bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tirapazamine Sensitizes Hepatocellular Carcinoma Cells to Topoisomerase I Inhibitors via Cooperative Modulation of Hypoxia-Inducible Factor-1α
Authors: Cai Tian-Yu , Liu Xiao-Wen , Zhu Hong , Cao Ji , Zhang Jun , Ding Ling , Lou Jian-Shu , He Qiao-Jun , Yang Bo 
Published: December 2013

Abstract
Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer. Here, we present in vitro and in vivo evidence that the extremely high level of hypoxia-inducible factor-1α (HIF-1α) in hepatocellular carcinoma is intimately correlated with resistance to topoisomerase I inhibitors. In a previous study conducted by our group, we found that tirapazamine could downregulate HIF-1α expression by decreasing HIF-1α protein synthesis. Therefore, we hypothesized that combining tirapazamine with topoisomerase I inhibitors may overcome the chemoresistance. In this study, we investigated that in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1α protein, decreased the HIF-1α transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs. Moreover, the increased anticancer efficacy of tirapazamine combined with irinotecan was further validated in a human liver cancer Bel-7402 xenograft mouse model. Taken together, our data show for the first time that HIF-1α is strongly correlated with resistance to topoisomerase I inhibitors in hepatocellular carcinoma. These results suggest that HIF-1α is a promising target and provide a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and tirapazamine in hepatocellular cancers. Mol Cancer Ther; 13(3); 630–42. ©2013 AACR.
Dinaciclib (SCH727965) Inhibits the Unfolded Protein Response through a CDK1- and 5-Dependent Mechanism
Authors: Nguyen Tri K. , Grant Steven 
Published: December 2013

Abstract
Evidence implicating dysregulation of the IRE1/XBP-1s arm of the unfolded protein response (UPR) in cancer pathogenesis (e.g., multiple myeloma) has prompted the development of IRE1 RNase inhibitors. Here, effects of cyclin-dependent kinase (CDK) inhibitor SCH727965 (dinaciclib) on the IRE1 arm of the UPR were examined in human leukemia and myeloma cells. Exposure of cells to extremely low (e.g., nmol/L) concentrations of SCH727965, a potent inhibitor of CDKs 1/2/5/9, diminished XBP-1s and Grp78 induction by the endoplasmic reticulum (ER) stress-inducers thapsigargin and tunicamycin, while sharply inducing cell death. SCH727965, in contrast to IRE1 RNase inhibitors, inhibited the UPR in association with attenuation of XBP-1s nuclear localization and accumulation rather than transcription, translation, or XBP-1 splicing. Notably, in human leukemia cells, CDK1 and 5 short hairpin RNA (shRNA) knockdown diminished Grp78 and XBP-1s upregulation while increasing thapsigargin lethality, arguing for a functional role for CDK1/5 in activation of the cytoprotective IRE1/XBP-1s arm of the UPR. In contrast, CDK9 or 2 inhibitors or shRNA knockdown failed to downregulate XBP-1s or Grp78. Furthermore, IRE1, XBP-1, or Grp78 knockdown significantly increased thapsigargin lethality, as observed with CDK1/5 inhibition/knockdown. Finally, SCH727965 diminished myeloma cell growth in vivo in association with XBP-1s downregulation. Together, these findings demonstrate that SCH727965 acts at extremely low concentrations to attenuate XBP-1s nuclear accumulation and Grp78 upregulation in response to ER stress inducers. They also highlight a link between specific components of the cell-cycle regulatory apparatus (e.g., CDK1/5) and the cytoprotective IRE1/XBP-1s/Grp78 arm of the UPR that may be exploited therapeutically in UPR-driven malignancies. Mol Cancer Ther; 13(3); 662–74. ©2013 AACR.
AKT-Induced Tamoxifen Resistance Is Overturned by RRM2 Inhibition
Authors: Shah Khyati N. , Mehta Kshama R. , Peterson David , Evangelista Marie , Livesey John C. , Faridi Jesika S. 
Published: December 2013

Abstract
Acquired tamoxifen resistance develops in the majority of hormone-responsive breast cancers and frequently involves overexpression of the PI3K/AKT axis. Here, breast cancer cells with elevated endogenous AKT or overexpression of activated AKT exhibited tamoxifen-stimulated cell proliferation and enhanced cell motility. To gain mechanistic insight on AKT-induced endocrine resistance, gene expression profiling was performed to determine the transcripts that are differentially expressed post-tamoxifen therapy under conditions of AKT overexpression. Consistent with the biologic outcome, many of these transcripts function in cell proliferation and cell motility networks and were quantitatively validated in a larger panel of breast cancer cells. Moreover, ribonucleotide reductase M2 (RRM2) was revealed as a key contributor to AKT-induced tamoxifen resistance. Inhibition of RRM2 by RNA interference (RNAi)–mediated approaches significantly reversed the tamoxifen-resistant cell growth, inhibited cell motility, and activated DNA damage and proapoptotic pathways. In addition, treatment of tamoxifen-resistant breast cancer cells with the small molecule RRM inhibitor didox significantly reduced in vitro and in vivo growth. Thus, AKT-expressing breast cancer cells upregulate RRM2 expression, leading to increased DNA repair and protection from tamoxifen-induced apoptosis.
Implications: These findings identify RRM2 as an AKT-regulated gene, which plays a role in tamoxifen resistance and may prove to be a novel target for effective diagnostic and preventative strategies. Mol Cancer Res; 12(3); 394–407. ©2013 AACR.
T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells
Authors: Dziegielewska Barbara , Brautigan David L. , Larner James M. , Dziegielewski Jaroslaw 
Published: December 2013

Abstract
Epithelial tumor cells express T-type Ca2+ channels, which are thought to promote cell proliferation. This study investigated the cellular response to T-type Ca2+ channel inhibition either by small-molecule antagonists or by RNAi-mediated knockdown. Selective T-type Ca2+ channel antagonists caused growth inhibition and apoptosis more effectively in HCT116 cells expressing wild-type p53 (p53wt), than in HCT116 mutant p53−/− cells. These antagonists increased p53-dependent gene expression and increased genomic occupancy of p53 at specific target sequences. The knockdown of a single T-type Ca2+ channel subunit (CACNA1G) reduced cell growth and induced caspase-3/7 activation in HCT116 p53wt cells as compared with HCT116 mutant p53−/− cells. Moreover, CaCo2 cells that do not express functional p53 were made more sensitive to CACNA1G knockdown when p53wt was stably expressed. Upon T-type Ca2+ channel inhibition, p38-MAPK promoted phosphorylation at Ser392 of p53wt. Cells treated with the inhibitor SB203580 or specific RNAi targeting p38-MAPKα/β (MAPK14/MAPK11) showed resistance to T-type Ca2+ channel inhibition. Finally, the decreased sensitivity to channel inhibition was associated with decreased accumulation of p53 and decreased expression of p53 target genes, p21Cip1 (CDKN1A) and BCL2-binding component 3 (BBC3/PUMA).
Implications: A novel pathway involving p53 and p38-MAPK is revealed and provides a rationale for antitumor therapies that target T-type Ca2+ channels. Mol Cancer Res; 12(3); 348–58. ©2013 AACR.
MAX Inactivation in Small Cell Lung Cancer Disrupts MYC–SWI/SNF Programs and Is Synthetic Lethal with BRG1
Authors: Romero Octavio A. , Torres-Diz Manuel , Pros Eva , Savola Suvi , Gomez Antonio , Moran Sebastian , Saez Carmen , Iwakawa Reika , Villanueva Alberto , Montuenga Luis M. , Kohno Takashi , Yokota Jun , Sanchez-Cespedes Montse 
Published: December 2013

Abstract
Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplification of L-MYC, N-MYC, and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1, the latter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAX dimerization protein, MGA, was also observed in both non–small cell lung cancer and SCLC. Our results provide evidence that an aberrant SWI/SNF–MYC network is essential for lung cancer development.
Significance: We discovered that the MYC-associated factor X gene, MAX, is inactivated in SCLCs. Furthermore, we revealed a preferential toxicity of the inactivation of the chromatin remodeler BRG1 in MAX-deficient lung cancer cells, which opens novel therapeutic possibilities for the treatment of patients with SCLC with MAX-deficient tumors. Cancer Discov; 4(3); 292–303. ©2013 AACR.
See related commentary by Rudin and Poirier, p. 273
This article is highlighted in the In This Issue feature, p. 259
Atrial Fibrillation Ablation Outcome Is Predicted by Left Atrial Remodeling on MRI
Authors: McGann Christopher , Akoum Nazem , Patel Amit , Kholmovski Eugene , Revelo Patricia , Damal Kavitha , Wilson Brent , Cates Josh , Harrison Alexis , Ranjan Ravi , Burgon Nathan S. , Greene Tom , Kim Dan , DiBella Edward V.R. , Parker Dennis , MacLeod Rob S. , Marrouche Nassir F. 
Published: December 2013

Background—
Although catheter ablation therapy for atrial fibrillation (AF) is becoming more common, results vary widely, and patient selection criteria remain poorly defined. We hypothesized that late gadolinium enhancement MRI (LGE-MRI) can identify left atrial (LA) wall structural remodeling (SRM) and stratify patients who are likely or not to benefit from ablation therapy.

Methods and Results—

LGE-MRI was performed on 426 consecutive patients with AF without contraindications to MRI before undergoing their first ablation procedure and on 21 non-AF control subjects. Patients were categorized by SRM stage (I–IV) based on the percentage of LA wall enhancement for correlation with procedure outcomes. Histological validation of SRM was performed comparing LGE-MRI with surgical biopsy. A total of 386 patients (91%) with adequate LGE-MRI scans were included in the study. After ablation, 123 patients (31.9%) experienced recurrent atrial arrhythmias during the 1-year follow-up. Recurrent arrhythmias (failed ablations) occurred at higher SRM stages with 28 of 133 (21.0%) in stage I, 40 of 140 (29.3%) in stage II, 24 of 71 (33.8%) in stage III, and 30 of 42 (71.4%) in stage IV. In multivariate analysis, ablation outcome was best predicted by advanced SRM stage (hazard ratio, 4.89;
P
<0.0001) and diabetes mellitus (hazard ratio, 1.64;
P
=0.036), whereas increased LA volume and persistent AF were not significant predictors. LA wall enhancement was significantly greater in patients with AF versus non-AF controls (16.6±11.2% versus 3.1±1.9%;
P
<0.0001). Histological evidence of remodeling from surgical biopsy specimens correlated with SRM on LGE-MRI.

Conclusions—
Atrial SRM is identified on LGE-MRI, and extensive LGE (≥30% LA wall enhancement) predicts poor response to catheter ablation therapy for AF.
Late Gadolinium Enhancement on Cardiac Magnetic Resonance Predicts Adverse Cardiovascular Outcomes in Nonischemic Cardiomyopathy
Authors: Kuruvilla Sujith , Adenaw Nebiyu , Katwal Arabindra B. , Lipinski Michael J. , Kramer Christopher M. , Salerno Michael 
Published: December 2013

Background—
Late gadolinium enhancement (LGE) by cardiac MR (CMR) is a predictor of adverse cardiovascular outcomes in patients with nonischemic cardiomyopathy (NICM). However, these findings are limited by single-center studies, small sample sizes, and low event rates. We performed a meta-analysis to evaluate the prognostic role of LGE by CMR (LGE-CMR) imaging in patients with NICM.

Methods and Results—

PubMed, Cochrane CENTRAL, and EMBASE were searched for studies looking at the prognostic value of LGE-CMR in patients with NICM. The primary end points included all-cause mortality, heart failure hospitalization, and a composite end point of sudden cardiac death (SCD) or aborted SCD. Pooling of odds ratios was performed using a random-effect model, and annualized event rates were assessed. Data were included from 9 studies with a total of 1488 patients and a mean follow-up of 30 months. Patients had a mean age of 52 years, 67% were men, and the average left ventricular ejection fraction was 37% on CMR. LGE was present in 38% of patients. Patients with LGE had increased overall mortality (odds ratio, 3.27;
P
<0.00001), heart failure hospitalization (odds ratio, 2.91;
P
=0.02), and SCD/aborted SCD (odds ratio, 5.32;
P
<0.00001) compared with those without LGE. The annualized event rates for mortality were 4.7% for LGE+ subjects versus 1.7% for LGE− subjects (
P
=0.01), 5.03% versus 1.8% for heart failure hospitalization (
P
=0.002), and 6.0% versus 1.2% for SCD/aborted SCD (
P
<0.001).

Conclusions—
LGE in patients with NICM is associated with increased risk of all-cause mortality, heart failure hospitalization, and SCD. Detection of LGE by CMR has excellent prognostic characteristics and may help guide risk stratification and management in patients with NICM.
Active Steps for Diabetes
Authors: Pariser Gina , Hager Kathy , Gillette Patricia , Golemboski Karen , Jackson Kimberly 
Published: December 2013

Purpose The purpose of this study was to examine the effects of Active Steps for Diabetes (ASD), a self-management education (DSME) program for aging adults with diabetes and frailty, on blood glucose control (A1C) and level of frailty of participants. Methods Fifty females (62.2 ± 10.1 years old) with type 2 diabetes and frailty completed the program; 16 used a walking aid. Outcome measures included A1C and the modified Physical Performance Test (mPPT). Repeated measures analysis of variance was used to compare outcomes before and after the program and between participants who did and did not use a walking aid. Results ASD was effective in reducing A1C and frailty in participants who did and did not use a walking aid. The reduction in A1C was similar for the 2 groups. The reduction in frailty was greater for the group that used a walking aid. Conclusion Physical activity, a keystone for blood glucose control, is difficult for older adults who are frail. ASD provides a model for DSME that may reduce frailty of participants and increase their capacity for physical activity.
The effect of nebivolol on internal mammary artery blood flow during coronary artery bypass graft surgery
Authors: Sarikaya S , Onk A , Boztosun B , Kocabay G , Sahin M , Fedakar A , Köksal C 
Published: December 2013

Background: During coronary artery bypass grafting (CABG), one of the most important complications related to the internal mammary artery (IMA) is perioperative spasm. Nebivolol causes endothelium-dependent vascular relaxation by increasing nitric oxide (NO) release and prevents endothelial dysfunction in long-term use. In our study, we measured the effect of a third generation beta blocker, nebivolol, on the flow dynamics of IMA grafts. Methods: We recruited 90 hypertensive patients undergoing isolated CABG operation, who were divided into three groups and each group included 30 patients: Group 1 patients were under antihypertensive treatment other than beta-blockers (angiontensin-converting enzyme [ACE] inhibitors, calcium channel blockers or diuretics; monotherapy or combination therapy), Group 2 received metoprolol (50 mg/day) and Group 3 received nebivolol (5 mg/day). These antihypertensive therapies were given for at least one week before the operation and continued thereafter. IMA blood flow volume was measured for one minute just before cardiopulmonary bypass (measurement A) and before left internal mammary artery (LIMA)-left anterior descending (LAD) artery anastomosis (measurement B) in the three groups. Cardiac output measurements were also achieved simultaneously. Results: The measurement A results were 56.3 ± 36.2, 54.6 ± 28.1 and 66.8 ± 34.2 mL/min in Groups 1, 2 and 3, respectively (p<0.05). The measurement B results were 78.3 ± 29.6, 80 ± 28.8 and 91.1 ± 40.8 mL/min in Groups 1, 2 and 3 (p<0.05), respectively. There were no differences in cardiac outputs among the groups; 5.2 ± 1.4, 5.0 ± 1.6 and 5.3 ± 1.1 L/min (p>0.05). While the cardiac outputs were similar within the three groups, the IMA free flow volume was higher in the nebivolol group after local papaverine use. Conclusion: Nebivolol might represent a good choice in hypertensive patients undergoing cardiac surgery by preventing perioperative myocardial hypoperfusion which increases early morbidity and mortality.
Triaxial coil embolization using Guglielmi detachable coils with the voltage-dependent coil-detaching technique
Authors: Shimohira Masashi , Hashizume Takuya , Ohta Kengo , Suzuki Kazushi , Kurosaka Kenichiro , Muto Masahiro , Shibamoto Yuta 
Published: December 2013

Background A triple co-axial (triaxial) system, consisting of a 1.9-Fr non-tapered microcatheter with one marker, a 2.7-Fr microcatheter, and a 4-Fr catheter, has been recently developed, and can be used in coil embolizations using 0.010-inch Guglielmi detachable coils (GDCs) with a voltage-dependent coil-detaching technique. Purpose To describe this new technique and evaluate its technical feasibility and clinical efficacy. Material and Methods Twenty patients underwent this procedure. Diseases were gastrointestinal bleeding in five patients, traumatic bleeding in three patients, and other diseases in 12 patients. The technical success rate, clinical success rate, and complications of this procedure were evaluated. Technical success was defined as the successful delivery and detachment of a GDC, and clinical success was defined as the immediate postembolic complete cessation of blood flow confirmed by digital subtraction angiography. Results A total of 140 GDCs were used and 20 arteries were embolized. The technical success rate was 94% (131/140) and clinical success rate was 95% (19/20). No major complications were reported. Conclusion The triaxial system in coil embolization using a GDC by monitoring the voltage for coil-detaching appeared to be safe and effective.
SpO2/FiO2 Ratio on Hospital Admission Is an Indicator of Early Acute Respiratory Distress Syndrome Development Among Patients at Risk
Authors: Festic Emir , Bansal Vikas , Kor Daryl J. , Gajic Ognjen ,   US Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG–LIPS)
Published: December 2013

Purpose: Oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) has been validated as a surrogate marker for partial pressure of oxygen to fraction of inspired oxygen ratio among mechanically ventilated patients with acute respiratory distress syndrome (ARDS). The validity of SpO2/FiO2 measurements in predicting ARDS has not been studied. Recently, a Lung Injury Prediction Score (LIPS) has been developed to help identify patients at risk of developing ARDS. Methods: This was a secondary analysis of the LIPS-1 cohort. A multivariate logistic regression included all established variables for LIPS, Acute Physiology and Chronic Health Evaluation 2, age, and comorbid conditions that could affect SpO2/FiO2. The primary outcome was development of ARDS in the hospital. The secondary outcomes included hospital mortality, hospital day of ARDS development, and hospital day of death. Results: Of the 5584 patients, we evaluated all 4646 with recorded SpO2/FiO2 values. Median SpO2/FiO2 in those who did and did not develop ARDS was 254 (100, 438) and 452 (329, 467), respectively. There was a significant association between SpO2/FiO2 and ARDS ( P ≤ .001). The SpO2/FiO2 was found to be an independent predictor of ARDS in a “dose-dependent” manner; for SpO2/FiO2 < 100—odds ratios (OR) 2.49 (1.69-3.64, P < .001), for SpO2/FiO2 100 < 200—OR 1.75 (1.16-2.58, P = .007), and for SpO2/FiO2 200 < 300—OR 1.62 (1.06-2.42, P = .025). The discriminatory characteristics of the multivariable model and SpO2/FiO2 as a single variable demonstrated area under the curve (AUC) of 0.81 and AUC of 0.74, respectively. Conclusions: The SpO2/FiO2, measured within the first 6 hours after hospital admission, is an independent indicator of ARDS development among patients at risk.
The Influence of Surrogate Decision Makers on Clinical Decision Making for Critically Ill Adults
Authors: Shah Raj D. , Rasinski Kenneth A. , Alexander G. Caleb 
Published: December 2013

Purpose: Intensive care unit patients rarely have decisional capacity and often surrogates make clinical decisions on their behalf. Little is known about how surrogate characteristics may influence end-of-life decision making for these patients. This study sought to determine how surrogate characteristics impact physicians’ approach to end-of-life decision making. Methods: From March 2011 to August 2011, a survey was fielded to 1000 randomly sampled critical care physicians using a modified Dillman approach. The survey included a hypothetical vignette to examine how physicians’ approach varied based on patient age, patient–surrogate relationship, surrogate–staff relationship, basis for surrogate’s stated preferences, and surrogate’s understanding of patient’s condition. Outcomes included physicians’ beliefs regarding (1) appropriateness of cardiopulmonary resuscitation (CPR); (2) appropriate locus of decision making for the patient; (3) degree to which a physician would try to influence a surrogate if disagreement was present; and (4) physician strategies to discussing end-of-life with surrogates. Results: Of 922 eligible physicians, 608 (66%) participated. Across all vignettes, CPR was felt to be less appropriate and surrogates less likely to be given priority with an older rather than younger patient (15% vs 63% and 50% vs 65%, both P values <.001). Cardiopulmonary resuscitation was considered less appropriate when the surrogate–patient relationship was not close (34% vs 44%, P = .03) and the surrogate’s understanding was poor (34% vs 43%, P = .05). No other surrogate characteristics examined yielded statistically significant associations. Conclusion: Some surrogate characteristics may modify clinicians’ beliefs and practices regarding end-of-life care, suggesting the nuances of the surrogate–physician relationship and clinical decision making for critically ill patients.