bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modified early warning score with rapid lactate level in critically ill medical patients: the ViEWS-L score
Authors: Jo Sion , Lee Jae Baek , Jin Young Ho , Jeong Tae Oh , Yoon Jae Chol , Jun Yong Kyu , Park Bo Young 
Published: March 2012

ObjectivesTo examine whether the predictive value of the early warning score (EWS) could be improved by including rapid lactate levels, and to compare the modified EWS with the pre-existing risk scoring systems.DesignRetrospective observational study in South Korea.SettingAn urban, academic, tertiary hospital.ParticipantsConsecutive adult patients who were admitted to the medical intensive care unit via the emergency department (ED).Outcome measuresA newly developed EWS—the VitalPAC EWS (ViEWS), was used in the present study. Lactate level, ViEWS and HOTEL score were obtained from patients at presentation to the ED, and APACHE II, SAPS II and SAPS III scores were obtained after admission. The area under curve of each risk scoring system for in-hospital, 1-week, 2-week and 4-week mortality was compared.Results151 patients were enrolled and the mortality was 42.4%. The ViEWS-L score was calculated as follows: ViEWS-L score=ViEWS+lactate (mmol/l) according to the regression coefficient. The mean ViEWS-L score was 11.6±7.3. The ViEWS-L score had a better predictive value than the ViEWS score for hospital mortality (0.802 vs 0.742, p=0.009), 1-week mortality (0.842 vs 0.707, p<0.001), 2-week mortality (0.827 vs 0.729, p<0.001) and 4-week mortality (0.803 vs 0.732, p=0.003). The ViEWS-L score also had a better predictive value than the HOTEL and APACHE II scores. The predictive value of ViEWS-L was comparable with SAPS II and SAPS III.ConclusionsThe ViEWS-L score performed as well as or better than the pre-existing risk scoring systems in predicting mortality in critically ill medical patients who were admitted to the medical intensive care unit via the ED.
Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
Authors: Terme Magali , Ullrich Evelyn , Aymeric Laetitia , Meinhardt Kathrin , Coudert Jérôme D. , Desbois Mélanie , Ghiringhelli François , Viaud Sophie , Ryffel Bernard , Yagita Hideo , Chen Lieping , Mécheri Salaheddine , Kaplanski Gilles , Prévost-Blondel Armelle , Kato Masashi , Schultze Joachim L. , Tartour Eric , Kroemer Guido , Degli-Esposti Mariapia , Chaput Nathalie , Zitvogel Laurence 
Published: March 2012

AbstractDuring cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1–dependent tumor progression in NK cell–controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit− (CD11b−) into Kit+ natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit+ NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit+ NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1–dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18–binding protein dramatically reduced the accumulation of Kit+CD11b− NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit+CD11b− NK cells endowed with B7-H1–dependent immunoablative functions in mice. Cancer Res; 72(11); 2757–67. ©2012 AACR.
New Strategies in Refractory and Recurrent Neuroblastoma: Translational Opportunities to Impact Patient Outcome
Authors: Cole Kristina A. , Maris John M. 
Published: March 2012

AbstractNeuroblastoma remains responsible for a disproportionate amount of childhood cancer morbidity and mortality despite recent significant advances in understanding the genetic basis of tumor initiation and progression. About half of newly diagnosed patients can be reliably identified as having tumors of low malignant potential, and these children have cure rates of greater than 95% with little or no cytotoxic therapy. On the other hand, the other half of neuroblastomas typically present in an explosive fashion with widely metastatic disease, and reliable tumor-specific biomarkers have been defined for this phenotype as well. Empiric approaches to high-risk neuroblastoma therapy have relied on dramatic escalation of chemotherapy dose intensity and, recently, the incorporation of targeted immunotherapy, but nearly 50% of children with high-risk disease will be refractory to therapy or suffer a relapse, both of which are invariably fatal. Future improvements in high-risk neuroblastoma outcomes will require the identification of disease and patient-specific oncogenic vulnerabilities that can be leveraged therapeutically. Rational development of novel approaches to neuroblastoma therapy requires forward-thinking strategies to unequivocally prove activity in the relapse setting and, ultimately, efficacy in curing patients when integrated into frontline treatment plans. Clin Cancer Res; 18(9); 2423–8. ©2012 AACR.
Upregulated JAG1 Enhances Cell Proliferation in Adrenocortical Carcinoma
Authors: Simon Derek P. , Giordano Thomas J. , Hammer Gary D. 
Published: March 2012

Abstract
Purpose: The purpose of this study was to examine the expression and molecular significance of JAG1, a ligand for the Notch developmental signaling pathway, in adrenocortical carcinoma (ACC).
Experimental Design: Human microarray data were analyzed for genes expressing ligands for the Notch pathway and validated with quantitative real-time PCR (QPCR) and immunoblots of RNA and protein, respectively. ACC cells lines were assessed for Notch pathway member expression by immunoblot, QPCR, and immunofluorescence. Notch pathway activity was also determined using a reporter gene (luciferase) activation. Proliferation experiments using a Jag1 knockdown strategy (Jag1KD) and an inhibitor of Notch-dependent transcription (DNMaml) used a coculture system with fluorescence-activated cell-sorting (FACS) analysis. Tumor stage and mitotic rate of human ACC samples were correlated to JAG1 expression.
Results: The Notch ligand JAG1 mRNA and protein are upregulated in ACCs. JAG1 upregulation can be modeled in the Y1 mouse ACC cell line that expresses Jag1, Notch receptors, downstream signaling molecules, and exhibits density-dependent Notch activation. Jag1 enhances cell proliferation through activation of canonical Notch signaling as shown through Jag1KD and coculture experiments. Inhibition of Notch signaling at the level of postreceptor signaling (DNMaml), results in similar inhibition of cell proliferation. Analysis of clinical data indicates that Jag1 expression correlates with both grade and stage of ACCs, supporting a role of JAG1-dependent Notch activation in late-stage ACCs.
Conclusions: JAG1 is the primary upregulated Notch ligand in ACCs and enhances ACC cell proliferation and tumor aggressiveness in a non–cell-autonomous manner through activation of Notch signaling in adjacent cells. Clin Cancer Res; 18(9); 2452–64. ©2012 AACR.
Competing Risk Analyses: How Are They Different and Why Should You Care?
Authors: Chappell Rick 
Published: March 2012

Abstract
Competing risks are events in which at least one precludes the observation of the other, such as toxicity and death. This commentary discusses and distinguishes between the two common types of competing risk analyses, the Kaplan–Meier and cumulative incidence curves. Clin Cancer Res; 18(8); 2127–9. ©2012 AACR.
Regulation of mTOR Complex 2 Signaling in Neurofibromatosis 2–Deficient Target Cell Types
Authors: James Marianne F. , Stivison Elizabeth , Beauchamp Roberta , Han Sangyeul , Li Hua , Wallace Margaret R. , Gusella James F. , Stemmer-Rachamimov Anat O. , Ramesh Vijaya 
Published: March 2012

Abstract
Inactivating mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene results in the development of schwannomas and meningiomas. Using NF2-deficient meningioma cells and tumors, together with the normal cellular counterparts that meningiomas derive, arachnoid cells, we identified merlin as a novel negative regulator of mTOR complex 1 (mTORC1). We now show that merlin positively regulates the kinase activity of mTORC2, a second functionally distinct mTOR complex, and that downstream phosphorylation of mTORC2 substrates, including Akt, is reduced upon acute merlin deficiency in cells. In response to general growth factor stimulation, Akt signaling is attenuated in merlin RNA interference-suppressed human arachnoid and Schwann cells by mechanisms mediated by hyperactive mTORC1 and impaired mTORC2. Moreover, Akt signaling is impaired differentially in a cell type–dependent manner in response to distinct growth factor stimuli. However, contrary to activation of mTORC1, the attenuated mTORC2 signaling profiles exhibited by normal arachnoid and Schwann cells in response to acute merlin loss were not consistently reflected in NF2-deficient meningiomas and schwannomas, suggesting additional genetic events may have been acquired in tumors after initial merlin loss. This finding contrasts with another benign tumor disorder, tuberous sclerosis complex, which exhibits attenuated mTORC2 signaling profiles in both cells and tumors. Finally, we examined rapamycin, as well as the mTOR kinase inhibitor, Torin1, targeting both mTOR complexes to identify the most efficacious class of compounds for blocking mTOR-mediated signaling and proliferation in merlin-deficient meningioma cells. These studies may ultimately aid in the development of suitable therapeutics for NF2-associated tumors. Mol Cancer Res; 10(5); 649–59. ©2012 AACR.
Degradation of Human RAP80 is Cell Cycle Regulated by Cdc20 and Cdh1 Ubiquitin Ligases
Authors: Cho Hyun Jung , Lee Eun Hee , Han Seung Hun , Chung Hee Jin , Jeong Ji Hoon , Kwon Junhye , Kim Hongtae 
Published: March 2012

Abstract
Receptor-associated protein 80 (RAP80) is a component of the BRCA1-A complex that recruits BRCA1 to DNA damage sites in the DNA damage–induced ubiquitin signaling pathway. RAP80-depleted cells showed defective G2–M phase checkpoint control. In this study, we show that RAP80 protein levels fluctuate during the cell cycle. Its expression level peaked in the G2 phase and declined during mitosis and progression into the G1 phase. Also, RAP80 is polyubiquitinated and degraded by the anaphase-promoting complex (APC/C)Cdc20 or (APC/C)Cdh1. Consistent with this, knockdown of Cdc20 or Cdh1 expression by transfecting with small interfering RNAs blocked RAP80 degradation during mitosis or the G1 phase, respectively. A conserved destruction box (D box) in RAP80 affected its stability and ubiquitination, which was dependent on APC/cyclosomeCdc20 (CCdc20) or APC/cyclosomeCdh1 (CCdh1). In addition, overexpression of RAP80 destruction box1 deletion mutant attenuated mitotic progression. Thus, APC/CCdc20 or APC/CCdh1 complexes regulate RAP80 stability during mitosis to the G1 phase, and these events are critical for a novel function of RAP80 in mitotic progression. Mol Cancer Res; 10(5); 615–25. ©2012 AACR.
Prevalence of Cervical Human Papillomavirus (HPV) Infection in Vanuatu
Authors: Aruhuri Bernadette , Tarivonda Len , Tenet Vanessa , Sinha Rohit , Snijders Peter J.F. , Clifford Gary , Pang James , McAdam Margaret , Meijer Chris J.L.M. , Frazer Ian H. , Franceschi Silvia 
Published: March 2012

Abstract
To provide information on human papillomavirus (HPV) prevalence and the distribution of individual HPV types in Pacific Islands, we conducted a population-based survey in Vanuatu, South Pacific. Nine hundred and eighty-seven women between 18 and 64 years of age were included. GP5+/6+-mediated PCR assay was used for HPV testing. The prevalence of 44 HPV types was 28.4% corresponding to an age (world)-standardized prevalence of 25.0% [95% confidence interval (CI), 21.9%–28.0%]. The prevalence of high-risk (HR) HPV types was 21.7% (age-standardized prevalence of 19.2%; 95% CI, 16.4%–22.0%). Among 840 women with adequate cytologic results, 13.6% showed cervical abnormalities, including 3.6% with high-grade squamous intraepithelial lesions (HSIL) and 0.8% with invasive cervical carcinoma. HPV prevalence declined from 46.1% in women aged ≤21 to 15.3% in those ≥45 years. Being single was significantly associated with HPV positivity. HR HPV findings by PCR assay and hybrid capture 2 (HC2; conducted in Vanuatu) were moderately correlated (κ test = 0.59). The positive predictive values of HR HPV positivity for HSIL or worse were 27.6% for PCR and 35.2% for HC2 among women aged ≥30. Nearly half of screening-positive women could not be reevaluated mainly on account of the difficulty to trace back women. The availability of a rapid HPV testing method that allows see-and-treat approaches at the same visit would be, therefore, essential. On account of their high cumulative burden of cervical lesions, also women older than 40 years should be included in at least the first screening round in unscreened populations. Cancer Prev Res; 5(5); 746–53. ©2012 AACR.
The Chemopreventive Effect of Mifepristone on Mammary Tumorigenesis Is Associated with an Anti-invasive and Anti-inflammatory Gene Signature
Authors: Yuan Hongyan , Upadhyay Geeta , Lu Jin , Kopelovich Levy , Glazer Robert I. 
Published: March 2012

Abstract
Progesterone receptor (PR) antagonists are potent antitumor agents in carcinogen and progestin-dependent mammary tumorigenesis models through both PR- and non-PR–mediated mechanisms. The PR antagonist mifepristone/RU486 has been used primarily as an abortifacient possessing high affinity for both the PR and glucocorticoid receptors (GR). To determine whether mifepristone would be effective as a chemopreventive agent, we assessed its effect on progestin/7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in wild-type (WT) and estrogen receptor-α–positive (ER+) transgenic mice expressing the dominant-negative Pax8PPARγ (Pax8) fusion protein. Mifepristone administered at a dose of 2.5 mg significantly delayed mammary tumorigenesis in WT, but not in Pax8 mice, whereas, a three-fold higher dose almost completely blocked tumorigenesis in both WT and Pax8 mice. The sensitivity of WT mice to 2.5 mg mifepristone correlated with an expression profile of 79 genes in tumors, 52 of which exhibited the opposite response in Pax8 mice, and corresponded primarily to the downregulation of genes associated with metabolism, inflammation, and invasion. These results suggest that the chemopreventive activity of mifepristone in WT mice correlates with a specific gene expression signature that is associated with multiple nuclear receptor signaling pathways. Cancer Prev Res; 5(5); 754–64. ©2012 AACR.
Proportion of Patients Treated With Thrombolysis in a Centralized Versus a Decentralized Acute Stroke Care Setting
Authors: Lahr Maarten M.H. , Luijckx Gert-Jan , Vroomen Patrick C.A.J. , van der Zee Durk-Jouke , Buskens Erik 
Published: March 2012

Background and Purpose—
Today, treatment of acute stroke consists of tissue-type plasminogen activator (tPA), admission to a stroke unit, and aspirin. Although tPA treatment is the most effective, there is substantial undertreatment. Centralized care may affect rate, timing, and outcome of thrombolysis compared to decentralized treatment in community hospitals. The present study aimed to assess the impact of organizational models on the proportion of patients undergoing tPA treatment.

Methods—
A prospective, multicenter, observational study among 13 hospitals in the North of the Netherlands was conducted. In the centralized model, tPA treatment for 4 hospitals was administered in 1 stroke center. The decentralized model comprised 9 community hospitals. Primary outcome was the proportion of patients treated with tPA. Secondary outcome measures were proportion of patients arriving within 4.5 hours, safety, 90-day functional outcome, and onset-to-door, door-to-needle, and onset-to-needle times. Potential confounders were adjusted using logistic regression analysis.

Results—

Two hundred eighty-three and 801 ischemic stroke patients were enrolled in the centralized and decentralized settings. Numbers of patients treated with tPA were 62 (21.9%) and 113 (14.1%) (OR, 1.72; 95% CI, 1.22–2.43). Adjusting for potential confounders did not alter results (OR, 2.03; 95% CI, 1.39–2.96). In the centralized setting, significantly more patients arrived at the hospital within the 4.5-hour time window (
P
<0.01), and shorter door-to-needle times were reached (35 versus 47 minutes). Other secondary outcome measures did not differ across setting.

Conclusions—
In a centralized setting, the results demonstrate a 50% increased likelihood of treatment. Prehospital factors seem to contribute to this result.
Long-Term Efficacy of an Ergonomics Program That Includes Patient-Handling Devices on Reducing Musculoskeletal Injuries to Nursing Personnel
Authors: Garg Arun , Kapellusch Jay M. 
Published: March 2012

Objective: The aim of this study was to evaluate long-term efficacy of an ergonomics program that included patient-handling devices in six long-term care facilities (LTC) and one chronic care hospital (CCH). Background: Patient handling is recognized as a major source of musculoskeletal disorders (MSDs) among nursing personnel, and several studies have demonstrated effectiveness of patient-handling devices in reducing those MSDs. However, most studies have been conducted in a single facility, for a short period, and/or without a comprehensive ergonomics program. Method: Patient-handling devices along with a comprehensive ergonomics program was implemented in six LTC facilities and one CCH. Pre- and post-intervention injury data were collected for 38.9 months (range = 29 to 54 months) and 51.2 months (range = 36 to 60 months), respectively. Results: Postintervention patient-handling injuries decreased by 59.8% (rate ratio [RR] = 0.36, 95% confidence interval [CI] [0.28, 0.49], p < .001), lost workdays by 86.7% (RR = 0.16, 95% CI [0.13, 0.18], p < .001), modified-duty days by 78.8% (RR = 0.25, 95% CI [0.22, 0.28], p < .001), and workers’ compensation costs by 90.6% (RR = 0.12, 95% CI [0.09, 0.15], p < .001). Perceived stresses to low back and shoulders among nursing staff were fairly low. A vast majority of patients found the devices comfortable and safe. Longer transfer times with the use of devices was not an issue. Conclusion: Implementation of patient-handling devices along with a comprehensive program can be effective in reducing MSDs among nursing personnel. Strategies to expand usage of patient-handling devices in most health care settings should be explored.
The Effect of SPAM Administration During a Dynamic Simulation
Authors: Pierce Russell S. 
Published: March 2012

Objective: The objective of this study was to determine whether administration of the situation present assessment method (SPAM) affects workload and/or task performance. Background: SPAM probes are thought to isolate workload from the assessment of situation awareness (SA) by including a warning signal before asking an SA-related question. However, there is a good reason to think that SPAM may still have an effect on dynamic workload and task performance. Specifically, nearly all dual tasks affect workload and performance; thus, it would be surprising if SPAM did not. Method: Following the methods of Durso, Bleckley, and Dattel, I evaluated workload and performance on the Air Traffic Scenarios Test in SPAM, non-SPAM probe, and no-probe conditions. Results: Global workload was unaffected by probe administration. However, at least with novice performers, SPAM probes affected task performance. Conclusion: The use of a warning signal does not eliminate performance decrements associated with secondary tasks. Moreover, there may be performance decrements unique to SPAM. Application: Cautious users of online assessment measures, such as SPAM, may want to remove performance immediately subsequent to probes from analysis, use an interprobe interval longer than 2.83 min, and construct their assessment measures to reduce display search times unrelated to primary task performance.
Acceleration of Tendon-Bone Healing of Anterior Cruciate Ligament Graft Using Autologous Ruptured Tissue
Authors: Matsumoto Tomoyuki , Kubo Seiji , Sasaki Ken , Kawakami Yohei , Oka Shinya , Sasaki Hiroshi , Takayama Koji , Tei Katsumasa , Matsushita Takehiko , Mifune Yutaka , Kurosaka Masahiro , Kuroda Ryosuke 
Published: March 2012

Background: It has been recently reported that human anterior cruciate ligament (ACL) ruptured tissue contains abundant vascular stem cells that contribute to tendon-bone healing in an immunodeficient rat model of ACL reconstruction. Hypothesis: Autologous ruptured ACL tissue has an effect on the maturation of bone-tendon integration in anterior cruciate ligament reconstruction. Study Design: Controlled laboratory study. Methods: Twenty healthy adult beagle dogs underwent bilateral ACL reconstruction using the ipsilateral flexor digitorum superficialis tendon and were divided into 2 groups: right knee (a tissue-treated group) and left knee (a control group). The tissue-treated group received autologous ruptured ACL tissue, which was obtained 2 days after resection and sutured to the tibial side of the graft. Histological, radiographic, and biomechanical assessments were performed. In addition, immunohistochemical staining was performed to assess angiogenesis and osteogenesis. Results: Histological assessment and staining for osteoblasts and endothelial cells at week 2 demonstrated early healing, inducing endochondral ossification-like integration with enhanced angiogenesis and osteogenesis in the tissue-treated group’s grafts. Computed tomography at week 4 showed a significantly smaller tibial bone tunnel in the tissue-treated group (tissue, 19.0 ± 4.4 mm2; control, 42.6 ± 4.7 mm2; P = .009, n = 5). Furthermore, biomechanical testing of force during loading to ultimate failure at week 4 demonstrated a significantly higher strength in the tissue-treated group (tissue, 66.4 ± 10.1 N; control, 30.5 ± 10.3 N; P = .009, n = 5). Conclusion: In the present study, the authors elucidated that transplantation of ACL-ruptured tissue, which was sutured to the tibial side of the graft, contributed to early tendon-bone healing in a canine model of ACL reconstruction. Clinical Relevance: Anterior cruciate ligament ruptured tissue has a therapeutic potential in promoting an appropriate environment for tendon-to-bone healing in bone tunnels of ACL reconstruction.