bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II, Open-Label Study of Brivanib as Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma
Authors: Finn Richard S. , Kang Yoon-Koo , Mulcahy Mary , Polite Blase N. , Lim Ho Yeong , Walters Ian , Baudelet Christine , Manekas Demetrios , Park Joong-Won 
Published: January 2012

Abstract
Purpose: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has recently been shown to have activity as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This phase II open-label study assessed brivanib as second-line therapy in patients with advanced HCC who had failed prior antiangiogenic treatment.
Experimental Design: Brivanib was administered orally at a dose of 800 mg once daily. The primary objectives were tumor response rate, time to response, duration of response, progression-free survival, overall survival (OS), disease control rate, time to progression (TTP), and safety and tolerability.
Results: Forty-six patients were treated. Best responses to treatment with brivanib (N = 46 patients) using modified World Health Organization criteria were partial responses for two patients (4.3%), stable disease for 19 patients (41.3%), and progressive disease for 19 patients (41.3%). The tumor response rate was 4.3%; the disease control rate was 45.7%. Median OS was 9.79 months. Median TTP as assessed by study investigators following second-line treatment with brivanib was 2.7 months. The most common adverse events were fatigue, decreased appetite, nausea, diarrhea, and hypertension.
Conclusion: Brivanib had a manageable safety profile and is one of the first agents to show promising antitumor activity in advanced HCC patients treated with prior sorafenib. Clin Cancer Res; 18(7); 2090–8. ©2012 AACR.
MET Activation Mediates Resistance to Lapatinib Inhibition of HER2-Amplified Gastric Cancer Cells
Authors: Chen Chin-Tung , Kim Hyaehwan , Liska David , Gao Sizhi , Christensen James G. , Weiser Martin R. 
Published: January 2012

Abstract
HER2 amplification is found in more than 15% of gastric cancers and is associated with poor clinical outcome. Lapatinib, a dual HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown promising in vitro results in treating HER2+ cancer cells. However, several studies have shown that activation of alternative receptor tyrosine kinases can mediate resistance to HER-targeted therapy. Here, we investigated whether activated MET can confer resistance to lapatinib inhibition of gastric cancer cells. A panel of gastric cancer cell lines was treated with lapatinib, and we observed that cell proliferation was reduced by 70% and that the degree of HER2 amplification corresponds to sensitivity to lapatinib. Immunoblotting analysis indicated that phosphorylation of HER2, EGFR, MET, AKT, and extracellular signal-regulated kinase was inhibited by lapatinib and presumably led to cell-cycle arrest as observed with flow cytometry. Hepatocyte growth factor (HGF) activation of MET receptors rescued cells from lapatinib-induced growth inhibition by restimulating the downstream pathways and restoring normal cell-cycle progression. This rescue effect could be abrogated by inhibiting MET with PHA-665752 (a highly specific MET inhibitor) or downregulating MET expression with short interfering RNA. No synergy in growth inhibition was observed when cells were treated with a combination of lapatinib and PHA-665752. Repeat studies using insulin-like growth factor 1 and fibroblast growth factor 3 could not uniformly rescue the lapatinib-treated gastric cancer cells. In conclusion, HGF/MET–mediated resistance to lapatinib is a novel mechanism of resistance to HER2-targeted agents in gastric cancer cells. Development of inhibitors targeting multiple receptors or common downstream signaling proteins merits further investigation. Mol Cancer Ther; 11(3); 660–9. ©2012 AACR.
A Role for ATM in Hereditary Pancreatic Cancer
Authors: Bakker Janine L. , de Winter Johan P. 
Published: January 2012

Abstract
The genetic risk factors that contribute to pancreatic cancers are largely unknown. A new next-generation sequencing study by Roberts and colleagues now adds ATM to the list of pancreatic ductal adenocarcinoma predisposition genes. Cancer Discovery; 2(1); 14–5. ©2012 AACR.
Commentary on Roberts et al., p. 41.
Tackling Formalin-Fixed, Paraffin-Embedded Tumor Tissue with Next-Generation Sequencing
Authors: Corless Christopher L. , Spellman Paul T. 
Published: January 2012

Abstract
Most tumor samples available for clinical genotyping are formalin-fixed and paraffin-embedded (FFPE), but there has been relatively little published on the suitability of such samples for next-generation sequencing approaches. A new study by Wagle and colleagues shows that a combination of hybridization-capture and deep sequencing yields high-quality data from FFPE specimens. Cancer Discovery; 2(1); 23–4. ©2012 AACR.
Commentary on Wagle et al., p. 82.
Methodologies for the generation of design summer years for building energy simulation using UKCP09 probabilistic climate projections
Authors: Smith S Th , Hanby VI 
Published: January 2012

Design summer years representing near-extreme hot summers have been used in the United Kingdom for the evaluation of thermal comfort and overheating risk. The years have been selected from measured weather data basically representative of an assumed stationary climate. Recent developments have made available ‘morphed’ equivalents of these years by shifting and stretching the measured variables using change factors produced by the UKCIP02 climate projections. The release of the latest, probabilistic, climate projections of UKCP09 together with the availability of a weather generator that can produce plausible daily or hourly sequences of weather variables has opened up the opportunity for generating new design summer years which can be used in risk-based decision-making. There are many possible methods for the production of design summer years from UKCP09 output: in this article, the original concept of the design summer year is largely retained, but a number of alternative methodologies for generating the years are explored. An alternative, more robust measure of warmth (weighted cooling degree hours) is also employed. It is demonstrated that the UKCP09 weather generator is capable of producing years for the baseline period, which are comparable with those in current use. Four methodologies for the generation of future years are described, and their output related to the future (deterministic) years that are currently available. It is concluded that, in general, years produced from the UKCP09 projections are warmer than those generated previously. Practical applications: The methodologies described in this article will facilitate designers who have access to the output of the UKCP09 weather generator (WG) to generate Design Summer Year hourly files tailored to their needs. The files produced will differ according to the methodology selected, in addition to location, emissions scenario and timeslice.
Completion Node Dissection in Patients with Sentinel Node–Positive Melanoma of the Head and Neck
Authors: Smith Valerie A. , Cunningham Joan E. , Lentsch Eric J. 
Published: January 2012

ObjectiveDetermine if completion lymph node dissection (CLND) is associated with improved survival in sentinel lymph node (SLN)–positive cutaneous melanoma of the head and neck (CMHN) patients.Study DesignRetrospective analysis of large population database.SettingSurveillance, Epidemiology and End Results (SEER) database/multiple settings.Subjects and MethodsUsing the SEER database, the authors identified patients with SLN‐positive CMHN. Clinicopathologic data and 5‐year disease‐specific survival (DSS) were examined for patients who underwent sentinel lymph node biopsy (SLNB) alone vs SLNB + CLND.ResultsAmong 350 SLN‐positive patients, 210 (60%) had SLNB + CLND, and 140 (40%) had SLNB only. Patients in the SLNB‐only group were significantly older (median age 62 vs 53 years, P <. 0001). The cohort as a whole did not significantly benefit from CLND; however, CLND was associated with improved DSS for a subgroup of patients age <60 years with nonulcerated tumors ≤2 mm thick (P =. 03). Relative to SLNB alone, CLND did not improve survival for patients age ≥60 years or those with thicker (>2 mm) or ulcerated tumors.ConclusionsCompared with SLNB alone, CLND does not seem to be associated with improved survival for most patients with SLN‐positive CMHN. CLND likely improves survival for patients age <60 years with thin (≤2 mm) nonulcerated tumors and when there is a low risk of identifying positive non‐SLNs.
Coexistence of hemiplegic migraine with SUNCT or SUNA: a case series
Authors: Lambru Giorgio , Nesbitt Alexander , Shanahan Paul , Matharu Manjit S 
Published: January 2012

Background: Hemiplegic migraine (HM) is a rare subtype of migraine with aura that includes transient hemiparesis of different degrees. The dominantly inherited type, called familial hemiplegic migraine, along with the sporadic type, in which no family history of similar attacks exists, have been recently recognized by the revised International Classification of Headache Disorders (ICHD-2). Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are also very rare conditions that are classified as trigeminal autonomic cephalalgias. This report provides the first description of an association between HM and SUNCT/SUNA. Cases: Eight females and two males with both these disorders were identified between 2007 and 2010. Conclusion: The coexistence of such rare primary headache disorders is probably due to a common underlining mechanism, with a sodium channelopathy being an attractive potential candidate.
Communicating with the Elderly: Decision Making and Informed Consent in Subjects with Frailty or Dementia
Authors: Hugonot-Diener Laurence , Husson Jean-Marc 
Published: January 2012

Obtaining a valid informed consent from an elderly person, especially when frail or with possible dementia, will initially involve the practical problem of assessing the ability to communicate. Only then can the assessment of decisionmaking capacities and the obtaining of informed consent for participation in research be progressed. Normal ageing does not impair communication or decision-making, but pathological status does, this may, or may not, be associated with the ageing process. Perceptual impairment may, in particular, interfere with the communication. Once the subject appreciates and understands that he/she has the right to make a choice then it is important to ensure that he/she fully understands the decision he/she is being asked to make and can communicate and explain in his/her own words why a particular decision was made. In this paper suggestions, based upon existing guidelines or texts, will be made as to how to improve communication with the elderly and the capabilities that the subject must demonstrate to show his capacity to make a decision will be discussed.
Protecting or Empowering the Vulnerable? Mental Illness, Communication and the Research Process
Authors: Atkinson Jacqueline M. 
Published: January 2012

People with mental illness are treated, in research, as a ‘class’ or category who are vulnerable, without always being clear why they should be treated as such, not why an individual, rather than the class, is vulnerable. The two main reasons given are lack of competence and power imbalance. Competence issues include incapacity and legislation, assessment and the impact of the illness in decisions. Power issues cover the role of mental health legislation, coercion, protectiveness and paternalism, stigma and discrimination and the ‘well’ and ‘ill’ self. These are examined within a framework of risk assessment, both to the patient and to others. Over-concern to protect the vulnerable can lead to gate-keepers preventing their inclusion in studies at various stages of the research. This denies such groups a voice in the research process. It is suggested that ethical scrutiny of research is not only to prevent harm to the vulnerable, but also to provide a framework to empower such people to take part in research. To do otherwise is to further stigmatize and marginalize them. One way forward is to look at the risk presented by different types of research, from clinical intervention trials to non-therapeutic, qualitative studies and to modify capacity and access requirements in the light of the risks presented.
Ethical Issues in Health Research on Ethnic Minority Populations: Focusing on Inclusion and Exclusion
Authors: Bhopal Raj 
Published: January 2012

Used wisely the concepts of race and ethnicity in research have great potential, but used unwisely they can do immense damage. We need to consider the potential issues that might require a change of emphasis or application of ethics in a multi-ethnic society. Doing no harm (non-maleficence) is the most important ethical pillar in the ethnicity and health field. Ethnic differences can be used in damaging ways. Without the ethic of beneficence in place it is better not to draw attention to ethnic differences. Respect is the pre-condition for autonomy. Autonomy of ethnic minority populations to live in their own traditional way is not easy to achieve in multi-ethnic societies. There are difficult issues in multi-ethnic societies that require great sensitivity to create a sense of fairness and justice. Justice is the core value that underpins equity. There is a deep paradox – to promote equality, we may need to treat people and groups unequally. Ethical codes need to be modified to emphasize the importance of including ethnic minority populations in research and not bypassing them, as has been happening. It is correct, for example, that potential research participants' personal details are guarded. If such a person, however, does not read it may be unethical to send written information about a project. It may be more ethical to tele phone or even call at the doorstep of such a person. The history of racism in research is worrying, not least the fear that it might return. We need a governing code of conduct. Ethical research can help ethnic minority groups to move from the shadows of society and participate in a vibrant, healthy, multi-ethnic society.
Regulation of CXCR4 conformation by the small GTPase Rac1: implications for HIV infection
Authors: Zoughlami Younes , Voermans Carlijn , Brussen Kim , van Dort Karel A. , Kootstra Neeltje A. , Maussang David , Smit Martine J. , Hordijk Peter L. , van Hennik Paula B. 
Published: January 2012

Abstract
The chemokine receptor CXCR4 is a critical regulator of cell migration and serves as a coreceptor for HIV-1. The chemokine stromal cell derived factor-1, also known as CXCL12, binds to CXCR4 and exerts its biologic functions partly through the small guanosine triphosphate hydrolase (GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1). We show in different cell types, including CD34+ hematopoietic stem and progenitor cells, that inhibition of Rac1 causes a reversible conformational change in CXCR4, but not in the related receptors CXCR7 or CCR5. Biochemical experiments showed that Rac1 associates with CXCR4. The conformational change of CXCR4 on Rac1 inhibition blocked receptor internalization and impaired CXCL12-induced Gαi protein activation. Importantly, we found that the conformation adopted by CXCR4 after Rac1 inhibition prevents HIV-1 infection of both the U87-CD4-CXCR4 cell line and of primary peripheral blood mononuclear cells. In conclusion, our data show that Rac1 activity is required to maintain CXCR4 in the responsive conformation that allows receptor signaling and facilitates HIV-1 infection; this implies that Rac1 positively regulates CXCR4 function and identifies the Rac1-CXCR4 axis as a new target for preventing HIV-1 infection.
Effect of modeled reduced gravity conditions on bacterial morphology and physiology
Authors: Vukanti Raja , Model Michael A , Leff Laura G 
Published: January 2012

AbstractBackgroundBacterial phenotypes result from responses to environmental conditions under which these organisms grow; reduced gravity has been demonstrated in many studies as an environmental condition that profoundly influences microorganisms. In this study, we focused on low-shear stress, modeled reduced gravity (MRG) conditions and examined, forEscherichia coli and Staphlyococcus aureus, a suite of bacterial responses (including total protein concentrations, biovolume, membrane potential and membrane integrity) in rich and dilute media and at exponential and stationary phases for growth. The parameters selected have not been studied inE. coliandS. aureusunder MRG conditions and provide critical information about bacterial viability and potential for population growth.ResultsWith the exception ofS. aureusin dilute Luria Bertani (LB) broth, specific growth rates (based on optical density) of the bacteria were not significantly different between normal gravity (NG) and MRG conditions. However, significantly higher bacterial yields were observed for both bacteria under MRG than NG, irrespective of the medium with the exception ofE. coligrown in LB. Also, enumeration of cells after staining with 4',6-diamidino-2-phenylindole showed that significantly higher numbers were achieved under MRG conditions during stationary phase forE. coliandS. aureusgrown in M9 and dilute LB, respectively. In addition, with the exception of smallerS. aureusvolume under MRG conditions at exponential phase in dilute LB, biovolume and protein concentrations per cell did not significantly differ between MRG and NG treatments. BothE. coliandS. aureushad higher average membrane potential and integrity under MRG than NG conditions; however, these responses varied with growth medium and growth phase.ConclusionsOverall, our data provides novel information aboutE. coliandS. aureusmembrane potential and integrity and suggest that bacteria are physiologically more active and a larger percentage are viable under MRG as compared to NG conditions. In addition, these results demonstrate that bacterial physiological responses to MRG conditions vary with growth medium and growth phase demonstrating that nutrient resources are a modulator of response.
Promoting fit bodies, healthy eating and physical activity among Indigenous Australian men: a study protocol
Authors: Ricciardelli Lina A , Mellor David , McCabe Marita P , Mussap Alexander J , Hallford David J , Tyler Matthew 
Published: January 2012

Abstract

Background
Overall the physical health of Indigenous men is among the worst in Australia. Research has indicated that modifiable lifestyle factors, such as poor nutrition and physical inactivity, appear to contribute strongly to these poor health conditions. To effectively develop and implement strategies to improve the health of Australia's Indigenous peoples, a greater understanding is needed of how Indigenous men perceive health, and how they view and care for their bodies. Further, a more systematic understanding of how sociocultural factors affect their health attitudes and behaviours is needed. This article presents the study protocol of a community-based investigation into the factors surrounding the health and body image of Indigenous Australian men.

Methods and design
The study will be conducted in a collaborative manner with Indigenous Australian men using a participatory action research framework. Men will be recruited from three locations around Australia (metropolitan, regional, and rural) and interviewed to understand their experiences and perspectives on a number of issues related to health and health behaviour. The information that is collected will be analysed using modified grounded theory and thematic analysis. The results will then be used to develop and implement community events in each location to provide feedback on the findings to the community, promote health enhancing strategies, and determine future action and collaboration.

Discussion
This study will explore both risk and protective factors that affect the health of Indigenous Australian men. This knowledge will be disseminated to the wider Indigenous community and can be used to inform future health promotion strategies. The expected outcome of this study is therefore an increased understanding of health and health change in Indigenous Australian men, the development of strategies that promote healthy eating and positive patterns of physical activity and, in the longer term, more effective and culturally-appropriate interventions to improve health.
Extracellular overexpression of recombinant Thermobifida fusca cutinase by alpha-hemolysin secretion system in E. coli BL21(DE3)
Authors: Su Lingqia , Chen Sheng , Yi Li , Woodard Ronald W , Chen Jian , Wu Jing 
Published: January 2012

Abstract

Background
Extracellular expression of proteins has an absolute advantage in a large-scale industrial production. In our previous study, Thermobifida fusca cutinase, an enzyme mainly utilized in textile industry, was expressed via type II secretory system in Escherichia coli BL21(DE3), and it was found that parts of the expressed protein was accumulated in the periplasmic space. Due to the fact that alpha-hemolysin secretion system can export target proteins directly from cytoplasm across both cell membrane of E. coli to the culture medium, thus in the present study we investigated the expression of cutinase using this alpha-hemolysin secretion system.

Results

T. fusca cutinase was fused with the specific signal peptide of alpha-hemolysin scretion system and expressed in E. coli BL21(DE3). In addition, HlyB and HlyD, strain-specific translocation components of alpha-hemolysin secretion system, were coexpressed to facilitate the enzyme expression. The cultivation of this engineered cell showed that cutinase activity in the culture medium reached 334 U/ml, which is 2.5 times that from type II secretion pathway under the same culture condition. The recombinant cutinase was further purified. Biochemical characterization of purified enzyme, which had an α-hemolysin secretion pathway signal peptide attached, had substrate specificity, pH and temperature profile, as well as application capability in bioscouring similar to that of wild-type cutinase.

Conclusions
In the present study, T. fusca cutinase was successfully secreted to the culture media by α-hemolysin secretion system. This is the first report of cutinase being efficiently secreted by this pathway. Due to the limited cases of successful expression of industrial enzyme by E. coli α-hemolysin secretion system, our study further explored the utilization of this pathway in industrial enzymes.