bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancers
Authors: Dave Bhuvanesh , Migliaccio Ilenia , Gutierrez M. Carolina , Wu Meng-Fen , Chamness Gary C. , Wong Helen , Narasanna Archana , Chakrabarty Anindita , Hilsenbeck Susan G. , Huang Jian , Rimawi Mothaffar , Schiff Rachel , Arteaga Carlos , Osborne C. Kent , Chang Jenny C. 
Published: December 2010

Purpose Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. Results Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). Conclusion Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.
Randomized Phase II Trial of Single-Agent Amrubicin or Topotecan as Second-Line Treatment in Patients With Small-Cell Lung Cancer Sensitive to First-Line Platinum-Based Chemotherapy
Authors: Jotte Robert , Conkling Paul , Reynolds Craig , Galsky Matthew D. , Klein Leonard , Fitzgibbons James F. , McNally Richard , Renschler Markus F. , Oliver Jennifer W. 
Published: December 2010

Purpose This phase II study evaluated the safety and efficacy of single-agent amrubicin versus topotecan in patients with small-cell lung cancer (SCLC) sensitive to first-line platinum-based chemotherapy. Patients and Methods Patients were randomly assigned 2:1 to amrubicin (40 mg/m2/d in a 5-minute intravenous [IV] infusion, days 1 through 3, every 21 days) or topotecan (1.5 mg/m2/d in a 30-minute IV infusion, days 1 through 5, every 21 days). The primary efficacy end point was overall response rate (ORR) for amrubicin. Secondary end points included time to progression, median progression-free survival (PFS), and median overall survival (OS). Results Of 76 patients enrolled, 50 patients were randomly assigned to amrubicin, and 26 patients were randomly assigned to topotecan. Amrubicin treatment resulted in a significantly higher ORR than topotecan (44% v 15%; P = .021). Median PFS and median OS were 4.5 months and 9.2 months with amrubicin and 3.3 months and 7.6 months with topotecan, respectively. Tolerability was similar with both agents. However, grade 3 or worse neutropenia and thrombocytopenia seemed to be more frequent in the topotecan group as compared with the amrubicin group (78% and 61% v 61% and 39%, respectively). Conclusion Amrubicin shows promising activity, with an ORR of 44% compared with an ORR of 15% for topotecan as second-line treatment in patients with SCLC sensitive to first-line platinum-based chemotherapy. In addition, the safety profiles were comparable; however, a trend was noted for more frequent grade 3 or worse neutropenia and thrombocytopenia in the topotecan group as compared with the amrubicin group. Additional studies are ongoing.
Immunohistochemical Methods for Predicting Cell of Origin and Survival in Patients With Diffuse Large B-Cell Lymphoma Treated With Rituximab
Authors: Meyer Paul N. , Fu Kai , Greiner Timothy C. , Smith Lynette M. , Delabie Jan , Gascoyne Randy D. , Ott German , Rosenwald Andreas , Braziel Rita M. , Campo Elias , Vose Julie M. , Lenz Georg , Staudt Louis M. , Chan Wing C. , Weisenburger Dennis D. 
Published: December 2010

Purpose Patients with diffuse large B-cell lymphoma (DLBCL) can be divided into prognostic groups based on the cell of origin of the tumor as determined by microarray analysis. Various immunohistochemical algorithms have been developed to replicate these microarray results and/or stratify patients according to survival. This study compares some of those algorithms and also proposes some modifications. Patients and Methods Two-hundred and sixty-two cases of de novo DLBCL treated with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy were examined. Results The Choi algorithm and Hans algorithm had high concordance with the microarray results. Modifications of the Choi and Hans algorithms for ease of use still retained high concordance with the microarray results. Although the Nyman and Muris algorithms had high concordance with the microarray results, each had a low value for either sensitivity or specificity. The use of LMO2 alone showed the lowest concordance with the microarray results. A new algorithm (Tally) using a combination of antibodies, but without regard to the order of examination, showed the greatest concordance with microarray results. All of the algorithms divided patients into groups with significantly different overall and event-free survivals, but with different hazard ratios. With the exception of the Nyman algorithm, this survival prediction was independent of the International Prognostic Index. Although the Muris algorithm had prognostic significance, it misclassified a large number of cases with activated B-cell type DLBCL. Conclusion The Tally algorithm showed the best concordance with the microarray data while maintaining prognostic significance and ease of use.
Phase II Study of Bevacizumab Plus Temozolomide During and After Radiation Therapy for Patients With Newly Diagnosed Glioblastoma Multiforme
Authors: Lai Albert , Tran Anh , Nghiemphu Phioanh L. , Pope Whitney B. , Solis Orestes E. , Selch Michael , Filka Emese , Yong William H. , Mischel Paul S. , Liau Linda M. , Phuphanich Surasak , Black Keith , Peak Scott , Green Richard M. , Spier Cynthia E. , Kolevska Tatjana , Polikoff Jonathan , Fehrenbacher Louis , Elashoff Robert , Cloughesy Timothy 
Published: December 2010

Purpose This open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity. Patients and Methods Seventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison. Results The overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials. Conclusion Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.
Heat Transfer Stages Recognition by Boiling Acoustic During Quenching
Authors: Ravnik Franc , Grum Janez 
Published: December 2010

Abstract
In order to control the quenching process and provide uniform quenching, wetting of the specimen with the quenching medium is very important since this will provide equable heat transfer and therefore uniform quenching conditions for the specimen. During the quenching of the specimens in liquids, in the boundary layer between the specimen and the quenching medium, three characteristic phenomena occur in the following sequence: Film boiling, bubble boiling, and convection. The phenomena concerned proceed with different rates of intensity at different locations at the specimen surface or at its entire surface. The quenching process is always accompanied by evaporation of the quenching medium at the specimen surface, where the characteristic boundary layer will form. Vaporization and boiling is always involved with sound generated by formation, oscillation, and decay of the bubbles, predominantly in the range of hearing, and which slightly round this threshold. During the experiment of dip quenching, the acoustic emission generated was captured with the hydrophone. The sound pressure changes are indicated in a digital sound record. A spectrum analysis of sound pressure is shown in the diagrams indicating variations of the sound pressure level as a function of frequency and time, in three-dimensional diagrams of sound pressure changes, as a time-variation of pressure amplitude, as a signal power spectrum, etc. The variations of sound pressure in dependence of the acoustic signal captured confirm the phenomena in the boundary layer between the specimen and the quenching medium. From the acoustic signals captured in the course of the quenching process, it can be inferred (1) the occurrence and continuing of film boiling, in which intense emission will occur due to the evaporation of a quenching medium followed by generation characteristic sound signals with high amplitude; (2) this is followed by bubble boiling with a characteristic calm emission of the vapor bubbles. Sound signals have constant amplitude values; and (3) at the conclusion of the quenching process, the bubble emission will reduce and eventually stop, which is reflected in the amplitude value of the sound signal. The aim of the experimental study of quenching by measuring the characteristics of the sound signal is to monitor the quenching process and obtain optimal results.
Dynamics of the “Popcorn” Wolbachia Infection in OutbredAedes aegyptiInforms Prospects for Mosquito Vector Control
Authors: Yeap H L , Mee P , Walker T , Weeks A R , O'Neill S L , Johnson P , Ritchie S A , Richardson K M , Doig C , Endersby N M , Hoffmann A A 
Published: December 2010

AbstractForty percent of the world's population is at risk of contracting dengue virus, which produces dengue fever with a potentially fatal hemorrhagic form. The wMelPop Wolbachia infection of Drosophila melanogaster reduces life span and interferes with viral transmission when introduced into the mosquito Aedes aegypti, the primary vector of dengue virus. Wolbachia has been proposed as an agent for preventing transmission of dengue virus. Population invasion by Wolbachia depends on levels of cytoplasmic incompatibility, fitness effects, and maternal transmission. Here we characterized these traits in an outbred genetic background of a potential target population of Ae. aegypti using two crossing schemes. Cytoplasmic incompatibility was strong in this background, and the maternal transmission rate of Wolbachia was high. The infection substantially reduced longevity of infected adult females, regardless of whether adults came from larvae cultured under high or low levels of nutrition or density. The infection reduced the viability of diapausing and nondiapausing eggs. Viability was particularly low when eggs were laid by older females and when diapausing eggs had been stored for a few weeks. The infection affected mosquito larval development time and adult body size under different larval nutrition levels and densities. The results were used to assess the potential for wMelPop-CLA to invade natural populations of Ae. aegypti and to develop recommendations for the maintenance of fitness in infected mosquitoes that need to compete against field insects.
A Cis-Acting tRNA Gene Imposes the Cell Cycle Progression Requirement for Establishing Silencing at the HMR Locus in Yeast
Authors: Lazarus Asmitha G , Holmes Scott G 
Published: December 2010

Abstract
Numerous studies have determined that the establishment of Sir protein-dependent transcriptional silencing in yeast requires progression through the cell cycle. In our study we examined the cell cycle requirement for the establishment of silencing at the HML and HMR loci using strains bearing conditional or inducible SIR3 alleles. Consistent with prior reports, we observed that establishing silencing at HMR required progression through the cell cycle. Unexpectedly, we found that the HML locus is far less dependent on cell cycle progression to establish silencing. Seeking cis-acting elements that could account for this difference, we found that deletion of a tRNA gene that serves as a chromatin boundary at HMR abolishes the cell cycle progression requirement at this locus, while insertion of sequences containing this tRNA gene adjacent to HML imposes dependence on cell cycle progression for the full establishment of silencing. Our results indicate that the cell cycle progression requirement is not a property intrinsic to the formation of heterochromatin in yeast, but is instead a cis-limited, locus-specific phenomenon. We show that inactivation of the Scc1 cohesin also abolishes the requirement for cell cycle progression and test models based on a possible link between the tRNA gene and cohesin association.
Dose Response of Inhaled Corticosteroids in Children With Persistent Asthma: A Systematic Review
Authors: Zhang Linjie , Axelsson Inge , Chung Mei , Lau Joseph 
Published: December 2010

OBJECTIVE:To assess the dose-response relationship (benefits and harms) of inhaled corticosteroids (ICSs) in children with persistent asthma.METHODS:We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared ≥2 doses of ICSs in children aged 3 to 18 years with persistent asthma. Medline was searched for articles published between 1950 and August 2009. Main outcomes of our analyses included morning and evening peak expiratory flow, forced expiratory volume in 1 second, asthma symptom score, β2-agonist use, withdrawal because of lack of efficacy, and adverse events. Meta-analyses were performed to compare moderate (300–400 μg/day) with low (≤200 μg/day beclomethasone-equivalent) doses of ICSs.RESULTS:Fourteen RCTs (5768 asthmatic children) that evaluated 5 ICSs were included. The pooled standardized mean difference from 6 trials revealed a small but statistically significant increase of moderate over low doses in improving forced expiratory volume in 1 second (standardized mean difference: 0.11 [95% confidence interval: 0.01–0.21]) among children with mild-to-moderate asthma. There was no significant difference between 2 doses in terms of other efficacy outcomes. Local adverse events were uncommon, and there was no evidence of dose-response relationship at low-to-moderate doses.CONCLUSIONS:Compared with low doses, moderate doses of ICSs may not provide clinically relevant therapeutic advantage in children with mild-to-moderate persistent asthma. Additional RCTs are needed to clarify the dose-response relationship of ICSs in persistent childhood asthma.
Translation of a Pediatric Asthma-Management Program Into a Community in Connecticut
Authors: Cloutier Michelle M. , Wakefield Dorothy B. 
Published: December 2010

OBJECTIVES:
We assessed whether a successful asthma-management program could be translated into pediatrician's offices, improve care, and reduce medical services use.

METHODS:
Pediatrician's offices from 6 communities in Connecticut were trained, and all children aged 6 months or older were eligible for enrollment. Quality measures included enrollment numbers, appropriate use of anti-inflammatory therapy, and distribution of a written treatment plan. Medical services utilization data for Medicaid-insured children were expressed as relative rates (RRs) (95% confidence intervals [CIs]) before and after enrollment, and we used historical and contemporaneous comparisons and generalized estimating equations.

RESULTS:
A total of 51 practices and 297 clinicians enrolled 32 680 children from 2002 to 2007; 10 467 had asthma, of whom 4354 were insured with Medicaid. Children with persistent asthma experienced decreases in the number of hospitalizations (RR: 0.51 [95% CI: 0.39–0.65]) and emergency-department visits (RR: 0.70 [95% CI: 0.68–0.84]), and there was no change in number of outpatient visits (RR: 0.99 [95% CI: 0.9–1.10]). Inhaled corticosteroid use doubled, appropriate use of anti-inflammatory therapy increased to 96%, and 94% of the children were given a written treatment plan.

CONCLUSIONS:
General pediatricians can successfully implement an asthma-management program that is effective in improving care for large numbers of children.
The Biological Framework: Translational Research from Bench to Clinic
Authors: Yarden Yosef 
Published: December 2010

Abstract
The understanding of cellular signaling pathways in malignant tumors is an important aspect of cancer research and modern targeted therapy strategies. Growth factors and their receptors in particular are critical to modern cancer therapy research, because these factors control all phases of tumor development and metastasis. Most importantly, growth factors are responsible for cell survival under cytotoxic drugs and radiotherapy. These growth factor signaling pathways are composed of complex networks that have adapted to efficiently respond to certain disturbances, such as a single agent that targets one aspect of the pathway. Meanwhile, multiple insults to the pathway, such as combination therapy regimens, are known to be effective in shutting down these pathways and, consequently, killing the tumor cell. Research is currently under way to find new ways to exploit fragile aspects of oncogenic networks, such as uncommon, multiple perturbations that target essential hubs through immunotherapy, combinations of antibodies, heat shock protein inhibitors, or novel drug combinations. Complex growth factor signaling networks and novel methods to shut down these networks are described within a framework of engineering and mathematical concepts.
Chemotherapy: Updates and New Perspectives
Authors: Swain Sandra M. 
Published: December 2010

Abstract
Treatment options for patients with breast cancer have progressively improved over the past 40 years, from an era of no chemotherapy to the introduction of taxanes, hormonal therapy, and biologic therapy. These advances have resulted in substantial, 15%–20% improvements in clinical outcomes. However, progress has yet to be made to improve the prognosis in many breast cancer patients, and research is currently under way to test new tools, or new applications of older tools, to advance breast cancer management. Chemotherapy clearly remains a cornerstone of adjuvant breast cancer treatment, because breast cancer can be very sensitive to the currently available agents. Meanwhile, the era of a one-size-fits-all approach to breast cancer management is over, and the maximum potential of chemotherapy should now be reached by targeting specific populations. Effective biomarkers are therefore needed to optimize chemotherapy, define more selective populations, and clearly tailor treatment. This paper discusses recent data, including new trials that are more fully incorporating current knowledge with respect to molecular markers and the underlying biology of breast cancer.
Molecular Stratification of Triple-Negative Breast Cancers
Authors: Perou Charles M. 
Published: December 2010

Abstract
Research focused on the analysis and classification of breast tumors, primarily using DNA microarrays and patterns of gene expression, has resulted in distinct tumor subtypes. Although no knowledge of patient survival or outcomes was used to derive these gene descriptions, these different classes based upon patterns of gene expression have important prognostic implications. Predictive markers in estrogen receptor–negative and triple-negative disease will be particularly important because in the absence of therapy, these tumor subtypes tend to have a poor prognosis. In addition, the claudin-low subgroup has been found to be common within the triple-negative cancers and may have further prognostic and therapeutic implications. Patients with triple-negative breast cancer do benefit from chemotherapy, but better treatment options are needed that are less toxic, reduce the risk of disease progression, and are more targeted to this patient population. Potential treatments include poly (ADP-ribose) polymerase inhibitors, and therapies that target cancer stem cells could also have an important impact in these patients. This article will focus on the molecular stratification of triple-negative breast cancers and the therapeutic implications of these classifications.
Salivary and Plasma Levels of Toll‐Like Receptor 2 and Toll‐Like Receptor 4 in Chronic Periodontitis
Authors: Buduneli Nurcan , Özçaka Özgün , Nalbantsoy Ayşe 
Published: December 2010

Background: This cross‐sectional study was planned to investigate whether patients with chronic periodontitis exhibit different salivary or plasma concentrations of Toll‐like receptor (TLR) 2 and TLR4 compared to subjects who are clinically healthy.Methods: Whole saliva and plasma samples were obtained and full‐mouth clinical periodontal measurements were recorded from 22 otherwise healthy patients with chronic periodontitis and 21 systemically and periodontally healthy control subjects. Salivary and plasma TLR2 and TLR4 levels were determined by enzyme‐linked immunoassays. Data were tested statistically using Mann‐Whitney U test.Results: The healthy group exhibited significantly lower values in all clinical measurements (P <0.001). The salivary TLR2 levels were similar in the two study groups (P >0.05). The patients with chronic periodontitis exhibited significantly higher salivary TLR4 (P <0.01) and plasma TLR2 and TLR4 levels (P <0.05).Conclusion: The present findings support a hypothesis that inflammation increases expression of TLRs which leads to an increased detection of TLRs in saliva and plasma, which could be useful as a diagnostic test for periodontal diseases.