bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Unfolded Protein Response Induces the Angiogenic Switch in Human Tumor Cells through the PERK/ATF4 Pathway
Authors: Wang Yugang , Alam Goleeta N. , Ning Yu , Visioli Fernanda , Dong Zhihong , Nör Jacques E. , Polverini Peter J. 
Published: August 2012

Abstract
Neovascularization is a limiting factor in tumor growth and progression. It is well known that changes in the tumor microenvironment, such as hypoxia and glucose deprivation (GD), can induce VEGF production. However, the mechanism linking GD to tumor growth and angiogenesis is unclear. We hypothesize that GD induces the angiogenic switch in tumors through activation of the unfolded protein response (UPR). We report that UPR activation in human tumors results in elevated expression of proangiogenic mediators and a concomitant decrease in angiogenesis inhibitors. cDNA microarray results showed that GD-induced UPR activation promoted upregulation of a number of proangiogenic mediators (VEGF, FGF-2, IL-6, etc.) and downregulation of several angiogenic inhibitors (THBS1, CXCL14, and CXCL10). In vitro studies revealed that partially blocking UPR signaling by silencing protein kinase RNA–like ER kinase (PERK) or activating transcription factor 4 (ATF4) significantly reduced the production of angiogenesis mediators induced by GD. However, suppressing the alpha subunit of hypoxia-inducible factors had no effect on this process. Chromatin immunoprecipitation (ChIP) confirmed binding of ATF4 to a regulatory site in the VEGF gene. In vivo results confirmed that knockdown of PERK in tumor cells slows down tumor growth and decreases tumor blood vessel density. Collectively, these results show that the PERK/ATF4 arm of UPR mediates the angiogenic switch and is a potential target for antiangiogenic cancer therapy. Cancer Res; 72(20); 5396–406. ©2012 AACR.
PD-1 Blockade Enhances T-cell Migration to Tumors by Elevating IFN-γ Inducible Chemokines
Authors: Peng Weiyi , Liu Chengwen , Xu Chunyu , Lou Yanyan , Chen Jieqing , Yang Yan , Yagita Hideo , Overwijk Willem W. , Lizée Gregory , Radvanyi Laszlo , Hwu Patrick 
Published: August 2012

Abstract
Adoptive cell transfer (ACT) is considered a promising modality for cancer treatment, but despite ongoing improvements, many patients do not experience clinical benefits. The tumor microenvironment is an important limiting factor in immunotherapy that has not been addressed fully in ACT treatments. In this study, we report that upregualtion of the immunosuppressive receptor programmed cell death-1 (PD-1) expressed on transferred T cells at the tumor site, in a murine model of ACT, compared with its expression on transferred T cells present in the peripheral blood and spleen. As PD-1 can attenuate T-cell–mediated antitumor responses, we tested whether its blockade with an anti–PD-1 antibody could enhance the antitumor activity of ACT in this model. Cotreatment with both agents increased the number of transferred T cells at the tumor site and also enhanced tumor regressions, compared with treatments with either agent alone. While anti–PD-1 did not reduce the number of immunosuppressive regulatory T cells and myeloid-derived suppressor cells present in tumor-bearing mice, we found that it increased expression of IFN-γ and CXCL10 at the tumor site. Bone marrow–transplant experiments using IFN-γR−/− mice implicated IFN-γ as a crucial nexus for controlling PD-1–mediated tumor infiltration by T cells. Taken together, our results imply that blocking the PD-1 pathway can increase IFN-γ at the tumor site, thereby increasing chemokine-dependent trafficking of immune cells into malignant disease sites. Cancer Res; 72(20); 5209–18. ©2012 AACR.
Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features
Authors: Navarro Alba , Clot Guillem , Royo Cristina , Jares Pedro , Hadzidimitriou Anastasia , Agathangelidis Andreas , Bikos Vasilis , Darzentas Nikos , Papadaki Theodora , Salaverria Itziar , Pinyol Magda , Puig Xavier , Palomero Jara , Vegliante Maria Carmela , Amador Virgina , Martinez-Trillos Alejandra , Stefancikova Lenka , Wiestner Adrian , Wilson Wyndham , Pott Christiane , Calasanz Maria Jose , Trim Nicola , Erber Wendy , Sander Birgitta , Ott German , Rosenwald Andreas , Colomer Dolors , Giné Eva , Siebert Reiner , Lopez-Guillermo Armando , Stamatopoulos Kostas , Beà Sílvia , Campo Elías 
Published: August 2012

Abstract
Mantle cell lymphoma (MCL) is a heterogeneous disease with most patients following an aggressive clinical course, whereas others having an indolent behavior. We conducted an integrative and multidisciplinary analysis of 177 MCL to determine whether the immunogenetic features of the clonotypic B-cell receptors (BcR) may identify different subsets of tumors. Truly unmutated (100% identity) IGHV genes were found in 24% cases, 40% were minimally/borderline mutated (99.9%–97%), 19% significantly mutated (96.9%–95%), and 17% hypermutated (&lt;95%). Tumors with high or low mutational load used different IGHV genes, and their gene expression profiles were also different for several gene pathways. A gene set enrichment analysis showed that MCL with high and low IGHV mutations were enriched in memory and naive B-cell signatures, respectively. Furthermore, the highly mutated tumors had less genomic complexity, were preferentially SOX11-negative, and showed more frequent nonnodal disease. The best cut-off of germline identity of IGHV genes to predict survival was 97%. Patients with high and low mutational load had significant different outcome with 5-year overall survival (OS) of 59% and 40%, respectively (P = 0.004). Nodal presentation and SOX11 expression also predicted for poor OS. In a multivariate analysis, IGHV gene status and SOX11 expression were independent risk factors. In conclusion, these observations suggest the idea that MCL with mutated IGHV, SOX11-negativity, and nonnodal presentation correspond to a subtype of the disease with more indolent behavior. Cancer Res; 72(20); 5307–16. ©2012 AACR.
Meta-Analysis of the Prognostic Value of Circulating Tumor Cells in Breast Cancer
Authors: Zhang Liling , Riethdorf Sabine , Wu Gang , Wang Tao , Yang Kunyu , Peng Gang , Liu Junli , Pantel Klaus 
Published: August 2012

Abstract
Purpose: The prognostic value of circulating tumor cells (CTC) detected in breast cancer patients is currently under debate. Different time points of blood collections and various CTC assays have been used in the past decades. Here, we conducted the first comprehensive meta-analysis of published literature on the prognostic relevance of CTC, including patients with early and advanced disease.
Experimental Design: A comprehensive search for articles published between January 1990 and January 2012 was conducted; reviews of each study were conducted and data were extracted. The main outcomes analyzed were overall survival (OS) and disease-free survival (DFS) in early-stage breast cancer patients, as well as progression-free survival (PFS) and OS in metastatic breast cancer patients. Pooled hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using the random and the fixed-effects models. Subgroup and sensitivity analyses were also conducted.
Results: Forty-nine eligible studies enrolling 6,825 patients were identified. The presence of CTC was significantly associated with shorter survival in the total population. The prognostic value of CTC was significant in both early (DFS: HR, 2.86; 95% CI, 2.19–3.75; OS: HR, 2.78; 95% CI, 2.22–3.48) and metastatic breast cancer (PFS: HR, 1.78; 95% CI, 1.52–2.09; OS: HR, 2.33; 95% CI, 2.09–2.60). Further subgroup analyses showed that our results were stable irrespective of the CTC detection method and time point of blood withdrawal.
Conclusion: Our present meta-analysis indicates that the detection of CTC is a stable prognosticator in patients with early-stage and metastatic breast cancer. Further studies are required to explore the clinical utility of CTC in breast cancer. Clin Cancer Res; 18(20); 5701–10. ©2012 AACR.
Preconditioning Deep Convection with Cumulus Congestus
Authors: Hohenegger Cathy , Stevens Bjorn 
Published: August 2012

Abstract
Recent studies have pushed forward the idea that congestus clouds, through their moistening of the atmosphere, could promote deep convection. On the other hand, older studies have tended to relate convective initiation to the large-scale forcing. These two views are here contrasted by performing a time-scale analysis. The analysis combines ship observations, large-eddy simulations, and 1 month of brightness temperature measurements with a focus on the tropical Atlantic and adjacent land areas.
The time-scale analysis suggests that previous work may have overstated the importance of congestus moistening in the preconditioning of deep convection. It is found that cumuli congestus transition very rapidly to deep convection, in 2 h over land and 4 h over ocean. This is much faster than the time needed (10 h and longer) by congestus clouds to sufficiently moisten the atmosphere. Moreover, the majority of congestus clouds seem unable to grow into cumulonimbus and the probability of transition does not increase with increasing congestus lifetime (i.e., more moistening). Finally, the presence of cumuli congestus over a given region generally does not enhance the likelihood for deep convection development, either with respect to other regions or to clear-sky conditions. Hence, the results do not support the view of an atmosphere slowly deepening by local moistening, but rather, they may be interpreted as reminiscent of an atmosphere marked by violent and sudden outbursts of convection forced by dynamical effects. This also implies that moisture convergence is more important than local surface fluxes to trigger deep convection over a certain region.
Multidecadal Mobility of the North Atlantic Oscillation
Authors: Moore G. W. K. , Renfrew I. A. , Pickart R. S. 
Published: August 2012

Abstract
The North Atlantic Oscillation (NAO) is one of the most important modes of variability in the global climate system and is characterized by a meridional dipole in the sea level pressure field, with centers of action near Iceland and the Azores. It has a profound influence on the weather, climate, ecosystems, and economies of Europe, Greenland, eastern North America, and North Africa. It has been proposed that around 1980, there was an eastward secular shift in the NAO’s northern center of action that impacted sea ice export through Fram Strait. Independently, it has also been suggested that the location of its southern center of action is tied to the phase of the NAO. Both of these attributes of the NAO have been linked to anthropogenic climate change. Here the authors use both the one-point correlation map technique as well as empirical orthogonal function (EOF) analysis to show that the meridional dipole that is often seen in the sea level pressure field over the North Atlantic is not purely the result of the NAO (as traditionally defined) but rather arises through an interplay among the NAO and two other leading modes of variability in the North Atlantic region: the East Atlantic (EA) and the Scandinavian (SCA) patterns. This interplay has resulted in multidecadal mobility in the two centers of action of the meridional dipole since the late nineteenth century. In particular, an eastward movement of the dipole has occurred during the 1930s to 1950s as well as more recently. This mobility is not seen in the leading EOF of the sea level pressure field in the region.
An Initial Assessment of Antarctic Sea Ice Extent in the CMIP5 Models
Authors: Turner John , Bracegirdle Thomas J. , Phillips Tony , Marshall Gareth J. , Hosking J. Scott 
Published: August 2012

Abstract
This paper examines the annual cycle and trends in Antarctic sea ice extent (SIE) for 18 models used in phase 5 of the Coupled Model Intercomparison Project (CMIP5) that were run with historical forcing for the 1850s to 2005. Many of the models have an annual SIE cycle that differs markedly from that observed over the last 30 years. The majority of models have too small of an SIE at the minimum in February, while several of the models have less than two-thirds of the observed SIE at the September maximum. In contrast to the satellite data, which exhibit a slight increase in SIE, the mean SIE of the models over 1979–2005 shows a decrease in each month, with the greatest multimodel mean percentage monthly decline of 13.6% decade−1 in February and the greatest absolute loss of ice of −0.40 × 106 km2 decade−1 in September. The models have very large differences in SIE over 1860–2005. Most of the control runs have statistically significant trends in SIE over their full time span, and all of the models have a negative trend in SIE since the mid-nineteenth century. The negative SIE trends in most of the model runs over 1979–2005 are a continuation of an earlier decline, suggesting that the processes responsible for the observed increase over the last 30 years are not being simulated correctly.
Minimized perfusion circuits: an alternative in the surgical treatment of Jehovah’s Witnesses
Authors: El-Essawi A , Breitenbach I , Ali K , Jungebluth P , Brouwer R , Anssar M , Harringer W 
Published: August 2012

Objectives: Jehovah’s Witnesses present a challenge to cardiac surgeons, as quality of care is not only defined by mortality and morbidity, but also by the avoidance of blood transfusions. Over the last years, minimized perfusion circuits (MPC) have contributed substantially to the achievement of this goal in our clinic. Presented is a retrospective analysis of our experience. Methods: Twenty-nine Jehovah’s Witnesses, aged 69 ± 10 years, have undergone cardiac surgery with a MPC in our institution since 2005. The ROCsafe (Reservoir Optional Circuit) MPC was used in most of these patients (n=27) as it offers the unique possibility of a speedy integration of a reservoir in the event of a major air leak, thereby, negligating any safety concerns. Results: There was no in-hospital or 30-day postoperative mortality. Mean ICU stay was 1.6 ± 2 days with a mean intubation time of 11.3 ± 9.1 hrs. Postoperative complications included one myocardial infarction with accompanying low cardiac output, one stroke, one transient delirium, one idiopathic thrombocytopenia and three re-operations (one sternal infection, one postoperative bleeding and one delayed tamponade). The mean postoperative hospital stay was 9.9 ± 2.3 days. Mean decrease in hemoglobin was 2.1 ± 1.3 g/dl during cardiopulmonary bypass and 3.4 ±1.4 g/dl at discharge. The lowest postoperative hemoglobin level was 9.3 ±1.8 (Range 6-12.9). Conclusions: These encouraging results emphasize the role MPCs can play in optimizing the quality of patient care. We hope that this report can serve as a stimulus for similar experiences.
Executive resting-state network connectivity in migraine without aura
Authors: Russo Antonio , Tessitore Alessandro , Giordano Alfonso , Corbo Daniele , Marcuccio Laura , De Stefano Manuela , Salemi Fabrizio , Conforti Renata , Esposito Fabrizio , Tedeschi Gioacchino 
Published: August 2012

Background: Converging neuropsychological evidence suggests that in migraine executive functions (EF) may be affected during interictal periods. Objective: To evaluate the functional connectivity of the fronto-parietal networks (FPN) known to be associated with EF, in migraine without aura (MwoA) patients, in the interictal period, in comparison to healthy controls (HC). Methods: Using resting-state functional MRI (RS-fMRI), we compared functional connectivity within the FPN in 14 patients with MwoA versus 14 sex- and age-matched HC, and assessed the correlation between functional connectivity within FPN, clinical features of MwoA patients, and EF. We used voxel-based morphometry to assess whether between-group differences in functional connectivity were dependent on structural differences. Results: Neuropsychological data revealed no significant executive dysfunction in MwoA patients. RS-fMRI showed that MwoA patients, compared to HC, had significant functional connectivity reduction within the right FPN and specifically in the middle frontal gyrus (MFG) and the dorsal anterior cingulate cortex. In addition, we found that MFG reduced connectivity was negatively correlated with the pain intensity of migraine attacks. There were no structural differences between the two groups. Conclusions: Our data suggest that, even in the absence of clinically evident EF deficits, MwoA is associated with reduced FPN functional connectivity. This study provides further insights into the complex scenario of migraine mechanisms.
A replication study of a GWAS finding in migraine does not identify association in a Spanish case-control sample
Authors: Sintas Cèlia , Carreño Oriel , Fernández-Morales Jèssica , Cacheiro Pilar , Sobrido María-Jesús , Narberhaus Bernat , Pozo-Rosich Patricia , Macaya Alfons , Cormand Bru 
Published: August 2012

Background: Migraine is a prevalent neurological disorder with a complex genetic background characterized by recurrent episodes of headache. The disease is subclassified into migraine with aura (MA) and migraine without aura (MO). Many association studies have been performed to date to identify genetic risk variants for common migraine, most of them focusing on selected candidate genes, with variable and often inconsistent results. Recently, a clinic-based genome-wide association study for migraine reported a functionally relevant risk variant (SNP rs1835740), involved in glutamate homeostasis, which showed a significant association with MA. We aimed to replicate this finding in a clinic-based study of a Spanish cohort with MA and MO patients. Methods: We genotyped SNP rs1835740 in a Spanish sample of 1521 patients and 1379 screened controls and performed a case-control association study. Conclusion: No association was found between the assayed SNP and any of the clinical groups considered.
Technical Efficiency of Comprehensive Emergency Obstetric and New-Born Care Centres in Tamil Nadu
Authors: Rajasulochana S. , Dash Umakant 
Published: August 2012

Background: The state government of Tamil Nadu in India has been implementing various health sector reforms to bring down maternal and infant deaths. One such significant step was to set up Comprehensive Emergency Obstetric and New-born Care (CEmONC) centres all over Tamil Nadu under the World Bank-funded Tamil Nadu Health Systems Project (TNHSP) in 2005. However, to date, except for the pilot study reported in this article, no attempt has been made to make an estimate of the efficiency of the CEmONC centres in Tamil Nadu. The objective of this study, based on data on performance indicators collected by the TNHSP for the period April 2009 to March 2010 was to estimate the relative technical efficiency (TE) and scale efficiency (SE) of Phase 1 CEmONC centres in Tamil Nadu using the DEA method. Methods: The Data Envelopment Analysis (DEA) method was used to estimate the efficiency of 48 Phase 1 CEmONC centres operating in secondary hospitals across Tamil Nadu. This is an exploratory study. Results: 10 (out of 48) centres were technically efficient, with an average TE score for inefficient centres of 72.3 per cent and a standard deviation (STD) of 15 per cent under the constant returns to scale assumption. Nineteen centres were technically efficient under variable returns to scale assumption with an average score of 81 per cent (STD of 14 per cent). Thirty-eight centres were scale inefficient with 84 per cent (STD of 11.79 per cent). Discussion: This pilot study demonstrates to the policy-makers the versatility of DEA in measuring inefficiencies among CEmONC centres. A key limitation of this study is that it has not accounted for quality of care. Further research is required to examine why certain centres out-perform others.
User Fee Management in India
Authors: Mariappan M. , Thakur Harshad P. 
Published: August 2012

Background: There have been a number of studies conducted on user fee across the world, however, very limited number of studies have been conducted in India. This study was one of studies conducted at government hospitals in four states in India with the support of the World Health Organization and the Ministry of Health and Family Welfare. Methodology: The data was collected from overall eight district hospitals, eight rural hospitals and four medical college hospitals, which were selected from the four selected states in India. Separately structured interview schedules were used for the stakeholders like employees and policy makers. The data was analyzed by the SPSS programme. Results: The results were reported under four major sections like views on policy guidelines, operational systems, revenue generation and value creation to the users. It was found that the state of Rajasthan was to develop and govern relatively better policy of the user fee scheme. In maintaining appropriate operational systems Rajasthan was doing best, followed by Karnataka and Gujarat. In implementing appropriate mechanisms for collection of revenue Rajasthan and Gujarat were doing better. In creating value and support to patients, Rajasthan and Gujarat was doing better. Overall the user fee management was not adequately done in the states; however the state of Rajasthan has relatively improved because of the organized structure of the user fee management. Conclusion: In the whole process, some of the important concerns of patients like value for money, meeting the genuine needs of patients and encouraging poor patients to utilize the services were inadequately addressed. After many years of implementation of the user fee scheme, the hospitals have been unable to improve quality of services up to patients’ expectations. The lesson learnt from the Rajasthan model may be replicated in other states which will be more useful. Further, it is very important for every state-run hospital to concentrate on viable systems, reduce unnecessary usage of services by the patients within the hospital and efficient operational management. It is to be noted in all four states, the policy makers and majority of the health care providers and some percentage of patients have considered that user fee should continue and it will be useful to the states.
Disintegration of chemotherapy tablets for oral administration in patients with swallowing difficulties
Authors: Siden Rivka , Wolf Matthew 
Published: August 2012

Purpose: The administration of oral chemotherapeutic drugs can be problematic in patients with swallowing difficulties. Inability to swallow solid dosage forms can compromise compliance and may lead to poor clinical outcome. The current technique of tablet crushing to aid in administration is considered an unsafe practice. By developing a technique to disintegrate tablets in an oral syringe, the risk associated with tablet crushing can be avoided. The purpose of this study was to determine the feasibility of using disintegration in an oral syringe for the administration of oral chemotherapeutic tablets. Eight commonly used oral chemotherapeutic drugs were tested. Methods: Tablets were placed in an oral syringe and allowed to disintegrate in tap water. Various volumes and temperatures were tested to identify which combination allows for complete disintegration of the tablet in the shortest amount of time. The oral syringe disintegration method was considered feasible if disintegration occurred in £≤15 min and in ≤£20 mL of water and the dispersion passed through an oral syringe tip. Results: The following tablets were shown to disintegrate within 15 min and in <20 mL of water: busulfan, cyclophosphamide 50 mg, dasatinib, imatinib, methotrexate, and thioguanine. For these drugs, drug-specific information pamphlets can be prepared for patient or caregiver use. Mercaptopurine, cyclophosphamide 25 mg, and mitotane tablets did not pass the disintegration test. Conclusion: Disintegrating oral chemotherapeutic tablets in a syringe provides a closed system to administer hazardous drugs and allows for the safe administration of oral chemotherapeutic drugs in a tablet form to patients with swallowing difficulties.