bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy
Authors: Shrivastava Ashutosh , Kuzontkoski Paula M. , Groopman Jerome E. , Prasad Anil 
Published: May 2011

Abstract
Cannabidiol (CBD), a major nonpsychoactive constituent of cannabis, is considered an antineoplastic agent on the basis of its in vitro and in vivo activity against tumor cells. However, the exact molecular mechanism through which CBD mediates this activity is yet to be elucidated. Here, we have shown CBD-induced cell death of breast cancer cells, independent of cannabinoid and vallinoid receptor activation. Electron microscopy revealed morphologies consistent with the coexistence of autophagy and apoptosis. Western blot analysis confirmed these findings. We showed that CBD induces endoplasmic reticulum stress and, subsequently, inhibits AKT and mTOR signaling as shown by decreased levels of phosphorylated mTOR and 4EBP1, and cyclin D1. Analyzing further the cross-talk between the autophagic and apoptotic signaling pathways, we found that beclin1 plays a central role in the induction of CBD-mediated apoptosis in MDA-MB-231 breast cancer cells. Although CBD enhances the interaction between beclin1 and Vps34, it inhibits the association between beclin1 and Bcl-2. In addition, we showed that CBD reduces mitochondrial membrane potential, triggers the translocation of BID to the mitochondria, the release of cytochrome c to the cytosol, and, ultimately, the activation of the intrinsic apoptotic pathway in breast cancer cells. CBD increased the generation of reactive oxygen species (ROS), and ROS inhibition blocked the induction of apoptosis and autophagy. Our study revealed an intricate interplay between apoptosis and autophagy in CBD-treated breast cancer cells and highlighted the value of continued investigation into the potential use of CBD as an antineoplastic agent. Mol Cancer Ther; 10(7); 1161–72. ©2011 AACR.
Hsp90 Inhibitor–Mediated Disruption of Chaperone Association of ATR with Hsp90 Sensitizes Cancer Cells to DNA Damage
Authors: Ha Kyungsoo , Fiskus Warren , Rao Rekha , Balusu Ramesh , Venkannagari Sreedhar , Nalabothula Narasimha Rao , Bhalla Kapil N. 
Published: May 2011

Abstract
Following DNA damage that results in stalled replication fork, activation of ATR-CHK1 signaling induces the DNA damage response (DDR) in transformed cells. In the present studies on human cervical and breast cancer cells, we determined the effects of hsp90 inhibition on the levels and accumulation of DNA damage/repair–associated proteins following exposure to γ-ionizing radiation (IR; 4 Gy). We show that hsp90 inhibition with 17-allylamino-demehoxygeldanamycin or the novel, nongeldanamycin analogue AUY922 (resorcinylic isoxazole amide; Novartis Pharma) dose-dependently reduced the levels of ATR and CHK1 without affecting ATM levels. AUY922-mediated depletion of ATR and CHK1 was associated with an increase in their polyubiquitylation and decreased binding to hsp90. Cotreatment with bortezomib partially restored AUY922-mediated depletion of ATR and CHK1 levels. Additionally, treatment with AUY922 reduced the accumulation of ATR, p53BP1, and CHK1 but not γ-H2AX to the sites of DNA damage. Following exposure to IR, AUY922 treatment abrogated IR-induced phospho (p)-ATR and p-CHK1 levels, but significantly enhanced γ-H2AX levels. AUY922 treatment also increased IR-induced accumulation of the cells in G2–M phase of the cell cycle, inhibited the repair of IR-induced DNA damage, and augmented IR-mediated loss of clonogenic survival. Short hairpin RNA–mediated depletion of ATR also inhibited IR-induced p-ATR and p-CHK1, but increased γ-H2AX levels, sensitizing cancer cells to IR-induced apoptosis and loss of clonogenic survival. These findings indicate that ATR is a bona fide hsp90 client protein and post-IR administration of AUY922, by inhibiting ATR-CHK1–mediated DDR, sensitizes cancer cells to IR. Mol Cancer Ther; 10(7); 1194–206. ©2011 AACR.
C-Raf Is Required for the Initiation of Lung Cancer by K-RasG12D
Authors: Karreth Florian A. , Frese Kristopher K. , DeNicola Gina M. , Baccarini Manuela , Tuveson David A. 
Published: May 2011

Abstract
The Ras/Raf/MEK/ERK (extracellular signal–regulated kinase) pathway is primarily responsible for mitogenesis in metazoans, and mutational activation of this pathway is common in cancer. A variety of selective chemical inhibitors directed against the mitogen-activated protein kinase pathway are now available for clinical investigation and thus the determination of the importance of each of the kinases in oncogenesis is paramount. We investigated the role of two Raf kinases, B-Raf and C-Raf, in Ras oncogenesis, and found that although B-Raf and C-Raf have overlapping functions in primary mesenchymal cells, C-Raf but not B-Raf is required for the proliferative effects of K-RasG12D in primary epithelial cells. Furthermore, in a lung cancer mouse model, C-Raf is essential for tumor initiation by oncogenic K-RasG12D, whereas B-Raf is dispensable for this process. Our findings reveal that K-RasG12D elicits its oncogenic effects primarily through C-Raf and suggest that selective C-Raf inhibition could be explored as a therapeutic strategy for K-Ras–dependent cancers.
Significance: Ras is one of the most prevalent oncogenes in human cancer; however, it is considered “undruggable.” Therefore, increasing our understanding of the importance of Ras effectors, including the Raf/MEK/ERK pathway, will create novel avenues for therapeutic intervention. Cancer Discovery; 1(2); 128–36. © 2011 AACR.
Read the Commentary on this article by Rebocho and Marais, p. 98
This article is highlighted in the In This Issue feature, p. 91
Human Umbilical Mesenchymal Stem Cells Promote Recovery After Ischemic Stroke
Authors: Lin Yu-Ching , Ko Tsui-Ling , Shih Yang-Hsin , Lin Maan-Yuh Anya , Fu Tz-Win , Hsiao Hsiao-Sheng , Hsu Jung-Yu C. , Fu Yu-Show 
Published: May 2011

Background and Purpose—
Stroke is a cerebrovascular defect that leads to many adverse neurological complications. Current pharmacological treatments for stroke remain unclear in their effectiveness, whereas stem cell transplantation shows considerable promise. Previously, we have shown that human umbilical mesenchymal stem cells (HUMSCs) can differentiate into neurons in neuronal-conditioned medium. Here we evaluate the therapeutic potential of HUMSC transplantation for ischemic stroke in rats.

Methods—
Focal cerebral ischemia was produced by middle cerebral artery occlusion and reperfusion. The HUMSCs treated with neuronal-conditioned medium or not treated were transplanted into the ischemic cortex 24 hours after surgery.

Results—
Histology and MRI revealed that rats implanted with HUMSCs treated with neuronal-conditioned medium or not treated exhibited a trend toward less infarct volume and significantly less atrophy compared with the control group, which received no HUMSCs. Moreover, rats receiving HUMSCs showed significant improvements in motor function, greater metabolic activity of cortical neurons, and better revascularization in the infarct cortex. Implanted HUMSCs, treated or not treated, survived in the infarct cortex for at least 36 days and released neuroprotective and growth-associated cytokines, including brain-derived neurotrophic factor, platelet-derived growth factor-AA, basic fibroblast growth factor, angiopoietin-2, CXCL-16, neutrophil-activating protein-2, and vascular endothelial growth factor receptor-3.

Conclusions—
Our results demonstrate the therapeutic benefits of HUMSC transplantation for ischemic stroke, likely due to the ability of the cells to produce growth-promoting factors. Thus, HUMSC transplantation may be an effective therapy in the future.
Transient Ischemic Attack and Incident Depression
Authors: Luijendijk Hendrika J. , Stricker Bruno H.Ch. , Wieberdink Renske G. , Koudstaal Peter J. , Hofman Albert , Breteler Monique M. , Tiemeier Henning 
Published: May 2011

Background and Purpose—
Depression after stroke is common. Like stroke, transient ischemic attack (TIA) is a manifestation of long-term atherosclerotic damage to the brain. However, the risk of depression developing after a TIA is uncertain. We studied whether TIA increases the risk of incident late-life depression.

Methods—
A cohort study of 5095 inhabitants of Rotterdam, the Netherlands, was performed between 1993 and 2005. Participants were aged 56 years or older and free of depression at baseline. TIA and depression were identified through regular standardized examinations and continuous monitoring of medical records. We estimated hazard ratios (HR) with time-varying Cox regression analyses, adjusting for sociodemographic and health-related factors.

Results—
During follow-up, 407 depressive syndromes occurred, of which 103 met criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM) for depressive disorders. TIA was significantly associated with the risk of incident depressive syndromes (HR, 1.68; 95% CI, 1.12–2.51) and DSM-defined depressive disorders (HR, 2.42; 95% CI, 1.26–4.67). The risk of depressive syndromes increased with the number of TIA a person had experienced (HR, 1.45; 95% CI, 1.17–1.81), as did the risk of depressive disorders (HR, 1.63; 95% CI, 1.18–2.24). In persons without a history of depression at baseline, we found an almost 3-fold increased risk of DSM-defined depressive disorders (HR, 2.91; 95% CI, 0.96–8.81).

Conclusions—
TIA was independently associated with an increased risk of incident depression. Our finding suggests that symptomatic cerebrovascular disease increases the vulnerability to late-life depression.
Outcomes of Intravenous Thrombolysis After Dissemination of the Stroke Code and Designation of New Referral Hospitals in Catalonia
Authors: Abilleira Sònia , Dávalos Antoni , Chamorro Ángel , Álvarez-Sabín José , Ribera Aida , Gallofré Miquel 
Published: May 2011

Background and Purpose—
From 2006, the Stroke Code system operates throughout Catalonia with full coverage. The objective of this study was to determine safety and effectiveness of intravenous thrombolysis in routine practice through a monitored study (Catalan Stroke Code and Thrombolysis [Cat-SCT]) and to assess outcomes according to hospitals' previous experience.

Methods—
We conducted a prospective, multicenter, observational, monitored study of recombinant tissue plasminogen activator-treated patients declared to the Cat-SCT by all treating hospitals in Catalonia (n=13, of which 6 were newly designated) over a 12-month period. Consecutive recruitment and quality of data were assured through comprehensive quality control. We estimated rates of outcome measures for the potential final sample (after inclusion of undeclared cases) and compared them with those reported for the actual sample. Symptomatic intracranial hemorrhage, mortality, and favorable outcome (modified Rankin Scale score 0 to 1) at 3 months were also evaluated according to hospitals' previous experience using multilevel logistic regression.

Results—
We analyzed 488 patients with a median age of 72 years (interquartile range: 63, 77), 57.2% males, with a baseline National Institutes of Health Stroke Scale score of 13 (interquartile range: 8, 19), and stroke to treatment time of 150 minutes (interquartile range: 120, 180 minutes). Symptomatic intracranial hemorrhage (Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy definition) was observed in 3.3% patients. Ninety-day mortality was 16.6% and 38.5% showed a favorable outcome at 3 months. External monitoring set inclusion losses at <5%. A sensitivity analysis including undeclared cases did not show significant changes in main outcomes. Inexperienced hospitals achieved similar outcomes, except for a higher rate of favorable outcome at 3 months.

Conclusions—
Health planning applied to acute stroke care and based on dissemination of the Stroke Code system and designation of new referral hospitals showed intravenous thrombolysis safe and effective in routine practice, even among inexperienced hospitals.
Natural History, Predictors, and Associations of Depression 5 Years After Stroke
Authors: Ayerbe Luis , Ayis Salma , Rudd Anthony G. , Heuschmann Peter U. , Wolfe Charles D.A. 
Published: May 2011

Background and Purpose—
The longer-term natural history of depression after stroke is poorly understood. We estimate frequency, predictors, and associations of depression up to 5 years after stroke in a population-based study.

Methods—
Data from 3689 patients registered in the South London Stroke Register 1995 to 2006 were used. Baseline data included age, sex, ethnicity, socioeconomic status, and stroke severity. At 3 months and at 1, 3, and 5 years, survivors were assessed for depression (Hospital Anxiety and Depression; depression subscale score >7 indicates depression), cognition, disability, activity, accommodation, employment, and social networks. Associations with depression were investigated with logistic regression. Data are reported with OR and 95% CI.

Results—
Depression frequencies were 33% (30%–36%), 28% (25%–30%), 32% (30%–35%), and 31% (27%–34%) at 3 months and at 1, 3, and 5 years after stroke, respectively. Forty-eight percent of patients were not depressed at any time point; 49% to 55% of depressed patients at 1 assessment remained depressed at follow-up; and 15% to 20% of patients at each assessment were new cases. Predictors of depression included stroke severity, inability to work, and impaired cognition. Associations with depression at follow-up included impaired cognition, lack of family support, institutionalization, inability to work, functional dependence, and low activity level.

Conclusions—
Frequency of depression up to 5 years after stroke is 30%; however, it is a dynamic situation with recovery and new cases diagnosed over time. These findings support the need for regular assessment of depression and its associated factors and for the development of effective interventions to reduce depression after stroke.
Are Distal Protection Devices ‘Protective’ During Carotid Angioplasty and Stenting?
Authors: Tallarita Tiziano , Rabinstein Alejandro A. , Cloft Harry , Kallmes David , Oderich Gustavo S. , Brown Robert D. , Lanzino Giuseppe 
Published: May 2011

Background and Purpose—
To evaluate the periprocedural outcome after carotid artery stenting with embolic brain protection (EBP+) versus without embolic brain protection (EBP−).

Methods—
We retrospectively reviewed data from a prospective nonrandomized database of 357 patients who underwent carotid artery stenting in the neuroradiology division of our institution from 1999 to 2009. One hundred five patients underwent angioplasty and stenting without distal protection, whereas 252 were treated with distal protection. Patients were analyzed according to their EBP status (+ or −) for the primary end points of perioperative stroke, death, or myocardial infarction.

Results—

Unprotected stenting was mostly performed in the early years of this study and this is reflected in significant baseline differences between the two groups. In our earlier experience, carotid artery stenting was used in patients with more significant comorbidities. Diabetes mellitus (
P
=0.04), previous coronary artery disease (
P
=0.02) and myocardial infarction (
P
=0.04), and symptomatic lesion (
P
=0.01) were significantly more common in the EBP− cohort. Despite these baseline differences, there were no significant differences in the primary end points (2% in the EBP+ group and 4.8% in the EBP−,
P
=0.15). The incidence of ipsilateral stroke in the EBP− and in the EBP+ group was 3.8% versus 0.8%, respectively (
P
=0.6). There were 2 perioperative deaths (1 in each group) and 4 myocardial infarctions (3 in the EBP+ arm and 1 in the EBP− arm, all non-Q infarcts;
P
=nonsignificant).

Conclusions—
In accordance with recent literature, this series cast doubts as to the real effectiveness of distal embolic protection devices in reducing periprocedural complications.
Response to Psychosocial Treatment in Poststroke Depression Is Associated With Serotonin Transporter Polymorphisms
Authors: Kohen Ruth , Cain Kevin C. , Buzaitis Ann , Johnson Vicki , Becker Kyra J. , Teri Linda , Tirschwell David L. , Veith Richard C. , Mitchell Pamela H. 
Published: May 2011

Background and Purpose—
The Living Well With Stroke study has demonstrated effectiveness of a brief psychosocial treatment in reducing depressive symptoms after stroke. The purpose of this analysis was to determine whether key variables associated with prevalence of poststroke depression also predicted treatment response.

Methods—
Response to a brief psychosocial/behavioral intervention for poststroke depression was measured with the Hamilton Rating Scale for Depression. Analysis of covariance models tested for interaction of potential predictor variables with treatment group on percent change in Hamilton Rating Scale for Depression from pre- to post-treatment as an outcome.

Results—

Initial depression severity, hemispheric location, level of social support, age, gender, and antidepressant adherence did not interact with the treatment with respect to percent change in Hamilton Rating Scale for Depression when considered 1 at a time. Participants who carried 1 or 2
s
-alleles at the 5-HTTLPR serotonin transporter polymorphism or 1 or 2 9- or 12-repeats of the STin2 VNTR polymorphism had significantly better response to psychosocial treatment than those with no
s
-alleles or no 9- or 12-repeats.

Conclusions—

Opposite to the effects of antidepressant drug treatment with selective serotonin reuptake inhibitors, the Living Well With Stroke psychotherapy intervention was most effective in 5-HTTLPR
s
-allele carriers and STin2 VNTR 9- or 12-repeat carriers.

Clinical Trial Registration—

URL:
www.clinicaltrials.gov/ct/show/NCT00194454?order_1
. Unique identifier: NCT00194454.
Sublingual Microvascular Changes in Patients With Cerebral Small Vessel Disease
Authors: Khalilzada Mostafa , Dogan Kemal , Ince Can , Stam Jan 
Published: May 2011

Background and Purpose—
It is unknown whether changes in cerebral small vessel disease (SVD) are limited to the brain or part of a generalized vascular disorder.

Methods—
We examined the sublingual microcirculation of 10 healthy controls, 10 patients with large vessel disease, and 8 with SVD, with side-stream dark field imaging. We analyzed 146 video fragments masked to the origin of the videos. Imaging software measured the functional capillary density per tissue surface unit. We scored the percentage of blood vessels with abnormal flow (abnormal flow index) and the presence of extravascular erythrocyte material as presumed evidence of past microbleeds or obliterated vessels.

Results—

Functional capillary density differed between the 3 groups (SVD, large vessel disease, and controls; means, 14.8, 17.0, and 16.1 mm/mm
2
;
P
=0.01). Abnormal flow was more frequent in SVD patients compared with large vessel disease patients and controls (medians, 10.5%, 6.1%, 5.5%;
P
=0.04). Extravascular erythrocyte material was almost exclusively present in patients with SVD (
P
=0.004).

Conclusions—
We found evidence of pathological changes in the sublingual microcirculation in patients with cerebral small vessel disease, which suggests that cerebral SVD is part of a generalized vascular disorder.
Association Between Stroke and Patients With Pelvic Inflammatory Disease
Authors: Chen Po-Chih , Tseng Teng-chu , Hsieh Jui-Yang , Lin Hui-Wen 
Published: May 2011

Background and Purpose—
The aim of this study is to estimate the risk of stroke in a 3-year period after pelvic inflammatory disease (PID) using a nationwide population-based study.

Methods—
Our study cohort consisted of all patients with a diagnosis of PID (N=64 515) between 2004 and 2005 with a control cohort (1:2) of age-matched controls (N=129 030). Each patient was tracked from hospitalization until the end of 2006. Cox regressions were performed to compute the 3-year stroke-free survival rates after adjusting for possible confounding factors.

Results—
We found that women with PID were more likely to have strokes than the control population. After adjusting for potential confounding factors, the adjusted hazard ratio of stroke was 1.63 (95% CI, 1.45–1.85) for PID patients as compared to the general population cohort. Sensitivity analysis using a bootstrap approach further ensured the validity of the results of our study.

Conclusions—
We concluded that patients with PID have an association with stroke. Further research is necessary to investigate the pathophysiology between PID and stroke.
Multiple Processes Underlying Dimensional Change Card Sort Performance: A Developmental Electrophysiological Investigation
Authors: Waxer Matthew , Morton J. Bruce 
Published: May 2011

Abstract
Cognitive flexibility follows a protracted developmental trajectory [Morton, J. B. Understanding genetic, neurophysiological, and experiential influences on the development of executive functioning: The need for developmental models. Wiley Interdisciplinary Reviews: Cognitive Science, 2010]. For example, performance and patterns of brain activity associated with the dimensional change card sort (DCCS) show continued age-related changes into early adolescence. According to many theoretical accounts, the DCCS places demands on a single underlying executive process. In the present study, we investigated the possibility that multiple processes unfold within the timeframe of a single DCCS trial through the use of ERPs. Children (n = 40), adolescents (n = 20), and adults (n = 20) performed a modified version of the DCCS with distinct instruction cue- and stimulus-related periods. On any particular trial, the sorting rule either changed (i.e., switch trials) or remained the same (i.e., repeat trials), and the imperative stimulus either embodied conflict (i.e., bivalent stimuli) or did not (i.e., univalent stimuli). Findings were consistent with the hypothesis that multiple distinct executive processes unfold within a single trial. First, for all age groups, rule switching and conflict processing made additive contributions to variability in RT. Second, ERPs time-locked to the instruction cue revealed a late frontal negativity whose amplitude was greater for switch trials relative to repeat trials and that was associated with the magnitude of the behavioral switch cost, whereas ERPs time-locked to the imperative stimulus revealed a fronto-central N2 whose amplitude was greater for bivalent than univalent stimuli and that was associated with the magnitude of the behavioral conflict cost. Finally, switch and conflict-related processes showed distinct developmental trajectories. Taken together, the findings suggest that multiple executive processes underlie DCCS performance and its development. Theoretical implications are discussed.
Functional Imaging Reveals Working Memory and Attention Interact to Produce the Attentional Blink
Authors: Johnston Stephen J. , Linden David E. J. , Shapiro Kimron L. 
Published: May 2011

AbstractIf two centrally presented visual stimuli occur within approximately half a second of each other, the second target often fails to be reported correctly. This effect, called the attentional blink (AB; Raymond, J. E., Shapiro, K. L., & Arnell, K. M. Temporary suppression of visual processing in an RSVP task: An attentional blink? Journal of Experimental Psychology, Human Perception and Performance, 18, 849–860, 1992], has been attributed to a resource “bottleneck,” likely arising as a failure of attention during encoding into or retrieval from visual working memory (WM). Here we present participants with a hybrid WM–AB study while they undergo fMRI to provide insight into the neural underpinnings of this bottleneck. Consistent with a WM-based bottleneck account, fronto-parietal brain areas exhibited a WM load-dependent modulation of neural responses during the AB task. These results are consistent with the view that WM and attention share a capacity-limited resource and provide insight into the neural structures that underlie resource allocation in tasks requiring joint use of WM and attention.