction (LVEF) after β-blockade. No study has analyzed the long-term echocardiographic and clinical follow-up of this subgroup of patients.

Methods and Results—

We included in this analysis 174 consecutive patients with LVSD who had an LVEF≥45% after β-blockade. We performed a long-term echocardiographic follow-up (median 7.7 [4–9.9] years) and clinical follow-up (median 9.2 [7.2–10.8] years). LVEF improved from 33±8% to 54±6% after β-blockade (
P
<0.0001). At the last echocardiographic evaluation, 26% of the patients had an LVEF<45% (mean±SD: 34±6%), whereas 74% still had an LVEF≥45% (mean±SD: 54±6%). Independent predictors of LVEF deterioration were a low LVEF, a high left ventricular end-diastolic diameter and a low heart rate after β-blockade, and the presence of a complete left bundle–branch block. In the overall study population, survival rates were 90% at 5 years and 75% at 10 years. Cardiovascular death rate was 9%, noncardiovascular death rate was 11%, and unknown death rate was 3%. Patients with subsequent LVEF deterioration had a higher cardiovascular mortality compared with patients with sustained recovered LVEF (22% versus 4%).

Conclusions—
The long-term survival of patients with LVSD and with near-normal LVEF after β-blockade is good. However, a quarter of these patients may experience a subsequent degradation of LVEF. These patients are at higher risk of cardiovascular mortality.
Left Ventricular Structure and Function in Transthyretin-Related Versus Light-Chain Cardiac Amyloidosis
Authors: Quarta Candida Cristina , Solomon Scott D. , Uraizee Imran , Kruger Jenna , Longhi Simone , Ferlito Marinella , Gagliardi Christian , Milandri Agnese , Rapezzi Claudio , Falk Rodney H. 
Published: February 2014

Background—
Immunoglobulin amyloid light-chain (AL)-related cardiac amyloidosis (CA) has a worse prognosis than either wild-type (ATTRwt) or mutant (ATTRm) transthyretin (TTR) CA. Detailed echocardiographic studies have been performed in AL amyloidosis but not in TTR amyloidosis and might give insight into this difference. We assessed cardiac structure and function and outcome in a large population of patients with CA and compared findings in TTR and AL-related disease.

Methods and Results—

We analyzed 172 patients with CA (AL amyloidosis, n=80; ATTRm, n=36; ATTRwt, n=56) by standard echocardiography and 2-dimensional speckle-tracking imaging-derived left ventricular (LV) longitudinal (LS), radial, and circumferential strains. Despite a preserved LV ejection fraction (55±12%), LS was severely impaired in CA. Standard measures of LV function and speckle-tracking imaging worsened as wall thickness increased, whereas apical LS was preserved regardless of the pathogenesis of CA and the degree of wall thickening. Compared with ATTRm and AL amyloidosis, ATTRwt was characterized by greater LV wall thickness and lower ejection fraction. LS was more depressed in both ATTRwt and AL amyloidosis (−11±3% and −12±4%, respectively,
P
=0.54) than in ATTRm (−15±4%,
P
<0.01 versus AL amyloidosis and ATTRwt). TTR-related causes were favorable predictors of survival, whereas LS and advanced New York Heart Association class were negative predictors.

Conclusions—
In patients with CA, worsening LV function correlated with increasing wall thickness regardless of pathogenesis. Patients with ATTRwt had a statistically greater wall thickness but lesser mortality than those with AL amyloidosis, despite very similar degrees of LS impairment. This paradox suggests an additional mechanism for LV dysfunction in AL amyloidosis, such as previously demonstrated light-chain toxicity.