bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tetrandrine (TET) Induces Death Receptors Apo Trail R1 (DR4) and Apo Trail R2 (DR5) and Sensitizes Prostate Cancer Cells to TRAIL-Induced Apoptosis
Authors: Shishodia Gauri , Koul Sweaty , Dong Qin , Koul Hari K. 
Published: March 2018

AbstractTNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, but not in normal cells; as such, it is a promising therapeutic agent. However, therapeutic resistance limits its clinical use in many malignancies, including prostate cancer. Strategies to sensitize cancer cells to TRAIL are urgently needed. We demonstrate here that small-molecule tetrandrine (TET) potentially sensitizes previously resistant (LNCaP and C4-2B cells) and mildly sensitive (PC3 cells) prostate cancer cells to TRAIL-induced apoptosis, and they do so by upregulating mRNA expression and protein levels of death receptors Apo Trail R1 (DR4) and Apo Trail R2 (DR5). Using shRNA knockdown, we show critical requirement of DR4 and DR5 in sensitization of prostate cancer cells to TRAIL. We show that double knockdown of DR4 and DR5 abrogated the apoptotic effects of TET and TRAIL. We also demonstrate that TET-induced DR4 and DR5 expression is independent of p53 status. Given that loss of p53 is associated with progression of prostate cancer to CRPC and NEPC, our results show that TET, by acting as a TRAIL-sensitizing agent in prostate cancer, could serve as a potential therapeutic agent in CRPC and NEPC, for which there is no cure to date. Mol Cancer Ther; 17(6); 1217–28. ©2018 AACR.
The DNA-PK Inhibitor VX-984 Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and as Orthotopic Xenografts
Authors: Timme Cindy R. , Rath Barbara H. , O'Neill John W. , Camphausen Kevin , Tofilon Philip J. 
Published: March 2018

Abstract
Radiotherapy is a primary treatment modality for glioblastomas (GBM). Because DNA-PKcs is a critical factor in the repair of radiation-induced double strand breaks (DSB), this study evaluated the potential of VX-984, a new DNA-PKcs inhibitor, to enhance the radiosensitivity of GBM cells. Treatment of the established GBM cell line U251 and the GBM stem-like cell (GSC) line NSC11 with VX-984 under in vitro conditions resulted in a concentration-dependent inhibition of radiation-induced DNA-PKcs phosphorylation. In a similar concentration-dependent manner, VX-984 treatment enhanced the radiosensitivity of each GBM cell line as defined by clonogenic analysis. As determined by γH2AX expression and neutral comet analyses, VX-984 inhibited the repair of radiation-induced DNA double-strand break in U251 and NSC11 GBM cells, suggesting that the VX-984-induced radiosensitization is mediated by an inhibition of DNA repair. Extending these results to an in vivo model, treatment of mice with VX-984 inhibited radiation-induced DNA-PKcs phosphorylation in orthotopic brain tumor xenografts, indicating that this compound crosses the blood–brain tumor barrier at sufficient concentrations. For mice bearing U251 or NSC11 brain tumors, VX-984 treatment alone had no significant effect on overall survival; radiation alone increased survival. The survival of mice receiving the combination protocol was significantly increased as compared with control and as compared with radiation alone. These results indicate that VX-984 enhances the radiosensitivity of brain tumor xenografts and suggest that it may be of benefit in the therapeutic management of GBM. Mol Cancer Ther; 17(6); 1207–16. ©2018 AACR.
Socioeconomic Disparities in Adherence and Outcomes After Heart Transplant
Authors: Wayda Brian , Clemons Autumn , Givens Raymond C. , Takeda Koji , Takayama Hiroo , Latif Farhana , Restaino Susan , Naka Yoshifumi , Farr Maryjane A. , Colombo Paolo C. , Topkara Veli K. 
Published: March 2018

Background:
There is mixed evidence of racial and socioeconomic disparities in heart transplant outcomes. Their underlying cause—and whether individual- or community-level traits are most influential—remains unclear. The current study aimed to characterize socioeconomic disparities in outcomes and identify time trends and mediators of these disparities.

Methods and Results:
We used United Network for Organ Sharing registry data and included 33 893 adult heart transplant recipients between 1994 and 2014. Socioeconomic status (SES) indicators included insurance, education, and neighborhood SES measured using a composite index. Black race and multiple indicators of low SES were associated with the primary outcome of death or retransplant, independent of baseline clinical characteristics. Blacks had lower HLA and race matching, but further adjustment for these and other graft characteristics only slightly attenuated the association with black race (HR, 1.25 after adjustment). This and the associations with neighborhood SES (HR, 1.19 for lowest versus highest decile), Medicare (HR, 1.17), Medicaid (HR, 1.29), and college education (HR, 0.90) remained significant after full adjustment. When comparing early (1994–2000) and late (2001–2014) cohorts, the disparities associated with the middle (second and third) quartiles significantly decreased over time, but those associated with lowest SES quartile and black race persisted. Low neighborhood SES was also associated with higher risks of noncompliance (HR, 1.76), rejection (HR, 1.28), hospitalization (HR, 1.13), and infection (HR, 1.10).

Conclusions:
Racial and socioeconomic disparities exist in heart transplant outcomes, but the latter may be narrowing over time. These disparities are not explained by differences in clinical or graft characteristics.
Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma
Authors: Catino Anna B. , Hubbard Rebecca A. , Chirinos Julio A. , Townsend Ray , Keefe Stephen , Haas Naomi B. , Puzanov Igor , Fang James C. , Agarwal Neeraj , Hyman David , Smith Amanda M. , Gordon Mary , Plappert Theodore , Englefield Virginia , Narayan Vivek , Ewer Steven , ElAmm Chantal , Lenihan Daniel , Ky Bonnie 
Published: March 2018

Background:
Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood.

Methods and Results:

In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e′), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0–17.1;
P
=0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3–10.0;
P
<0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid–femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all
P
<0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time.

Conclusions:
In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function.
Bleeding Severity After Percutaneous Coronary Intervention
Authors: Redfors Björn , Généreux Philippe , Witzenbichler Bernhard , Kirtane Ajay J. , McAndrew Thomas , Weisz Giora , Stuckey Thomas D. , Henry Timothy D. , Maehara Akiko , Mehran Roxana , Stone Gregg W. 
Published: March 2018

Background—
In-hospital bleeding after percutaneous coronary intervention is associated with increased mortality. We studied the impact of bleeding severity, defined as magnitude of Hgb (hemoglobin) reduction from baseline (ΔHgb), on the risk of death and other adverse events.

Methods and Results—

We studied the association between ΔHgb, baseline characteristics, and outcomes among 7608 patients in the ADAPT-DES registry (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) who had information on Hgb values before and after they underwent successful percutaneous coronary intervention. Post-percutaneous coronary intervention, 5985 (78.7%) patients had a drop in Hgb, with 2684 patients (35.3%) having a ΔHgb <1.0 g/dL, 2338 (30.7%) ≥1.0 to <2.0 g/dL, 745 (9.8%) ≥2.0 to <3.0 g/dL, 145 (1.9%) ≥3.0 to <4.0 g/dL, and 73 (1.0%) ≥4.0 g/dL. The risk of dying within 2 years was 3.3% with <1.0 g/dL ΔHgb, 3.4% with ΔHgb ≥1.0 to <2.0 g/dL, 3.7% with ΔHgb ≥2.0 to <3.0 g/dL, 4.1% with ΔHgb ≥3.0 to <4.0 g/dL, and 9.8% with ΔHgb ≥4.0 g/dL (
P
=0.03). The risk of major adverse cardiac events (defined as cardiac death, myocardial infarction, or stent thrombosis) was higher for patients with ΔHgb ≥4.0 g/dL (adjusted hazard ratio, 3.39; 95% confidence interval, 1.97–5.83;
P
<0.001) and for patients with ΔHgb ≥3.0 to <4.0 g/dL (adjusted hazard ratio, 2.17; 95% confidence interval, 1.34–3.53;
P
=0.002).

Conclusions—
Among patients who undergo successful percutaneous coronary intervention, bleeding events that result in ΔHgb ≥4.0 g/dL are associated with a considerably increased risk of dying.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00638794.
Clinical Outcomes and Prognosis Markers of Patients With Liver Disease Undergoing Transcatheter Aortic Valve Replacement
Authors: Tirado-Conte Gabriela , Rodés-Cabau Josep , Rodríguez-Olivares Ramón , Barbanti Marco , Lhermusier Thibault , Amat-Santos Ignacio , Toggweiler Stefan , Cheema Asim N. , Muñoz-García Antonio J. , Serra Vicenc , Giordana Francesca , Veiga Gabriela , Jiménez-Quevedo Pilar , Campelo-Parada Francisco , Loretz Lucca , Todaro Denise , del Trigo María , Hernández-García José M. , García del Blanco Bruno , Bruno Francesco , de la Torre Hernández José M. , Stella Pieter , Tamburino Corrado , Macaya Carlos , Nombela-Franco Luis 
Published: March 2018

Background—
Chronic liver disease is a known risk factor for perioperative morbidity and mortality in patients undergoing cardiac surgery. Very little data exist about such patients treated with transcatheter aortic valve replacement (TAVR). Our objective was to evaluate early and late clinical outcomes in a large cohort of patients with liver disease undergoing TAVR and to determine predictive factors of mortality among these patients.

Methods and Results—

This multicenter study collected data from 114 patients with chronic liver disease who underwent TAVR in 12 institutions. Perioperative and long-term outcomes were compared with a cohort of 1118 patients without liver disease after a propensity score–matching analysis (114 matched pairs). In-hospital mortality and vascular and bleeding complications were similar between matched groups. Acute kidney injury was more common in liver disease group (30.8% versus 13.5%;
P
=0.010). Although cardiovascular mortality was similar between groups (9.4% versus 6.5%;
P
=0.433) at 2-year follow-up, noncardiac mortality was higher in the liver group (26.4% versus 14.8%;
P
=0.034). Lower glomerular filtration rate (hazard ratio, 1.10, for each decrease of 5 mL/min in estimated glomerular filtration rate; 95% confidence interval, 1.03–1.17;
P
=0.005) and Child-Pugh class B or C (hazard ratio, 3.11; 95% confidence interval, 1.47–6.56;
P
=0.003) were the predictors of mortality in patients with chronic liver disease, with a mortality rate of 83.2% at 2-year follow-up in patients with both factors (estimated glomerular filtration rate <60 mL/min and Child-Pugh B or C).

Conclusions—
These findings suggested that TAVR is a feasible treatment for severe aortic stenosis in patients with early-stage liver disease or as bridge therapy before a curative treatment of the hepatic condition. Patients with Child-Pugh class B-C, especially in combination with renal impairment, had a very low survival rate, and TAVR should be carefully considered to avoid a futile treatment. These results may contribute to improve the clinical decision-making process and management in patients with liver disease.
Risk Factors for Poststroke Cognitive Decline
Authors: Levine Deborah A. , Wadley Virginia G. , Langa Kenneth M. , Unverzagt Frederick W. , Kabeto Mohammed U. , Giordani Bruno , Howard George , Howard Virginia J. , Cushman Mary , Judd Suzanne E. , Galecki Andrzej T. 
Published: March 2018

Background and Purpose—
Poststroke cognitive decline causes disability. Risk factors for poststroke cognitive decline independent of survivors’ prestroke cognitive trajectories are uncertain.

Methods—
Among 22 875 participants aged ≥45 years without baseline cognitive impairment from the REGARDS cohort (Reasons for Geographic and Racial Differences in Stroke), enrolled from 2003 to 2007 and followed through September 2015, we measured the effect of incident stroke (n=694) on changes in cognitive functions and cognitive impairment (Six-Item Screener score <5) and tested whether patient factors modified the effect. Median follow-up was 8.2 years.

Results—

Incident stroke was associated with acute declines in global cognition, new learning, verbal memory, and executive function. Acute declines in global cognition after stroke were greater in survivors who were black (
P
=0.04), men (
P
=0.04), and had cardioembolic (
P
=0.001) or large artery stroke (
P
=0.001). Acute declines in executive function after stroke were greater in survivors who had <high school education versus college graduates (
P
=0.01). Incident stroke was associated with faster declines in global cognition and executive function but not new learning or verbal memory compared with prestroke slopes. Faster declines in global cognition over years after stroke were greater in survivors who were older (
P
<0.01), resided outside the Stroke Belt (
P
=0.005), or had cardioembolic stroke (
P
=0.01). Faster declines in executive function over years after stroke were greater in survivors who were older (
P
<0.01) or lacked hypertension (
P
=0.03).

Conclusions—
Incident stroke alters a patient’s cognitive trajectory, and this effect is greater with increasing age and cardioembolic stroke. Race, sex, geography, and hypertension status may modify the risk of poststroke cognitive decline.
Time From Imaging to Endovascular Reperfusion Predicts Outcome in Acute Stroke
Authors: Tsai Jenny P. , Mlynash Michael , Christensen Soren , Kemp Stephanie , Kim Sun , Mishra Nishant K. , Federau Christian , Nogueira Raul G. , Jovin Tudor G. , Devlin Thomas G. , Akhtar Naveed , Yavagal Dileep R. , Bammer Roland , Straka Matus , Zaharchuk Gregory , Marks Michael P. , Albers Gregory W. , Lansberg Maarten G. 
Published: March 2018

Background and Purpose—
This study aims to describe the relationship between computed tomographic (CT) perfusion (CTP)-to-reperfusion time and clinical and radiological outcomes, in a cohort of patients who achieve successful reperfusion for acute ischemic stroke.

Methods—
We included data from the CRISP (Computed Tomographic Perfusion to Predict Response in Ischemic Stroke Project) in which all patients underwent a baseline CTP scan before endovascular therapy. Patients were included if they had a mismatch on their baseline CTP scan and achieved successful endovascular reperfusion. Patients with mismatch were categorized into target mismatch and malignant mismatch profiles, according to the volume of their Tmax >10s lesion volume (target mismatch, <100 mL; malignant mismatch, >100 mL). We investigated the impact of CTP-to-reperfusion times on probability of achieving functional independence (modified Rankin Scale, 0–2) at day 90 and radiographic outcomes at day 5.

Results—

Of 156 included patients, 108 (59%) had the target mismatch profile, and 48 (26%) had the malignant mismatch profile. In patients with the target mismatch profile, CTP-to-reperfusion time showed no association with functional independence (
P
=0.84), whereas in patients with malignant mismatch profile, CTP-to-reperfusion time was strongly associated with lower probability of functional independence (odds ratio, 0.08;
P
=0.003). Compared with patients with target mismatch, those with the malignant mismatch profile had significantly more infarct growth (90 [49–166] versus 43 [18–81] mL;
P
=0.006) and larger final infarct volumes (110 [61–155] versus 48 [21–99] mL;
P
=0.001).

Conclusions—
Compared with target mismatch patients, those with the malignant profile experience faster infarct growth and a steeper decline in the odds of functional independence, with longer delays between baseline imaging and reperfusion. However, this does not exclude the possibility of treatment benefit in patients with a malignant profile.
Rescue Stenting for Failed Mechanical Thrombectomy in Acute Ischemic Stroke
Authors: Chang Yoonkyung , Kim Byung Moon , Bang Oh Young , Baek Jang-Hyun , Heo Ji Hoe , Nam Hyo Suk , Kim Young Dae , Yoo Joonsang , Kim Dong Joon , Jeon Pyoung , Baik Seung Kug , Suh Sang Hyun , Lee Kyung-Yul , Kwak Hyo Sung , Roh Hong Gee , Lee Young-Jun , Kim Sang Heum , Ryu Chang-Woo , Ihn Yon-Kwon , Kim Byungjun , Jeon Hong Jun , Kim Jin Woo , Byun Jun Soo , Suh Sangil , Park Jeong Jin , Lee Woong Jae , Roh Jieun , Shin Byoung-Soo , Kim Jeong-Min 
Published: March 2018

Background and Purpose—
Effective rescue treatment has not yet been suggested in patients with mechanical thrombectomy (MT) failure. This study aimed to test whether rescue stenting (RS) improved clinical outcomes in MT-failed patients.

Methods—
This is a retrospective analysis of the cohorts of the 16 comprehensive stroke centers between September 2010 and December 2015. We identified the patients who underwent MT but failed to recanalize intracranial internal carotid artery or middle cerebral artery M1 occlusion. Patients were dichotomized into 2 groups: patients with RS and without RS after MT failure. Clinical and laboratory findings and outcomes were compared between the 2 groups. It was tested whether RS is associated with functional outcome.

Results—

MT failed in 148 (25.0%) of the 591 patients with internal carotid artery or middle cerebral artery M1 occlusion. Of these 148 patients, 48 received RS (RS group) and 100 were left without further treatment (no stenting group). Recanalization was successful in 64.6% (31 of 48 patients) of RS group. Compared with no stenting group, RS group showed a significantly higher rate of good outcome (modified Rankin Scale score, 0–2; 39.6% versus 22.0%;
P
=0.031) without increasing symptomatic intracranial hemorrhage (16.7% versus 20.0%;
P
=0.823) or mortality (12.5% versus 19.0%;
P
=0.360). Of the RS group, patients who had recanalization success had 54.8% of good outcome, which is comparable to that (55.4%) of recanalization success group with MT. RS remained independently associated with good outcome after adjustment of other factors (odds ratio, 3.393; 95% confidence interval, 1.192–9.655;
P
=0.022). Follow-up vascular imaging was available in the 23 (74.2%) of 31 patients with recanalization success with RS. The stent was patent in 20 (87.0%) of the 23 patients. Glycoprotein IIb/IIIa inhibitor was significantly associated with stent patency but not with symptomatic intracranial hemorrhage.

Conclusions—
RS was independently associated with good outcomes without increasing symptomatic intracranial hemorrhage or mortality. RS seemed considered in MT-failed internal carotid artery or middle cerebral artery M1 occlusion.
Ischemic Stroke Alters the Expression of the Transcribed Ultraconserved Regions of the Genome in Rat Brain
Authors: Mehta Suresh L. , Vemuganti Raghu 
Published: March 2018

Background and Purpose—
Human and rodent genomes diverged ≈75 million years ago. However, 481 regions of their genomes (200–779 nucleotide each) remained absolutely conserved and form noncoding RNAs known as transcribed ultraconserved regions (T-UCRs). The functional significance of T-UCRs is not apparent, but their altered expression is associated with many diseases, and thus thought to be critical for life. We presently investigated the poststroke temporal changes in the expression of T-UCRs with potential functional significance.

Methods—
Male, spontaneously hypertensive rats were subjected to transient middle cerebral artery occlusion. Expression profile of T-UCRs was determined at 3, 6, and 12 hours of reperfusion using microarrays and real-time polymerase chain reaction in the peri-infarct cortex. The putative functional significance of stroke-responsive T-UCRs was identified by bioinformatics.

Results—
Ischemia altered expression of 69 T-UCRs at ≥1 time points of reperfusion compared with sham. Poststroke expression of the intragenic T-UCRs is independent of the expression of their parent gene mRNAs. Bioinformatics showed that the upstream/downstream and the parent genes of the T-UCRs modulate several biological and molecular functions, including metabolism, response to stimuli, cell communication, protein and nucleic acid binding.

Conclusions—
This first report shows that ischemic stroke temporally alters the noncoding ultraconserved RNAs in spontaneously hypertensive rats, but their functional significance is yet to be evaluated.
Critical Investigations of Resilience: A Brief Introduction to Indigenous
Environmental Studies & Sciences
Authors: Whyte Kyle 
Published: March 2018

Abstract
Indigenous peoples are among the most active environmentalists in the world, working through advocacy, educational programs, and research. The emerging field of Indigenous Environmental Studies and Sciences (iess) is distinctive, investigating social resilience to environmental change through the research lens of how moral relationships are organized in societies. Examples of iess research across three moral relationships are discussed here: responsibility, spirituality, and justice. iess develops insights on resilience that can support Indigenous peoples' struggles with environmental justice and political reconciliation; makes significant contributions to global discussions about the relationship between human behavior and the environment; and speaks directly to Indigenous liberation as well as justice issues impacting everyone.