bluuebunny/crossref_metadata_2025_split huggingface dataset:
Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4+T Cell Immunity and Protection in Mice
Authors: Kastenmüller Kathrin , Espinosa Diego A. , Trager Lauren , Stoyanov Cristina , Salazar Andres M. , Pokalwar Santosh , Singh Sanjay , Dutta Sheetij , Ockenhouse Christian F. , Zavala Fidel , Seder Robert A. 
Published: December 2012

ABSTRACTThePlasmodium falciparumcircumsporozoite (CS) protein (CSP) is a major vaccine target for preventing malaria infection. Thus, developing strong and durable antibody and T cell responses against CSP with novel immunogens and potent adjuvants may improve upon the success of current approaches. Here, we compare four distinct full-lengthP. falciparumCS proteins expressed inEscherichia coliorPichia pastorisfor their ability to induce immunity and protection in mice when administered with long-chain poly(I·C) [poly(I·C)LC] as an adjuvant. CS proteins expressed inE. coliinduced high-titer antibody responses against the NANP repeat region and potent CSP-specific CD4+T cell responses. Moreover,E. coli-derived CS proteins in combination with poly(I·C)LC induced potent multifunctional (interleukin 2-positive [IL-2+], tumor necrosis factor alpha-positive [TNF-α+], gamma interferon-positive [IFN-γ+]) CD4+effector T cell responses in blood, in spleen, and particularly in liver. Using transgenicPlasmodium bergheiexpressing the repeat region ofP. falciparumCSP [Pb-CS(Pf)], we showed that there was a 1- to 4-log decrease in malaria rRNA in the liver following a high-dose challenge and ∼50% sterilizing protection with a low-dose challenge compared to control levels. Protection was directly correlated with high-level antibody titers but not CD4+T cell responses. Finally, protective immunity was also induced using the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE) as the adjuvant, which also correlated with high antibody titers yet CD4+T cell immunity that was significantly less potent than that with poly(I·C)LC. Overall, these data suggest that full-length CS proteins and poly(I·C)LC or GLA-SE offer a simple vaccine formulation to be used alone or in combination with other vaccines for preventing malaria infection.
The Unique Structure of Haemophilus influenzae Protein E Reveals Multiple Binding Sites for Host Factors
Authors: Singh Birendra , Al-Jubair Tamim , Mörgelin Matthias , Thunnissen Marjolein M. , Riesbeck Kristian 
Published: December 2012

ABSTRACT

Haemophilus influenzae
protein E (PE) is a multifunctional adhesin involved in direct interactions with lung epithelial cells and host proteins, including plasminogen and the extracellular matrix proteins vitronectin and laminin. We recently crystallized PE and successfully collected X-ray diffraction data at 1.8 Å. Here, we solved the structure of a recombinant version of PE and analyzed different functional regions. It is a dimer in solution and in the asymmetric unit of the crystals. The dimer has a structure that resembles a flattened β-barrel. It is, however, not a true β-barrel, as there are differences in both the hydrogen-bonding pattern and the shape. Each monomer consisted of a 6-stranded antiparallel β-sheet with a rigid α-helix at the C terminus tethered to the concave side of the sheet by a disulfide bridge. The laminin/plasminogen binding region (residues 41 to 68) is exposed, while the vitronectin binding region (residues 84 to 108) is partially accessible in the dimer. The dimerized PE explains the simultaneous interaction with laminin and vitronectin. In addition, we found this unique adhesin to be present in many bacterial genera of the family
Pasteurellaceae
and also orthologues in other, unrelated species (
Enterobacter cloacae
and
Listeria monocytogenes
). Peptides corresponding to the surface-exposed regions PE 24 to 37, PE 74 to 89, and PE 134 to 156 were immunogenic in the mouse. Importantly, these peptide-based antibodies also recognized PE at the bacterial surface. Taken together, our detailed structure of PE explains how this important virulence factor of
H. influenzae
simultaneously interacts with host vitronectin, laminin, or plasminogen, promoting bacterial pathogenesis.
Validity of theInternational Classification of Diseases 10th revisioncode for hospitalisation with hyponatraemia in elderly patients
Authors: Gandhi Sonja , Shariff Salimah Z , Fleet Jamie L , Weir Matthew A , Jain Arsh K , Garg Amit X 
Published: December 2012

ObjectiveTo evaluate the validity of theInternational Classification of Diseases, 10th Revision(ICD-10) diagnosis code for hyponatraemia (E87.1) in two settings: at presentation to the emergency department and at hospital admission.DesignPopulation-based retrospective validation study.SettingTwelve hospitals in Southwestern Ontario, Canada, from 2003 to 2010.ParticipantsPatients aged 66 years and older with serum sodium laboratory measurements at presentation to the emergency department (n=64 581) and at hospital admission (n=64 499).Main outcome measuresSensitivity, specificity, positive predictive value and negative predictive value comparing various ICD-10 diagnostic coding algorithms for hyponatraemia to serum sodium laboratory measurements (reference standard). Median serum sodium values comparing patients who were code positive and code negative for hyponatraemia.ResultsThe sensitivity of hyponatraemia (defined by a serum sodium ≤132 mmol/l) for the best-performing ICD-10 coding algorithm was 7.5% at presentation to the emergency department (95% CI 7.0% to 8.2%) and 10.6% at hospital admission (95% CI 9.9% to 11.2%). Both specificities were greater than 99%. In the two settings, the positive predictive values were 96.4% (95% CI 94.6% to 97.6%) and 82.3% (95% CI 80.0% to 84.4%), while the negative predictive values were 89.2% (95% CI 89.0% to 89.5%) and 87.1% (95% CI 86.8% to 87.4%). In patients who were code positive for hyponatraemia, the median (IQR) serum sodium measurements were 123 (119–126) mmol/l and 125 (120–130) mmol/l in the two settings. In code negative patients, the measurements were 138 (136–140) mmol/l and 137 (135–139) mmol/l.ConclusionsThe ICD-10 diagnostic code for hyponatraemia differentiates between two groups of patients with distinct serum sodium measurements at both presentation to the emergency department and at hospital admission. However, these codes underestimate the true incidence of hyponatraemia due to low sensitivity.
Identifying clinical criteria to predict Type 1 diabetes, as defined by absolute insulin deficiency: a systematic review protocol
Authors: Shields Beverley M , Peters Jaime L , Cooper Chris , Powell Roy J , Knight Bridget A , Hyde Christopher , Hattersley Andrew T 
Published: December 2012

IntroductionManagement of a patient's diabetes is entirely dependent upon the type of diabetes they are deemed to have. Patients with Type 1 diabetes are insulin deficient so require multiple daily insulin injections, whereas patients with Type 2 diabetes still have some endogenous insulin production so insulin treatment is only required when diet and tablets do not establish good glycaemic control. Despite the importance of a correct diagnosis, classification of diabetes is based on aetiology and relies on clinical judgement. There are no clinical guidelines on how to determine whether a patient has Type 1 or Type 2 diabetes. We aim to systematically review the literature to derive evidence-based clinical criteria for the classification of the major subtypes of diabetes.Methods and analysisWe will perform a systematic review of diagnostic accuracy studies to establish clinical criteria that predict the subsequent development of absolute insulin deficiency seen in Type 1 diabetes. Insulin deficiency will be determined by reference standard C-peptide concentrations. Synthesis of criteria identified will be undertaken using hierarchical summary receiver operating characteristic curves.Ethics and disseminationAs this is a systematic review, there will be no ethical issues. We will disseminate results by writing up the final systematic review and synthesis for publication in a peer-reviewed journal and will present at national and international diabetes-related meetings.
Racial/Ethnic Differences in Use and Duration of Adjuvant Hormonal Therapy for Breast Cancer in the Women's Health Initiative
Authors: Livaudais Jennifer C. , LaCroix Andrea , Chlebowski Rowan T. , Li Christopher I. , Habel Laurel A. , Simon Michael S. , Thompson Beti , Erwin Deborah O. , Hubbell F. Allan , Coronado Gloria D. 
Published: December 2012

AbstractBackground: Five-year breast cancer survival rates are lower among Hispanic and African-American women than among Non-Hispanic White women. Differences in breast cancer treatment likely play a role. Adjuvant hormonal therapies increase overall survival among women with hormone receptor-positive breast cancer.Methods: We examined racial/ethnic differences in use and duration of adjuvant hormonal therapy among 3,588 postmenopausal women enrolled in the Women's Health Initiative (WHI) Extension Study. Women diagnosed with hormone receptor-positive localized or regional stage breast cancer after study enrollment were surveyed between September 2009 and August 2010 and asked to recall prior use and duration of adjuvant hormonal breast cancer therapy. ORs comparing self-reported use and duration with race/ethnicity (Hispanic, African-American, Asian/Pacific Islander vs. Non-Hispanic White) were estimated using multivariable-adjusted logistic regression.Results: Of the 3,588 women diagnosed from 1994 to 2009; 3,039 (85%) reported any use of adjuvant hormonal therapy, and 67% of women reporting ever-use who were diagnosed before 2005 reported using adjuvant hormonal therapy for the optimal duration of 5 years or more. In adjusted analysis, no statistically significant differences in use or duration by race/ethnicity were observed.Conclusions: This study did not find significant differences in use or duration of use of adjuvant hormonal therapy by race/ethnicity.Impact: Findings should be confirmed in other population-based samples, and potential reasons for discontinuation of therapy across all racial/ethnic groups should be explored. Cancer Epidemiol Biomarkers Prev; 22(3); 365–73. ©2012 AACR.
Suppression of Prostate Epithelial Proliferation and Intraprostatic Progrowth Signaling in Transgenic Mice by a New Energy Restriction-Mimetic Agent
Authors: Berman-Booty Lisa D. , Chu Po-Chen , Thomas-Ahner Jennifer M. , Bolon Brad , Wang Dasheng , Yang Tiffany , Clinton Steven K. , Kulp Samuel K. , Chen Ching-Shih 
Published: December 2012

Abstract
Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis. This glycolytic shift, called the Warburg effect, provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents (ERMA). We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition. The lead ERMA in this class, OSU-CG5, decreases the production of ATP and NADH in LNCaP prostate cancer cells. In this study, we examined the effect of OSU-CG5 on the severity of preneoplastic lesions in male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Daily oral treatment with OSU-CG5 at 100 mg/kg from 6 to 10 weeks of age resulted in a statistically significant decrease in the weight of urogenital tract and microdissected dorsal, lateral, and anterior prostatic lobes relative to vehicle controls. The suppressive effect of OSU-CG5 was evidenced by marked decreases in Ki67 immunostaining and proliferating cell nuclear antigen (PCNA) expression in the prostate. OSU-CG5 treatment was not associated with evidence of systemic toxicity. Microarray analysis indicated a central role for Akt, and Western blot analysis showed reduced phosphorylation and/or expression levels of Akt, Src, androgen receptor, and insulin-like growth factor-1 receptor in prostate lobes. These findings support further investigation of OSU-CG5 as a potential chemopreventive agent. Cancer Prev Res; 6(3); 232–41. ©2012 AACR.
β-Cryptoxanthin Restores Nicotine-Reduced Lung SIRT1 to Normal Levels and Inhibits Nicotine-Promoted Lung Tumorigenesis and Emphysema in A/J Mice
Authors: Iskandar Anita R. , Liu Chun , Smith Donald E. , Hu Kang-Quan , Choi Sang-Woon , Ausman Lynne M. , Wang Xiang-Dong 
Published: December 2012

Abstract
Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosamino-1-(3-pyridyl)-1-butanone (NNK)-initiated lung cancer in A/J mice. This tumor-promoting effect of nicotine was accompanied by significant reductions in survival probability and lung Sirtuin 1 (SIRT1) expression, which has been proposed as a tumor suppressor. The decreased level of SIRT1 was associated with increased levels of AKT phosphorylation and interleukin (il)-6 mRNA but decreased tumor suppressor p53 and retinoic acid receptor (RAR)-β mRNA levels in the lungs. Using this mouse model, we then determined whether β-cryptoxanthin (BCX), a xanthophyll that is strongly associated with a reduced risk of lung cancer in several cohort studies, can inhibit nicotine-induced emphysema and lung tumorigenesis. We found that BCX supplementation at two different doses was associated with reductions of the nicotine-promoted lung tumor multiplicity and volume, as well as emphysema in mice treated with both NNK and nicotine. Moreover, BCX supplementation restored the nicotine-suppressed expression of lung SIRT1, p53, and RAR-β to that of the control group, increased survival probability, and decreased the levels of lung il-6 mRNA and phosphorylation of AKT. The present study indicates that BCX is a preventive agent against emphysema and lung cancer with SIRT1 as a potential target. In addition, our study establishes a relevant animal lung cancer model for studying tumor growth within emphysematous microenvironments. Cancer Prev Res; 6(4); 309–20. ©2012 AACR.
Combined Lifestyle Factors and Risk of Incident Colorectal Cancer in a Chinese Population
Authors: Odegaard Andrew O. , Koh Woon-Puay , Yuan Jian-Min 
Published: December 2012

Abstract
A body of research links dietary intake, alcohol consumption, smoking, physical activity, body mass index (BMI), and possibly sleep patterns with colorectal cancer risk. However, little research has examined the association of the combination of these lifestyle factors with incidence of colorectal cancer, especially in non-Western populations. A protective lifestyle factor index of these six aforementioned factors was created and examined in relation to risk of developing colorectal cancer. This study is a prospective observational study of 50,466 Chinese men and women in Singapore ages 45 to 74 years during enrollment in the Singapore Chinese Health Study in 1993–1998 and followed up through 2007. The main outcome measures were standardized rates and HRs of incident colorectal cancer. The protective levels of each lifestyle factor were independently associated with reduced age- and sex-standardized incidence rates of colon cancer. When all the factors were combined into a single protective lifestyle factor index, there was a strong, monotonic decrease in incidence rate of colon cancer with an increasing score. Relative to participants with an index score of 0 to 3, the HRs (95% confidence intervals) of colon cancer for an index score of 4, 5, 6, 7, 8, and 9/10 were 0.58 (0.35–0.95), 0.56 (0.36–0.86), 0.50 (0.33–0.76), 0.43 (0.28–0.66), 0.39 (0.25–0.63), and 0.25 (0.12–0.54; Ptrend &lt; 0.0001). The results were consistent by sex. Conversely, there was no association with rectal cancer risk. An increasing protective lifestyle factor index score is associated with a marked decreased risk of developing colon cancer in Chinese men and women. Cancer Prev Res; 6(4); 360–7. ©2012 AACR.
Mutant N-RAS Protects Colorectal Cancer Cells from Stress-Induced Apoptosis and Contributes to Cancer Development and Progression
Authors: Wang Yufang , Velho Sérgia , Vakiani Efsevia , Peng Shouyong , Bass Adam J. , Chu Gerald C. , Gierut Jessica , Bugni James M. , Der Channing J. , Philips Mark , Solit David B. , Haigis Kevin M. 
Published: December 2012

Abstract
N-RAS is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in NRAS occur in a subset of colorectal cancers, but little is known about how the mutant protein contributes to the onset and progression of the disease. Using genetically engineered mice, we find that mutant N-RAS strongly promotes tumorigenesis in the context of inflammation. The protumorigenic nature of mutant N-RAS is related to its antiapoptotic function, which is mediated by activation of a noncanonical mitogen-activated protein kinase pathway that signals through STAT3. As a result, inhibition of MAP–ERK kinase selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-RAS. The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for patients with colorectal cancer. These data show for the first time the important role that N-RAS plays in colorectal cancer.
Significance: Little is known about N-RAS function in normal biology or in cancer. Our study links the antiapoptotic function of mutant N-RAS to its ability to promote colorectal cancer in an inflammatory context. In addition, our study pinpoints a therapeutic strategy for this distinct colorectal cancer subtype. Cancer Discov; 3(3); 294–307. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 239
Mcl-1 and FBW7 Control a Dominant Survival Pathway Underlying HDAC and Bcl-2 Inhibitor Synergy in Squamous Cell Carcinoma
Authors: He Lei , Torres-Lockhart Kristine , Forster Nicole , Ramakrishnan Saranya , Greninger Patricia , Garnett Mathew J. , McDermott Ultan , Rothenberg Stephen M. , Benes Cyril H. , Ellisen Leif W. 
Published: December 2012

Abstract
Effective targeted therapeutics for squamous cell carcinoma (SCC) are lacking. Here, we uncover Mcl-1 as a dominant and tissue-specific survival factor in SCC, providing a roadmap for a new therapeutic approach. Treatment with the histone deacetylase (HDAC) inhibitor vorinostat regulates Bcl-2 family member expression to disable the Mcl-1 axis and thereby induce apoptosis in SCC cells. Although Mcl-1 dominance renders SCC cells resistant to the BH3-mimetic ABT-737, vorinostat primes them for sensitivity to ABT-737 by shuttling Bim from Mcl-1 to Bcl-2/Bcl-xl, resulting in dramatic synergy for this combination and sustained tumor regression in vivo. Moreover, somatic FBW7 mutation in SCC is associated with stabilized Mcl-1 and high Bim levels, resulting in a poor response to standard chemotherapy but a robust response to HDAC inhibitors and enhanced synergy with the combination vorinostat/ABT-737. Collectively, our findings provide a biochemical rationale and predictive markers for the application of this therapeutic combination in SCC.
Significance: This study reveals the tissue-specific landscape and biochemistry of the Bcl-2 family in SCC, which underlie moderate sensitivity of these tumors to HDAC inhibitor therapy but dramatic synergy in combination with BH3-mimetic therapy. By establishing predictive biomarkers, we provide evidence that tumors most likely to respond to this therapeutic combination, including those harboring somatic FBW7 mutations, are those most resistant to standard chemotherapy. Cancer Discov; 3(3); 324–37. ©2012 AACR.
See related commentary by Pickering and Myers, p. 258
This article is highlighted in the In This Issue feature, p. 239
Microembolism and Catheter Ablation II
Authors: Haines David E. , Stewart Mark T. , Barka Noah D. , Kirchhof Nicole , Lentz Linnea R. , Reinking Nicki M. , Urban Jon F. , Halimi Franck , Deneke Thomas , Kanal Emanuel 
Published: December 2012

Background—
Asymptomatic cerebral lesions have been observed on diffusion weighted MRI (DWI) scans shortly after catheter ablation of atrial fibrillation, but the pathogenesis of these lesions is incompletely understood.

Methods and Results—
Twelve dogs underwent selective catheterization of the internal carotid or vertebral arteries. Either a microbubbled mixture of air (1.0–4.0 mL), blood, contrast, and saline (n=5), or heat-dried pulverized blood (particle size <600 μm) mixed with saline and contrast (n=6) was injected. One sham control experiment was performed. MRI scans were performed preinjection, and at 1, 2, and 4 days postinjection. Neurological tests were performed daily. Gross pathology and histopathology were performed on the brains after being euthanized on day 4. Three animals died <24 hours after injection. Hyperintense lesions were observed on DWI (median maximum diameter 3.1 mm) in 2 of 4 animals after air embolism and in 3 of 5 animals after particulate embolism. No DWI lesions were detected in the remaining 5 animals (including the sham control). Lesions seen on DWI and confirmed on the fluid attenuating inversion recovery sequence correlated well with anatomic lesions on histopathology.

Conclusions—
Cerebral embolization of air microbubbles or microparticulate debris that approximate the embolic sources from catheter ablation can create hyperintense DWI punctate lesions in a canine model. The location and size of the DWI/fluid attenuating inversion recovery lesions correlate with pathological findings.