bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV-1 Conserved-Element Vaccines: Relationship between Sequence Conservation and Replicative Capacity
Authors: Rolland Morgane , Manocheewa Siriphan , Swain J. Victor , Lanxon-Cookson Erinn C. , Kim Moon , Westfall Dylan H. , Larsen Brendan B. , Gilbert Peter B. , Mullins James I. 
Published: March 2013

ABSTRACT

To overcome the problem of HIV-1 variability, candidate vaccine antigens have been designed to be composed of conserved elements of the HIV-1 proteome. Such candidate vaccines could be improved with a better understanding of both HIV-1 evolutionary constraints and the fitness cost of specific mutations. We evaluated the
in vitro
fitness cost of 23 mutations engineered in the HIV-1 subtype B Gag-p24 Center-of-Tree (COT) protein through fitness competition assays. While some mutations at conserved sites exacted a high fitness cost, as expected under the assumption that the most conserved residue confers the highest fitness, there was no overall strong relationship between sequence conservation and replicative capacity. By comparing sites that have evolved since the beginning of the epidemic to those that have remain unchanged, we found that sites that have evolved over time were more likely to correspond to HLA-associated sites and that their mutation had limited fitness costs. Our data showed no transcendent link between high conservation and high fitness cost, indicating that merely focusing on conserved segments of HIV-1 would not be sufficient for a successful vaccine strategy. Nonetheless, a subset of sites exacted a high fitness cost upon mutation—these sites have been under selective pressure to change since the beginning of the epidemic but have proved virtually nonmutable and could constitute preferred targets for vaccine design.
Heterogeneity in Neutralization Sensitivities of Viruses Comprising the Simian Immunodeficiency Virus SIVsmE660 Isolate and Vaccine Challenge Stock
Authors: Lopker Michael , Easlick Juliet , Sterrett Sarah , Decker Julie M. , Barbian Hannah , Learn Gerald , Keele Brandon F. , Robinson James E. , Li Hui , Hahn Beatrice H. , Shaw George M. , Bar Katharine J. 
Published: March 2013

ABSTRACT

The sooty mangabey-derived simian immunodeficiency virus (SIV) strain E660 (SIVsmE660) is a genetically heterogeneous, pathogenic isolate that is commonly used as a vaccine challenge strain in the nonhuman primate (NHP) model of human immunodeficiency virus type 1 (HIV-1) infection. Though it is often employed to assess antibody-based vaccine strategies, its sensitivity to antibody-mediated neutralization has not been well characterized. Here, we utilize single-genome sequencing and infectivity assays to analyze the neutralization sensitivity of the uncloned SIVsmE660 isolate, individual viruses comprising the isolate, and transmitted/founder (T/F) viruses arising from low-dose mucosal inoculation of macaques with the isolate. We found that the SIVsmE660 isolate overall was highly sensitive to neutralization by SIV-infected macaque plasma samples (50% inhibitory concentration [IC
50
] < 10
−5
) and monoclonal antibodies targeting V3 (IC
50
< 0.01 μg/ml), CD4-induced (IC
50
< 0.1 μg/ml), CD4 binding site (IC
50
∼ 1 μg/ml), and V4 (IC
50
, ∼5 μg/ml) epitopes. In comparison, SIVmac251 and SIVmac239 were highly resistant to neutralization by these same antibodies. Differences in neutralization sensitivity between SIVsmE660 and SIVmac251/239 were not dependent on the cell type in which virus was produced or tested. These findings indicate that in comparison to SIVmac251/239 and primary HIV-1 viruses, SIVsmE660 generally exhibits substantially less masking of antigenically conserved Env epitopes. Interestingly, we identified a minor population of viruses (∼10%) in both the SIVsmE660 isolate and T/F viruses arising from it that were substantially more resistant (>1,000-fold) to antibody neutralization and another fraction (∼20%) that was intermediate in neutralization resistance. These findings may explain the variable natural history and variable protection afforded by heterologous Env-based vaccines in rhesus macaques challenged by high-dose versus low-dose SIVsmE660 inoculation regimens.
The London 2012 Summer Olympic Games: an analysis of usage of the Olympic Village ‘Polyclinic’ by competing athletes
Authors: Vanhegan Ivor S , Palmer-Green Debbie , Soligard Torbjørn , Steffen Kathrin , O'Connor Philip , Bethapudi Sarath , Budgett Richard , Haddad Fares S , Engebretsen Lars 
Published: March 2013

BackgroundThe London 2012 Summer Olympic Games involved 10 568 elite athletes representing 204 competing nations. To manage the varied healthcare needs of this diverse population, a Polyclinic was constructed in the athletes’ village.AimThis work aims to summarise the usage of the Polyclinic by competing athletes and the facilities available to them.MethodsAll Polyclinic encounters were entered into a database from which data were exported for the time frame 28 July–12 August 2012, inclusive to cover the first to last full day of competition. Only Polyclinic data involving accredited athletes were analysed. All types of encounters were collected for analysis, not just sports-related issues.ResultsThere were a total of 3220 encounters within the Polyclinic. This figure combines medical consultations, radiology/pathology investigations and prescriptions dispensed. Of these 3220 encounters, there were 2105 medical consultations; musculoskeletal comprised the greatest number (52%), followed by dental (30%) and ophthalmic (9%). The most frequently used imaging modality was MRI and diagnostic CT was used the least. After correction for multiple entries, Africa provided the largest proportion of athletes attending the Polyclinic (44%) and Europe the least (9%). Peak usage of all facilities was seen around days 9 and 10 of competition, reflecting the busiest time of the competition and the largest number of athletes in the village.ConclusionsThe Polyclinic managed a wide variety of both sports-related and non-sports-related injuries and illnesses. The breadth of specialists available for consultation was appropriate as was the ease of access to them. The radiology department was able to satisfy the demand, as were the pharmacy and pathology services. We would recommend a similar structure of facilities and available expertise in one clinic when planning future mass participation sporting events.
Characteristics, risk factors and mortality of stroke patients in Kyoto, Japan
Authors: Shigematsu Kazuo , Nakano Hiromi , Watanabe Yoshiyuki , Sekimoto Tatsuyuki , Shimizu Kouichiro , Nishizawa Akihiko , Makino Masahiro , Okumura Atsushi , Bando Kazuhiko , Kitagawa Yasushi 
Published: March 2013

ObjectivesThe aim of the study was to evaluate the characteristics, risk factors and outcome of recent stroke patients in Kyoto, Japan.DesignWe analysed stroke patients in the registry with regard to their characteristics, risk factors and mortality. Cox proportional hazards regressions were used to calculate adjusted HRs for death.SettingsThe Kyoto prefecture of Japan has established a registry to enrol new stroke patients in cooperation with the Kyoto Medical Association and its affiliated hospitalsParticipantsThe registry now has data on 14 268 patients enrolled from 1 January 1999 to 31 December 2009. Of these, 12 774(89.5%) underwent CT, 9232 (64.7%) MRI, 2504 (17.5%) angiography and 342 (2.4%) scintigraphy. Excluding 480 (3.3%) unclassified patients, 13 788 (96.6%) patients formed the basis of further analyses which were divided into three subtypes: cerebral infarction (CI), cerebral haemorrhage (CH) and subarachnoid haemorrhage (SAH).ResultsA total of 13 788 confirmed stroke patients in the study cohort comprised 9011 (86.3%) CI, 3549 (25.7%) CH and 1197 (8.7%) SAH cases. The mean age ±SD was 73.3±11.8, 69.1±13.6 and 62.7±13.5 in the CI, CH and SAH cases, respectively. Men were predominant in the CI and CH cases, whereas women were predominant in the SAH cases. The frequencies of risk factors were different among the subtypes. Mortality was worst in SAH, followed by CH, and least in CI. HRs for death adjusted for age, sex, histories of hypertension, arrhythmia, diabetes mellitus and hyperlipaemia and use of tobacco and/or alcohol showed a significant (p<0.001) difference among CI (as reference), CH (3.71; 3.11 to 4.43) and SAH (8.94; 7.21 to 11.11).ConclusionsThe characteristics, risk factors and mortality were evaluated in a quantitative manner in a large Japanese study cohort to shed light on the present status of stroke medicine.
Dormant Cancer Cells Contribute to Residual Disease in a Model of Reversible Pancreatic Cancer
Authors: Lin Wan-chi , Rajbhandari Nirakar , Liu Chengbao , Sakamoto Kazuhito , Zhang Qian , Triplett Aleata A. , Batra Surinder K. , Opavsky Rene , Felsher Dean W. , DiMaio Dominick J. , Hollingsworth Michael A. , Morris John P. , Hebrok Matthias , Witkiewicz Agnieszka K. , Brody Jonathan R. , Rui Hallgeir , Wagner Kay-Uwe 
Published: March 2013

Abstract
The initiation and progression of pancreatic ductal adenocarcinoma (PDAC) is governed by a series of genetic and epigenetic changes, but it is still unknown whether these alterations are required for the maintenance of primary and metastatic PDAC. We show here that the c-Myc oncogene is upregulated throughout the entire process of neoplastic progression in human PDAC and in genetically engineered mice that express mutant Kras. To experimentally address whether c-Myc is essential for the growth and survival of cancer cells, we developed a novel mouse model that allows a temporally and spatially controlled expression of this oncogene in pancreatic progenitors and derived lineages of the exocrine pancreas. Unlike previous reports, upregulation of c-Myc was sufficient to induce the formation of adenocarcinomas after a short latency without additional genetic manipulation of cell survival pathways. Deficiency in Cdkn2a increased the rate of metastasis but had no effect on tumor latency or c-Myc–mediated cancer maintenance. Despite a macroscopically complete regression of primary, metastatic, and transplantable tumors following the ablation of c-Myc, some cancer cells remained dormant. A significant number of these residual neoplastic cells expressed cancer stem cell markers, and re-expression of exogenous c-Myc in these cells led to rapid cancer recurrence. Collectively, the results of this study suggest that c-Myc plays a significant role in the progression and maintenance of PDAC, but besides targeting this oncogene or its downstream effectors, additional therapeutic strategies are necessary to eradicate residual cancer cells to prevent disease recurrence. Cancer Res; 73(6); 1821–30. ©2012 AACR.
Mammographic Breast Density Response to Aromatase Inhibition
Authors: Vachon Celine M. , Suman Vera J. , Brandt Kathleen R. , Kosel Matthew L. , Buzdar Aman U. , Olson Janet E. , Wu Fang-Fang , Flickinger Lynn M. , Ursin Giske , Elliott Catherine R. , Shepherd Lois , Weinshilboum Richard M. , Goss Paul E. , Ingle James N. 
Published: March 2013

Abstract
Purpose: Mammographic breast density (MBD) is decreased by tamoxifen, but the effect of aromatase inhibitors is less clear.
Experimental Design: We enrolled early-stage postmenopausal patients with breast cancer initiating adjuvant aromatase inhibitor therapy and ascertained mammograms before and at an average 10 months of aromatase inhibitor therapy. We matched cases to healthy postmenopausal women (controls) from a large mammography screening cohort on age, baseline body mass index, baseline MBD, and interval between mammograms. We estimated change in MBD using a computer-assisted thresholding program (Cumulus) and compared differences between cases and matched controls.
Results: In predominantly White women (96%), we found 14% of the 387 eligible cases had a MBD reduction of at least 5% after an average of 10 months of aromatase inhibitor therapy. MBD reductions were associated with higher baseline MBD, aromatase inhibitor use for more than 12 months, and prior postmenopausal hormone use. Comparing each case with her matched control, there was no evidence of an association of change in MBD with aromatase inhibitor therapy [median case–control difference among 369 pairs was −0.1% (10th and 90th percentile: −5.9%, 5.2%) P = 0.51]. Case–control differences were similar by type of aromatase inhibitor (P's 0.41 and 0.56); prior use of postmenopausal hormones (P = 0.85); baseline MBD (P = 0.55); and length of aromatase inhibitor therapy (P = 0.08).
Conclusions: In postmenopausal women treated with aromatase inhibitors, 14% of cases had a MBD reduction of more than 5%, but these decreases did not differ from matched controls. These data suggest that MBD is not a clinically useful biomarker for predicting the value of aromatase inhibitor therapy in White postmenopausal women. Clin Cancer Res; 19(8); 2144–53. ©2013 AACR.
Combining Hedgehog Signaling Inhibition with Focal Irradiation on Reduction of Pancreatic Cancer Metastasis
Authors: Gu Dongsheng , Liu Hailan , Su Gloria H. , Zhang Xiaoli , Chin-Sinex Helen , Hanenberg Helmut , Mendonca Marc S. , Shannon Harlan E. , Chiorean E. Gabriela , Xie Jingwu 
Published: March 2013

Abstract
Pancreatic cancer often presents in advanced stages and is unresponsive to conventional treatments. Thus, the need to develop novel treatment strategies for pancreatic cancer has never been greater. Here, we report that combination of focal irradiation with hedgehog (Hh) signaling inhibition exerts better than additive effects on reducing metastases. In an orthotopic model, we found that focal irradiation alone effectively reduced primary tumor growth but did not significantly affect metastasis. We hypothesized that cancer stem cells (CSC) of pancreatic cancer are responsible for the residual tumors following irradiation, which may be regulated by Hh signaling. To test our hypothesis, we showed that tumor metastasis in our model was accompanied by increased expression of CSC cell surface markers as well as Hh target genes. We generated tumor spheres from orthotopic pancreatic and metastatic tumors, which have elevated levels of CSC markers relative to the parental cells and elevated expression of Hh target genes. Irradiation of tumor spheres further elevated CSC cell surface markers and increased Hh target gene expression. Combination of Hh signaling inhibition with radiation had more than additive effects on tumor sphere regeneration in vitro. This phenotype was observed in two independent cell lines. In our orthotopic animal model, focal radiation plus Hh inhibition had more than additive effects on reducing lymph node metastasis. We identified several potential molecules in mediating Hh signaling effects. Taken together, our data provide a rationale for combined use of Hh inhibition with irradiation for clinical treatment of patients with pancreatic cancer. Mol Cancer Ther; 12(6); 1038–48. ©2013 AACR.
Curcumin-Targeting Pericellular Serine Protease Matriptase Role in Suppression of Prostate Cancer Cell Invasion, Tumor Growth, and Metastasis
Authors: Cheng Tai-Shan , Chen Wen-Chi , Lin Ya-Yun , Tsai Chin-Hsien , Liao Chia-I , Shyu Hsin-Yi , Ko Chun-Jung , Tzeng Sheue-Fen , Huang Chun-Yin , Yang Pan-Chyr , Hsiao Pei-Wen , Lee Ming-Shyue 
Published: March 2013

Abstract
Curcumin has been shown to possess potent chemopreventive and antitumor effects on prostate cancer. However, the molecular mechanism involved in curcumin's ability to suppress prostate cancer cell invasion, tumor growth, and metastasis is not yet well understood. In this study, we have shown that curcumin can suppress epidermal growth factor (EGF)- stimulated and heregulin-stimulated PC-3 cell invasion, as well as androgen-induced LNCaP cell invasion. Curcumin treatment significantly resulted in reduced matrix metalloproteinase 9 activity and downregulation of cellular matriptase, a membrane-anchored serine protease with oncogenic roles in tumor formation and invasion. Our data further show that curcumin is able to inhibit the induction effects of androgens and EGF on matriptase activation, as well as to reduce the activated levels of matriptase after its overexpression, thus suggesting that curcumin may interrupt diverse signal pathways to block the protease. Furthermore, the reduction of activated matriptase in cells by curcumin was also partly due to curcumin's effect on promoting the shedding of matriptase into an extracellular environment, but not via altering matriptase gene expression. In addition, curcumin significantly suppressed the invasive ability of prostate cancer cells induced by matriptase overexpression. In xenograft model, curcumin not only inhibits prostate cancer tumor growth and metastasis but also downregulates matriptase activity in vivo. Overall, the data indicate that curcumin exhibits a suppressive effect on prostate cancer cell invasion, tumor growth, and metastasis, at least in part via downregulating matriptase function. Cancer Prev Res; 6(5); 495–505. ©2013 AACR.
New Perspectives of Curcumin in Cancer Prevention
Authors: Park Wungki , Amin A.R.M. Ruhul , Chen Zhuo Georgia , Shin Dong M. 
Published: March 2013

AbstractNumerous natural compounds have been extensively investigated for their potential for cancer prevention over the decades. Curcumin, from Curcuma longa, is a highly promising natural compound that can be potentially used for chemoprevention of multiple cancers. Curcumin modulates multiple molecular pathways involved in the lengthy carcinogenesis process to exert its chemopreventive effects through several mechanisms: promoting apoptosis, inhibiting survival signals, scavenging reactive oxidative species (ROS), and reducing the inflammatory cancer microenvironment. Curcumin fulfills the characteristics for an ideal chemopreventive agent with its low toxicity, affordability, and easy accessibility. Nonetheless, the clinical application of curcumin is currently compromised by its poor bioavailability. Here, we review the potential of curcumin in cancer prevention, its molecular targets, and mechanisms of action. Finally, we suggest specific recommendations to improve its efficacy and bioavailability for clinical applications. Cancer Prev Res; 6(5); 387–400. ©2013 AACR.
The association of smoking with venous thrombosis in women
Authors: Wiggins Kerri L. , McKnight Barbara , Psaty Bruce M. , Rice Kenneth M. , Heckbert Susan R. , Smith Nicholas L. , Blondon Marc 
Published: March 2013

SummaryThe evidence for an association between smoking and venous thrombosis (VT) is inconsistent, and its mediation pathways remain to be fully elucidated. A population-based, case-control study was conducted in a large, integrated healthcare system in Washington State, USA. Cases were women aged 18–90 years who experienced a validated incident deep-vein thrombosis or pulmonary embolism between January 1, 1995, and December 31, 2009. Controls were randomly selected from members of the healthcare system. Smoking status (current, former, never) was assessed from medical records review and, for a subset, also by telephone interview. Multivariable logistic regression was used to estimate odds ratios (OR) associated with smoking status. We identified 2,278 cases and 5,927 controls. Subjects comprised mostly postmenopausal white women with a mean age of 66 years and a current smoking prevalence of 10%. Compared to never-smokers, current and former smokers were at higher risk of VT (adjusted OR 1.21, 95% confidence interval [CI] 1.02–1.44 and OR 1.15, 95%CI 1.03–1.29, respectively). These associations were attenuated with further adjustment for potential mediators (cardiovascular disease, congestive heart failure, cancer, recent hospitalisations and physical activity): OR 1.02 (95%CI 0.83–1.25) and 0.95 (95%CI 0.83–1.08), respectively. In conclusion, the modestly increased risk of VT in women who are current or former smokers might be explained by the occurrence of smoking-related diseases and decreased physical activity. Our results do not support a direct biological effect of smoking on the risk of VT that is clinically relevant.Note: Part of this work has been presented as a poster at the 58th annual meeting of the Scientific & Standardization Committee of the ISTH in June 2012.
Antimicrobial activity of fibrinogen and fibrinogen-derived peptides – a novel link between coagulation and innate immunity
Authors: Mörgelin Matthias , Kasetty Gopinath , Olin Anders I. , Schmidtchen Artur , Herwald Heiko , Påhlman Lisa I. 
Published: March 2013

SummaryFibrinogen is a key player in the blood coagulation system, and is upon activation with thrombin converted into fibrin that subsequently forms a fibrin clot. In the present study, we investigated the role of fibrinogen in the early innate immune response. Here we show that the viability of fibrinogen-binding bacteria is affected in human plasma activated with thrombin. Moreover, we found that the peptide fragment GHR28 released from the p-chain of fibrinogen has antimicrobial activity against bacteria that bind fibrinogen to their surface, whereas non-binding strains are unaffected. Notably, bacterial killing was detected in Group A Streptococcus bacteria entrapped in a fibrin clot, suggesting that fibrinogen and coagulation is involved in the early innate immune system to quickly wall off and neutralise invading pathogens.
Platelet function testing and prediction of procedural bleeding risk
Authors: Grove Erik L. , Hossain Rashed , Storey Robert F. 
Published: March 2013

SummaryThe essential role of platelets in haemostasis underlies the relationship between platelet function and spontaneous or procedure-related bleeding, which has important prognostic implications. Although not routinely undertaken, platelet function testing offers the potential to tailor antiplatelet therapy for individual patients. However, uncertainties remain about how well platelet function testing may predict haemostasis and guide management of bleeding risk. Studies of aspirin, P2Y12 inhibitors and other antiplatelet drugs clearly demonstrate how inhibition of platelet function increases bleeding risk. More potent antiplatelet drugs are associated with higher bleeding rates, consistent with the levels of platelet inhibition achieved by these drugs. Studies of patients treated with clopidogrel, which is associated with wide inter-individual variation in antiplatelet effect, suggest that platelet function testing may predict bleeding risk related to coronary artery bypass grafting (CABG) surgery and potentially guide the timing of surgery following discontinuation of clopidogrel. Similarly, some studies have demonstrated a relationship between clopidogrel response and bleeding in patients undergoing percutaneous coronary intervention (PCI), although other studies have not supported this. Carriage of the *17 allele of cytochrome P450 2C19, which is associated with gain of function and enhanced response to clopidogrel, seems to be associated with increased bleeding risk, although studies showing lack of apparent effect of loss-of-function alleles provide contradictory evidence. Further large studies are needed to guide best practice in the application of platelet function testing in the clinical management of patients treated with antiplatelet drugs in order to optimise individual care.