bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib Treatment Sensitizes Oncolytic HSV-1–Treated Tumors to NK Cell Immunotherapy
Authors: Yoo Ji Young , Jaime-Ramirez Alena Cristina , Bolyard Chelsea , Dai Hongsheng , Nallanagulagari Tejaswini , Wojton Jeffrey , Hurwitz Brian S. , Relation Theresa , Lee Tae Jin , Lotze Michael T. , Yu Jun-Ge , Zhang Jianying , Croce Carlo M. , Yu Jianhua , Caligiuri Michael A. , Old Matthew , Kaur Balveen 
Published: July 2016

Abstract
Purpose: Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV)–expressing GM-CSF are currently FDA approved. Although proteasome blockade can increase oHSV replication, immunologic consequences, and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to natural killer (NK) cell immunotherapy.
Experimental Design: Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of apoptosis/autophagy and/or necroptotic cell death. Cellular and mitochondrial reactive oxygen species (ROS) production was measured using CellROX and MitoSOX. Inhibitors/shRNA–targeting ROS, JNK and RIP1 kinase (RIPK1) were used to investigate the mechanism of cell killing. The synergistic interaction between oHSV and bortezomib was calculated using a Chou–Talalay analysis. NK cells isolated from normal human blood were co-cultured with tumor cells to evaluate cellular interactions. Q-PCR, ELISA, and FACS analysis were used to evaluate NK cell activation. Intracranial tumor xenografts were used to evaluate antitumor efficacy.
Results: Combination treatment with bortezomib- and oHSV-induced necroptotic cell death and increased the production of mitochondrial ROS and JNK phosphorylation. Inhibitors/shRNA of RIPK1 and JNK rescued synergistic cell killing. Combination treatment also significantly enhanced NK cell activation and adjuvant NK cell therapy of mice treated with bortezomib and oHSV improved antitumor efficacy.
Conclusions: This study provides a significant rationale for triple combination therapy with bortezomib, oHSV, and NK cells to improve efficacy, in glioblastoma patients. Clin Cancer Res; 22(21); 5265–76. ©2016 AACR.
See related commentary by Suryadevara et al., p. 5164
Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer
Authors: Chen Long , Li Jie , Farah Elia , Sarkar Sukumar , Ahmad Nihal , Gupta Sanjay , Larner James , Liu Xiaoqi 
Published: July 2016

Abstract
Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) reactivation is responsible for the recurrence of prostate cancer after ADT. Thus, targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSP) are chaperones that modify stability and activity of their client proteins. HSP90, a major player in the HSP family, regulates stability of many proteins, including AR and Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events. Further, HSP90 is overexpressed in different cancers, including prostate cancer. Herein, we show that cotreatment of prostate cancer with AR antagonist enzalutamide and HSP90 inhibitor leads to more severe cell death due to a synergistic reduction of AR protein. Interestingly, we show that overexpression of Plk1 rescued the synergistic effect and that cotargeting HSP90 and Plk1 also leads to more severe cell death. Mechanistically, we show that E3 ligase CHIP, in addition to targeting AR, is responsible for the degradation of Plk1 as well. These findings suggest that cotargeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC. Mol Cancer Ther; 15(9); 2107–18. ©2016 AACR.
Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin
Authors: Ganesh Shanthi , Koser Martin L. , Cyr Wendy A. , Chopda Girish R. , Tao Junyan , Shui Xue , Ying Bo , Chen Dongyu , Pandya Purva , Chipumuro Edmond , Siddiquee Zakir , Craig Kevin , Lai Chengjung , Dudek Henryk , Monga Satdarshan P. , Wang Weimin , Brown Bob D. , Abrams Marc T. 
Published: July 2016

AbstractThe Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level and therefore can be applied to previously undruggable targets. Lipid nanoparticles (LNP) represent an elegant solution for the delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have been mostly restricted to applications in the liver. In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Significant tumor growth inhibition was achieved in Wnt-dependent colorectal and hepatocellular carcinoma models, but not in Wnt-independent tumors. Finally, no evidence of accelerated blood clearance or sustained liver transaminase elevation was observed after repeated dosing in nonhuman primates. These data support further investigation to gain mechanistic insight, optimize dose regimens, and identify efficacious combinations with standard-of-care therapeutics. Mol Cancer Ther; 15(9); 2143–54. ©2016 AACR.
Endothelial Dysfunction, and A Prothrombotic, Proinflammatory Phenotype Is Caused by Loss of Mitochondrial Thioredoxin Reductase in Endothelium
Authors: Kirsch Julian , Schneider Holger , Pagel Judith-Irina , Rehberg Markus , Singer Miriam , Hellfritsch Juliane , Chillo Omary , Schubert Kai Michael , Qiu Jiehua , Pogoda Kristin , Kameritsch Petra , Uhl Bernd , Pircher Joachim , Deindl Elisabeth , Müller Susanna , Kirchner Thomas , Pohl Ulrich , Conrad Marcus , Beck Heike 
Published: July 2016

Objective—
Although the investigation on the importance of mitochondria-derived reactive oxygen species (ROS) in endothelial function has been gaining momentum, little is known on the precise role of the individual components involved in the maintenance of a delicate ROS balance. Here we studied the impact of an ongoing dysregulated redox homeostasis by examining the effects of endothelial cell–specific deletion of murine thioredoxin reductase 2 (Txnrd2), a key enzyme of mitochondrial redox control.

Approach and Results—
We analyzed the impact of an inducible, endothelial cell–specific deletion of Txnrd2 on vascular remodeling in the adult mouse after femoral artery ligation. Laser Doppler analysis and histology revealed impaired angiogenesis and arteriogenesis. In addition, endothelial loss of Txnrd2 resulted in a prothrombotic, proinflammatory vascular phenotype, manifested as intravascular cellular deposits, as well as microthrombi. This phenotype was confirmed by an increased leukocyte response toward interleukin-1 in the mouse cremaster model. In vitro, we could confirm the attenuated angiogenesis measured in vivo, which was accompanied by increased ROS and an impaired mitochondrial membrane potential. Ex vivo analysis of femoral arteries revealed reduced flow-dependent vasodilation in endothelial cell Txnrd2-deficient mice. This endothelial dysfunction could be, at least partly, ascribed to inadequate nitric oxide signaling.

Conclusions—
We conclude that the maintenance of mitochondrial ROS via Txnrd2 in endothelial cells is necessary for an intact vascular homeostasis and remodeling and that Txnrd2 plays a vitally important role in balancing mitochondrial ROS production in the endothelium.
New Functional Tools for Antithrombogenic Activity Assessment of Live Surface Glycocalyx
Authors: Dimitrievska Sashka , Gui Liqiong , Weyers Amanda , Lin Tylee , Cai Chao , Wu Wei , Tuggle Charles T. , Sundaram Sumati , Balestrini Jenna L. , Slattery David , Tchouta Lise , Kyriakides Themis R. , Tarbell John M. , Linhardt Robert J. , Niklason Laura E. 
Published: July 2016

Objective—
It is widely accepted that the presence of a glycosaminoglycan-rich glycocalyx is essential for endothelialized vasculature health; in fact, a damaged or impaired glycocalyx has been demonstrated in many vascular diseases. Currently, there are no methods that characterize glycocalyx functionality, thus limiting investigators’ ability to assess the role of the glycocalyx in vascular health.

Approach and Results—

We have developed novel, easy-to-use, in vitro assays that directly quantify live endothelialized surface’s functional heparin weights and their anticoagulant capacity to inactivate Factor Xa and thrombin. Using our assays, we characterized 2 commonly used vascular models: native rat aorta and cultured human umbilical vein endothelial cell monolayer. We determined heparin contents to be ≈10 000 ng/cm
2
on the native aorta and ≈10-fold lower on cultured human umbilical vein endothelial cells. Interestingly, human umbilical vein endothelial cells demonstrated a 5-fold lower anticoagulation capacity in inactivating both Factor Xa and thrombin relative to native aortas. We verified the validity and accuracy of the novel assays developed in this work using liquid chromatography–mass spectrometry analysis.

Conclusions—
Our assays are of high relevance in the vascular community because they can be used to establish the antithrombogenic capacity of many different types of surfaces such as vascular grafts and transplants. This work will also advance the capacity for glycocalyx-targeting therapeutics development to treat damaged vasculatures.
Nonischemic Left Ventricular Scar as a Substrate of Life-Threatening Ventricular Arrhythmias and Sudden Cardiac Death in Competitive Athletes
Authors: Zorzi Alessandro , Perazzolo Marra Martina , Rigato Ilaria , De Lazzari Manuel , Susana Angela , Niero Alice , Pilichou Kalliopi , Migliore Federico , Rizzo Stefania , Giorgi Benedetta , De Conti Giorgio , Sarto Patrizio , Serratosa Luis , Patrizi Giampiero , De Maria Elia , Pelliccia Antonio , Basso Cristina , Schiavon Maurizio , Bauce Barbara , Iliceto Sabino , Thiene Gaetano , Corrado Domenico 
Published: July 2016

Background—
The clinical profile and arrhythmic outcome of competitive athletes with isolated nonischemic left ventricular (LV) scar as evidenced by contrast-enhanced cardiac magnetic resonance remain to be elucidated.

Methods and Results—

We compared 35 athletes (80% men, age: 14–48 years) with ventricular arrhythmias and isolated LV subepicardial/midmyocardial late gadolinium enhancement (LGE) on contrast-enhanced cardiac magnetic resonance (group A) with 38 athletes with ventricular arrhythmias and no LGE (group B) and 40 healthy control athletes (group C). A stria LGE pattern with subepicardial/midmyocardial distribution, mostly involving the lateral LV wall, was found in 27 (77%) of group A versus 0 controls (group C;
P
<0.001), whereas a spotty pattern of LGE localized at the junction of the right ventricle to the septum was respectively observed in 11 (31%) versus 10 (25%;
P
=0.52). All athletes with stria pattern showed ventricular arrhythmias with a predominant right bundle branch block morphology, 13 of 27 (48%) showed ECG repolarization abnormalities, and 5 of 27 (19%) showed echocardiographic hypokinesis of the lateral LV wall. The majority of athletes with no or spotty LGE pattern had ventricular arrhythmias with a predominant left bundle branch block morphology and no ECG or echocardiographic abnormalities. During a follow-up of 38±25 months, 6 of 27 (22%) athletes with stria pattern experienced malignant arrhythmic events such as appropriate implantable cardiac defibrillator shock (n=4), sustained ventricular tachycardia (n=1), or sudden death (n=1), compared with none of athletes with no or LGE spotty pattern and controls.

Conclusions—
Isolated nonischemic LV LGE with a stria pattern may be associated with life-threatening arrhythmias and sudden death in the athlete. Because of its subepicardial/midmyocardial location, LV scar is often not detected by echocardiography.
Escape behaviour in the leopard lizard (Gambelia wislizenii): effects of starting distance and sex
Authors: Jacobson Faelan , Garrison Grace , Penner Jacob , Gebin João Zecchini , Eifler Maria , Eifler Douglas 
Published: July 2016

Predation risk influences decision making, escape behaviour, and resource use. Risk assessment and behavioural responses to predation can depend on demographic and environmental factors. We studied the escape behaviour of the long-nosed leopard lizard (Gambelia wislizenii) when approached by a human predator (= “simulated predator”), analysing flight initiation distance (FID) and flight distance (FD) relative to demographic and environmental variables. Starting distance (SD) of the simulated predator and orientation of prey lizards relative to the simulated predator influenced FID, but body size of the prey lizard did not. Sex interacted with SD to affect FID. Females lengthened their FIDs as SD increased, while male FID was unrelated to SD. Flight distance increased with increasing SD.Gambelia wislizenii’s ecological role as an ambush predator may explain their escape behaviour; reproductive status potentially affected the interaction between sex and SD.
Two new species of the genus Centromacronema Ulmer 1905 (Hydropsychidae: Macronematinae) from Brazil
Authors: DIAS EVERTON S. , CALOR ADOLFO R. 
Published: July 2016

Centromacronema is an endemic genus from the Neotropics, with distribution ranging from Mexico to southern Brazil. The genus comprises 15 described species, but only two of them have been recorded in Brazil: Centromacronema auripenne (Rambur 1842) and C. obscurum (Ulmer 1905). Two new species are herein described and illustrated from Brazil, C. pioneira n. sp. from Serra da Jiboia, Bahia state, including the first description of a female for the genus, and C. poyanawa n. sp. from Serra do Divisor, Acre state.
A new species of the genus Melita (Amphipoda, Hadzioidea, Melitidae) from anchialine pool on the Cozumel Island, NE Caribbean Sea
Authors: ORTIZ MANUEL , WINFIELD IGNACIO 
Published: July 2016

A new species of genus Melita collected from anchialine pool (Cenote Aerolito) on Cozumel Island is described. Distinctive characters of male of the new species include an accessory flagellum 4–articulate; palm of gnathopod 2 with long setae; urosomite 2 with two robust setae on right side, and one on left. Female of the new species differs by coxa 6 without lateral ridge at base of hook, and anteroventral angle without stridulating ridges on anteroventral process; gnathopods 1–2 covered with long setae on articles 5–6. The main morphological differences between males of Melita species recorded previously for the Gulf of Mexico and the Caribbean Sea and the new species are also given.
Single crossclamp: Safe training tool for coronary artery bypass grafting
Authors: Srivastava Vivek , Purohit Manoj , Bose Amal , Bittar Mohamed Nidal , Rogers Shaun , Zacharias Joseph 
Published: July 2016

Objective The single-crossclamp technique for coronary artery bypass grafting is recognized to reduce manipulation of the ascending aorta, and thereby improve neurological outcomes. However, there is a perceived disadvantage of long cardiopulmonary bypass and crossclamp times. Our objective was to evaluate outcomes with this technique and determine whether it is safe for training. Methods Patients undergoing coronary artery bypass between October 2005 and February 2014 with use of the single-crossclamp method were divided into 2 groups: a consultant group ( n = 1024), and a trainee group ( n = 504), depending on the primary surgeon. Their outcomes were compared. Results The consultants operated on more nonelective patients who had a higher risk profile (mean additive EuroSCORE I 4.05 vs. 3.80, p = 0.085; logistic EuroSCORE I 4.36 vs. 3.64, p = 0.002). There were 9 (0.9%) deaths in the consultant group and 5 (1%) in the trainee group. The mean number of grafts in the consultant group was greater, but the crossclamp time was similar and cardiopulmonary bypass time was shorter. There were 4 (0.4%) cerebrovascular events in the consultant group and 3 (0.6%) in the trainee group. Postoperative stay was shorter in the trainee group (7.19 vs. 7.97 days, p = 0.033). Other complication rates were similar. Conclusions The technique has excellent outcomes, especially neurological, and is safe for training junior surgeons.
Point-of-care platelet function testing to predict blood loss after coronary artery bypass grafting surgery: a prospective observational pilot study
Authors: Ellis James , Valencia Oswaldo , Crerar-Gilbert Agnieszka , Phillips Simon , Meeran Hanif , Sharma Vivek 
Published: July 2016

Aim: With an increase in the number of patients who are on antiplatelet medications until the day of surgery, we undertook a prospective observational study to assess the ability of thromboelastography, thromboelastography platelet mapping and aggregometry via multiplate to detect platelet dysfunction and predict blood loss following coronary artery bypass grafting (CABG) surgery. Methods: Platelet function was evaluated pre- and post-cardiopulmonary bypass via thromboelastography, thromboelastography platelet mapping and aggregometry via multiplate in 52 patients undergoing coronary artery bypass grafting surgery. The median chest tube drainage of all patients in the study was ascertained to stratify patients into two groups: patients with and those without evidence of excessive blood loss after cardiac surgery. Results: Although all modalities could detect a decrease in platelet function following cardiopulmonary bypass, univariate and multivariate regression analysis identified preoperative arachidonic acid and adenosine diphosphate testing via multiplate as independent predictors of bleeding after cardiac surgery. Receiver operating curves on these multiplate parameters showed an area under the curve of 0.68 (p=0.03) and 0.66 (p=0.01) for arachidonic acid and adenosine diphosphate assays, respectively. Conclusion: This pilot study shows that preoperative multiplate testing may be a better predictor of platelet dysfunction and the resultant blood loss following cardiac surgery.
Cell-free DNA increase over first 48 hours in emergency intensive care unit predicts fatal outcome in patients with shock
Authors: Xia Dun Ling , Zhang Hong , Luo Qing Li , Zhang A Fang , Zhu Li Xin 
Published: July 2016

Objective To investigate whether circulating cell-free (cf)-DNA levels are a useful biomarker for survival in patients with shock in the emergency intensive care unit (EICU). Methods This prospective observational study enrolled patients admitted to the EICU diagnosed with shock. Blood cf-DNA levels were analysed on admission, and after 24 and 48 h. As a measure of circulating cf-DNA, copy number of the β-globin gene in plasma was assessed using quantitative real-time polymerase chain reaction. Results Circulating cf-DNA levels were higher at hospital admission and after 24 h in EICU patients with shock who died than in those who recovered. Change in cf-DNA levels over the first 48 h in critical care was independently associated with 28-day mortality. The critical cut-off value for cf-DNA change over 48 h in predicting 28-day mortality was +16.12% (sensitivity 68.9%, specificity 89.7%). Conclusions Increased circulating cf-DNA levels in EICU patients with shock are associated with risk of death and measuring cf-DNA change over 48 h improves risk prediction. The present study suggests that cf-DNA may serve as a viable plasma biomarker of mortality risk in EICU patients with shock.
Incidence and possible causes of nontraumatic convexal subarachnoid haemorrhage in Chinese patients: A retrospective review
Authors: Zhao Haiyan , Han Jintao , Lu Ming , Zhang Yingshuang , Fan Dongsheng 
Published: July 2016

Objective To explore the incidence and possible underlying pathogenic mechanisms of nontraumatic convexal subarachnoid haemorrhage (cSAH; a rarely reported condition) in a cohort of Chinese patients. Methods Medical records from all patients with subarachnoid haemorrhage (SAH) who had been treated at Peking University Third Hospital, China, between January 2010 and December 2014 were retrospectively reviewed to identify cases of cSAH. Results Of 144 patients with SAH, cSAH was observed in 14 cases (9.7%). The most frequent presenting symptoms in cSAH cases were severe headache ( n = 8) and a focal neurological deficit ( n = 8). The parietal (10/14 patients, 71.4%) and frontal (9/14 patients, 64.3%) lobes were the most common haemorrhage sites. Cause of cSAH was identified in 11 patients: in seven cases (50.0%), significant stenosis or occlusion in the internal carotid artery system, ipsilateral to cSAH, was reported; in four cases, cSAH was caused by cerebral venous sinus thrombosis, cerebrovascular malformation, anticoagulant therapy or possible cerebral amyloid angiopathy. Conclusion cSAH is an important subtype of nonaneurysmal SAH, with diverse aetiologies. In the present study, internal carotid artery system atherosclerotic stenosis was the most frequent cause of cSAH.
Exploring the High Reinjury Rate in Younger Patients Undergoing Anterior Cruciate Ligament Reconstruction
Authors: Webster Kate E. , Feller Julian A. 
Published: July 2016

Background: Younger age is being increasingly recognized as a risk factor for anterior cruciate ligament (ACL) graft rupture and contralateral ACL injury after ACL reconstruction. Recent reports estimate second ACL injury rates to be in the range of 20% to 40%, which is a significant concern and requires further exploration. Purpose: The primary purpose was to determine the rates of graft rupture and injury to the contralateral native ACL in younger athletes. We also sought to explore the influence of sex and age groupings (<18 years vs 18-19 years at the time of surgery) on the risk of subsequent ACL injury. Study Design: Cohort study; Level of evidence, 3. Methods: The study cohort consisted of 354 consecutive patients who were younger than 20 years when they underwent their first primary hamstring tendon autograft ACL reconstruction. The number of subsequent ACL injuries (graft rupture or a contralateral injury to the native ACL) was determined at a mean follow-up of 5 years (range, 3-10 years). Subgroup analysis included sex and age (<18 years vs 18-19 years at the time of surgery) comparisons. Descriptive statistics were calculated for the timing of ACL graft rupture and contralateral ACL injury. Results: The overall follow-up rate was 89% (316/354). Graft ruptures occurred in 57 patients (18%) at an average time of 1.8 years after surgery. Almost half (47%) occurred within the first postoperative year, and 74% occurred within the first 2 years. The highest graft rupture rate of 28.3% was in the youngest males (<18 years), and this was significantly higher than in females of the same age (12.9%), as well as in male patients older than 18 years (13.8%). Contralateral ACL injuries occurred in 56 patients (17.7%) at an average time of 3.7 years after surgery. There were no significant age- or sex-based differences for contralateral ACL injuries. The total number of patients who had at least 1 further ACL injury subsequent to the primary surgery was 110 (35%). Conclusion: The high rate of subsequent ACL injury in younger patients was confirmed. Early graft ruptures were more prevalent in patients who underwent surgery when they were younger than 18 years versus those in the 18- to 19-year age group. Males had higher rates of graft rupture than did females, with the youngest males (<18 years) at the highest risk in the investigated cohort.