bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized, Double-Blind Trial of Carboplatin and Paclitaxel With Either Daily Oral Cediranib or Placebo in Advanced Non–Small-Cell Lung Cancer: NCIC Clinical Trials Group BR24 Study
Authors: Goss Glenwood D. , Arnold Andrew , Shepherd Frances A. , Dediu Mircea , Ciuleanu Tudor-Eliade , Fenton David , Zukin Mauro , Walde David , Laberge Francis , Vincent Mark D. , Ellis Peter M. , Laurie Scott A. , Ding Keyue , Frymire Eliot , Gauthier Isabelle , Leighl Natasha B. , Ho Cheryl , Noble Jonathan , Lee Christopher W. , Seymour Lesley 
Published: November 2009

Purpose This phase II/III double-blind study assessed efficacy and safety of cediranib with standard chemotherapy as initial therapy for advanced non–small-cell lung cancer (NSCLC). Patients and Methods Paclitaxel (200 mg/m2) and carboplatin (area under the serum concentration-time curve 6) were given every 3 weeks, with daily oral cediranib or placebo at 30 mg (first 45 patients received 45 mg). Progression-free survival (PFS) was the primary outcome of the phase II interim analysis; phase III would proceed if the hazard ratio (HR) for PFS ≤ 0.77 and toxicity were acceptable. Results A total of 296 patients were enrolled, 251 to the 30-mg cohort. The phase II interim analysis demonstrated a significantly higher response rate (RR) for cediranib than for placebo, HR of 0.77 for PFS, no excess hemoptysis, and a similar number of deaths in each arm. The study was halted to review imbalances in assigned causes of death. In the primary phase II analysis (30-mg cohort), the adjusted HR for PFS was 0.77 (95% CI, 0.56 to 1.08) with a higher RR for cediranib than for placebo (38% v 16%; P < .0001). Cediranib patients had more hypertension, hypothyroidism, hand-foot syndrome, and GI toxicity. Hypoalbuminemia, age ≥ 65 years, and female sex predicted increased toxicity. Survival update (N = 296) 10 months after study unblinding favored cediranib over placebo (median of 10.5 months v 10.1 months; HR, 0.78; 95% CI, 0.57 to 1.06; P = .11). Causes of death in the cediranib 30-mg cohort were NSCLC (81%), protocol toxicity ± NSCLC (13%), and other (6%); for the placebo group, they were 98%, 0%, and 2%, respectively. Conclusion The addition of cediranib to carboplatin/paclitaxel results in improved response and PFS, but does not appear tolerable at a 30-mg dose. Consequently, the National Cancer Institute of Canada Clinical Trials Group and the Australasian Lung Cancer Trials Group initiated a randomized, double-blind, placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in advanced NSCLC.
Induction Chemotherapy and Cetuximab for Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Results From a Phase II Prospective Trial
Authors: Kies Merrill S. , Holsinger Floyd Christopher , Lee J. Jack , William William N. , Glisson Bonnie S. , Lin Heather Y. , Lewin Jan S. , Ginsberg Lawrence E. , Gillaspy Katharine A. , Massarelli Erminia , Byers Lauren , Lippman Scott M. , Hong Waun K. , El-Naggar Adel K. , Garden Adam S. , Papadimitrakopoulou Vassiliki 
Published: November 2009

Purpose To determine the potential efficacy of combining cetuximab with chemotherapy in patients with advanced nodal disease, we conducted a phase II trial with induction chemotherapy (ICT) consisting of six weekly cycles of paclitaxel 135 mg/m2 and carboplatin (area under the curve = 2) with cetuximab 400 mg/m2 in week 1 and then 250 mg/m2 (PCC). Patients and Methods Forty-seven previously untreated patients (41 with oropharynx primaries; 33 men, 14 women; median age, 53 years; performance status of 0 or 1) with squamous cell carcinoma of the head and neck (SCCHN; T1-4, N2b/c/3) were treated and evaluated for clinical and radiographic response. After ICT, patients underwent risk-based local therapy, which consisted of either radiation, concomitant chemoradiotherapy, or surgery, based on tumor stage and site at diagnosis. Results After induction PCC, nine patients (19%) achieved a complete response, and 36 patients (77%) achieved a partial response. The most common grade 3 or 4 toxicity was skin rash (45%), followed by neutropenia (21%) without fever. At a median follow-up time of 33 months, locoregional or systemic disease progression was observed in six patients. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 87% (95% CI, 78% to 97%) and 91% (95% CI, 84% to 99%), respectively. Human papillomavirus (HPV) 16, found in 12 (46%) of 26 biopsies, was associated with improved PFS (P = .012) and OS (P = .046). Conclusion ICT with weekly PCC followed by risk-based local therapy seems to be feasible, effective, and well tolerated. PFS is promising, and this sequential treatment strategy should be further investigated. Patients with HPV-positive tumors have an excellent prognosis.
Tumor-Associated Lymphocytes As an Independent Predictor of Response to Neoadjuvant Chemotherapy in Breast Cancer
Authors: Denkert Carsten , Loibl Sibylle , Noske Aurelia , Roller Marc , Müller Berit Maria , Komor Martina , Budczies Jan , Darb-Esfahani Silvia , Kronenwett Ralf , Hanusch Claus , von Törne Christian , Weichert Wilko , Engels Knut , Solbach Christine , Schrader Iris , Dietel Manfred , von Minckwitz Gunter 
Published: November 2009

Purpose Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. Methods We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell–related markers CD3D and CXCL9 with pCR. Conclusion The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.
Peritoneal Colorectal Carcinomatosis Treated With Surgery and Perioperative Intraperitoneal Chemotherapy: Retrospective Analysis of 523 Patients From a Multicentric French Study
Authors: Elias Dominique , Gilly François , Boutitie Florent , Quenet François , Bereder Jean-Marc , Mansvelt Baudouin , Lorimier Gérard , Dubè Pierre , Glehen Olivier 
Published: November 2009

Purpose Peritoneal carcinomatosis (PC) from colorectal cancer traditionally is considered a terminal condition. Approaches that combine cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) have been developed recently. The purpose of this study was to assess early and long-term survival in patients treated with that strategy. Patients and Methods A retrospective-cohort, multicentric study from French-speaking countries was performed. All consecutive patients with PC from colorectal cancer who were treated with CRS and PIC (with or without hyperthermia) were included. Patients with PC of appendiceal origin were excluded. Results The study included 523 patients from 23 centers in four French-speaking countries who underwent operation between 1990 and 2007. The median follow-up was 45 months. Mortality and grades 3 to 4 morbidity at 30 days were 3% and 31%, respectively. Overall median survival was 30.1 months. Five-year overall survival was 27%, and five-year disease-free survival was 10%. Complete CRS was performed in 84% of the patients, and median survival was 33 months. Positive independent prognostic factors identified in the multivariate analysis were complete CRS, PC that was limited in extent, no invaded lymph nodes, and the use of adjuvant chemotherapy. Neither the grade of disease nor the presence of liver metastases had a significant prognostic impact. Conclusion This combined treatment approach against PC achieved low postoperative morbidity and mortality, and it provided good long-term survival in patients with peritoneal scores lower than 20. These results should improve in the future, because the different teams involved will gain experience. This approach, when feasible, is now considered the gold standard in the French guidelines.
Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma: Multi-Institutional Experience
Authors: Yan Tristan D. , Deraco Marcello , Baratti Dario , Kusamura Shigeki , Elias Dominique , Glehen Olivier , Gilly François N. , Levine Edward A. , Shen Perry , Mohamed Faheez , Moran Brendan J. , Morris David L. , Chua Terence C. , Piso Pompiliu , Sugarbaker Paul H. 
Published: November 2009

PurposeThis multi-institutional registry study evaluated cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for diffuse malignant peritoneal mesothelioma (DMPM).Patients and MethodsA multi-institutional data registry that included 405 patients with DMPM treated by a uniform approach that used CRS and HIPEC was established. The primary end point was overall survival. The secondary end point was evaluation of prognostic variables for overall survival.ResultsFollow-up was complete in 401 patients (99%). The median follow-up period for the patients who were alive was 33 months (range, 1 to 235 months). The mean age was 50 years (standard deviation [SD], 14 years). Three hundred eighteen patients (79%) had epithelial tumors. Twenty-five patients (6%) had positive lymph nodes. The mean peritoneal cancer index was 20. One hundred eighty-seven patients (46%) had complete or near-complete cytoreduction. Three hundred seventy-two patients (92%) received HIPEC. One hundred twenty-seven patients (31%) had grades 3 to 4 complications. Nine patients (2%) died perioperatively. The mean length of hospital stay was 22 days (SD, 15 days). The overall median survival was 53 months (1 to 235 months), and 3- and 5-year survival rates were 60% and 47%, respectively. Four prognostic factors were independently associated with improved survival in the multivariate analysis: epithelial subtype (P < .001), absence of lymph node metastasis (P < .001), completeness of cytoreduction scores of CC-0 or CC-1 (P < .001), and HIPEC (P = .002).ConclusionThe data suggest that CRS combined with HIPEC achieved prolonged survival in selected patients with DMPM.
Clinical Results of Long-Term Follow-Up of a Large, Active Surveillance Cohort With Localized Prostate Cancer
Authors: Klotz Laurence , Zhang Liying , Lam Adam , Nam Robert , Mamedov Alexandre , Loblaw Andrew 
Published: November 2009

PurposeWe assessed the outcome of a watchful-waiting protocol with selective delayed intervention by using clinical prostate-specific antigen (PSA), or histologic progression as treatment indications for clinically localized prostate cancer.Patients and MethodsThis was a prospective, single-arm, cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a PSA doubling time of less than 3 years, Gleason score progression (to 4 + 3 or greater), or unequivocal clinical progression. Survival analysis and Cox proportional hazard model were applied to the data.ResultsA total of 450 patients have been observed with active surveillance. Median follow-up was 6.8 years (range, 1 to 13 years). Overall survival was 78.6%. The 10-year prostate cancer actuarial survival was 97.2%. Overall, 30% of patients have been reclassified as higher risk and have been offered definitive therapy. Of 117 patients treated radically, the PSA failure rate was 50%, which was 13% of the total cohort. PSA doubling time of 3 years or less was associated with an 8.5-times higher risk of biochemical failure after definitive treatment compared with a doubling time of more than 3 years (P < .0001). The hazard ratio for nonprostate cancer to prostate cancer mortality was 18.6 at 10 years.ConclusionWe observed a low rate of prostate cancer mortality. Among the patients who were reclassified as higher risk and who were treated, PSA failure was relatively common. Other-cause mortality accounted for almost all of the deaths. Additional studies are warranted to improve the identification of patients who harbor more aggressive disease despite favorable clinical parameters at diagnosis.
Online Wiki Collaboration By Teachers of Students With Autism Spectrum Disorders
Authors: Kilham Chris 
Published: November 2009

AbstractAshared understanding of autism spectrum disorders (ASD) and a coordinated approach to teaching diagnosed students is essential because of the complex learning needs of this cohort. This research examines the ways in which special educators used wiki technology to create a working document and to share and develop their perspectives about fundamental autism constructs. The teachers appreciated the flexibility and convenience of wikis in a postgraduate course and collaboratively authored a working document. This suggested the wiki facilitated the development of a community of practice. Analysis of wiki comments further showed that, despite considerable experience in face-to-face communication, the teachers did not construct transparent protocols to guide the online decision-making process so did not fully exploit the capacity of this technology. Teachers had confidence in the privacy of a password-protected site but did not consider that the collaborative e-learning tool would be gainfully used by students on the spectrum because of their social and communication deficits. Nevertheless, teachers envisaged potential benefits if wikis were to be adopted by school staff.
Engagement of Children With Autism in Learning
Authors: Keen Deb 
Published: November 2009

AbstractEarly engagement with the world around us provides opportunities for learning and practising new skills and acquiring knowledge critical to cognitive and social development. Children with autism typically display low levels of engagement, particularly in their social world, which limits the opportunities for learning that occur for their typically developing peers. An investigation of the literature on engagement suggests a lack of consensus about definition and measurement that may undermine the usefulness of this construct to educators. This article argues that the engagement construct can assist educators in the development and implementation of effective teaching interventions for children with autism.
Structural studies of the phosphatidylinositol 3-kinase (PI3K) SH3 domain in complex with a peptide ligand: role of the anchor residue in ligand binding
Authors: Batra-Safferling Renu , Granzin Joachim , Mödder Susanne , Hoffmann Silke , Willbold Dieter 
Published: November 2009

Abstract
Src homology 3 (SH3) domains are mediators of protein-protein interactions. They comprise approximately 60 amino acid residues and are found in many intracellular signaling proteins. Here, we present the crystal structure of the SH3 domain from phosphatidylinositol 3-kinase (PI3K) in complex with the 12-residue proline-rich peptide PD1R (HSKRPLPPLPSL). The crystal structure of the PI3K SH3-PD1R complex at a resolution of 1.7 Å reveals type I ligand orientation of the bound peptide with an extended conformation where the central portion forms a left-handed type II polyproline (PPII) helix. The overall structure of the SH3 domain shows minimal changes on ligand binding. In addition, we also attempted crystallization with another peptide ligand (PD1) where the residue at anchor position P-3 is a tyrosine. The crystals obtained did not contain the PD1 ligand; instead, the ligand binding site is partially occupied by residues Arg18 and Trp55 from the symmetry-related PI3K SH3 molecule. Considering these crystal structures of PI3K SH3 together with published reports, we provide a comparative analysis of protein-ligand interactions that has helped us identify the individual residues which play an important role in defining target specificity.
Biochemical characterization of human Ecdysoneless reveals a role in transcriptional regulation
Authors: Kim Jun Hyun , Gurumurthy Channabasavaiah Basavaraju , Band Hamid , Band Vimla 
Published: November 2009

AbstractEcdysoneless (Ecd) is an evolutionarily conserved protein and its function is essential for embryonic development inDrosophilaand cell growth in yeast. However, its function has remained unknown until recently. Studies in yeast suggested a potential role of Ecd in transcription; however, Ecd lacks a DNA-binding domain. Using a GAL4-luciferase reporter assay and a GAL4 DNA-binding domain fusion with Ecd or its mutants, we present evidence that human Ecd has a transactivation activity in its C-terminal region. Importantly, further analyses using point mutants showed that a single amino acid change at either Asp-484 or Leu-489 essentially completely abolishes the transactivation activity of Ecd. We further demonstrate that Ecd interacts with p300, a histone acetyltransferase, and coexpression of Ecd with p300 enhances the Ecd-mediated transactivation activity. Ecd localizes to both nucleus and cytoplasm and shuttles between the nucleus and cytoplasm; however, it exhibits strong nuclear export. Based on previous yeast studies and evidence provided here, we suggest that Ecd functions as a transcriptional regulator. Our results indicate an important function of human Ecd and provide a basis to explore the transcriptional partners of Ecd.
The oxygen-independent coproporphyrinogen III oxidase HemN utilizes harderoporphyrinogen as a reaction intermediate during conversion of coproporphyrinogen III to protoporphyrinogen IX
Authors: Rand Katrin , Noll Claudia , Schiebel Hans Martin , Kemken Dorit , Dülcks Thomas , Kalesse Markus , Heinz Dirk W. , Layer Gunhild 
Published: November 2009

AbstractDuring heme biosynthesis the oxygen-independent coproporphyrinogen III oxidase HemN catalyzes the oxidative decarboxylation of the two propionate side chains on rings A and B of coproporphyrinogen III to the corresponding vinyl groups to yield protoporphyrinogen IX. Here, the sequence of the two decarboxylation steps during HemN catalysis was investigated. A reaction intermediate of HemN activity was isolated by HPLC analysis and identified as monovinyltripropionic acid porphyrin by mass spectrometry. This monovinylic reaction intermediate exhibited identical chromatographic behavior during HPLC analysis as harderoporphyrin (3-vinyl-8,13,17-tripropionic acid-2,7,12,18-tetramethylporphyrin). Furthermore, HemN was able to utilize chemically synthesized harderoporphyrinogen as substrate and converted it to protoporphyrinogen IX. These results suggest that during HemN catalysis the propionate side chain of ring A of coproporphyrinogen III is decarboxylated prior to that of ring B.
Bovine β-lactoglobulin acts as an acid-resistant drug carrier by exploiting its diverse binding regions
Authors: Barbiroli Alberto , Beringhelli Tiziana , Bonomi Francesco , Donghi Daniela , Ferranti Pasquale , Galliano Monica , Iametti Stefania , Maggioni Daniela , Rasmussen Patrizia , Scanu Sandra , Vilardo Maria Caterina 
Published: November 2009

Abstract
Binding of fluorine-containing drugs to bovine β-lactoglobulin, the most abundant whey protein in bovine milk, was investigated by means of 19F NMR and mass spectrometry. The stoichiometry of the binding and its stability in acidic medium, where β-lactoglobulin is folded and stable, were also studied, along with competition from molecules that can be regarded as analogs of physiological ligands to bovine β-lactoglobulin. Conditional binding data were combined with protein structural information derived from circular dichroism and limited proteolysis studies. Spectroscopic techniques were also used to assess whether the bound drugs stabilize the protein structure against denaturation by chaotropes or temperature at various pH values. The results obtained provide evidence for the presence of multiple binding regions on the protein, with a specific and different affinity for structurally different classes of hydrophobic drugs and, more generally, that bovine β-lactoglobulin can bind and protect against low pH values various classes of drugs of pharmaceutical relevance.
A novel matrix metalloprotease-like enzyme (karilysin) of the periodontal pathogen Tannerella forsythia ATCC 43037
Authors: Karim Abdulkarim Y. , Kulczycka Magdalena , Kantyka Tomasz , Dubin Grzegorz , Jabaiah Abeer , Daugherty Patrick S. , Thogersen Ida B. , Enghild Jan J. , Nguyen Ky-Anh , Potempa Jan 
Published: November 2009

AbstractProteases ofTannerella forsythia, a pathogen associated with periodontal disease, are implicated as virulence factors. Here, we characterized a matrix metalloprotease (MMP)-like enzyme ofT. forsythiareferred to as karilysin. Full-length (without a signal peptide) recombinant karilysin (49.9 kDa) processed itself into the mature 18-kDa enzyme through sequential autoproteolytic cleavage at both N- and C-terminal profragments. The first cleavage at the Asn14-Tyr15 peptide bond generated the fully active enzyme (47.9 kDa) and subsequent truncations at the C-terminus did not affect proteolytic activity. Mutation of Tyr15 to Ala generated a prokarilysin variant that processed itself into the final 18-kDa form with greatly reduced kinetics. Inactive prokarilysin with the mutated catalytic Glu residue (E136A) was processed by active karilysin at the same sites as the active enzymes. Karilysin proteolytic activity and autoprocessing were inhibited by 1,10-phenanthroline and EDTA. Calcium ions were found to be important for both the activity and thermal stability of karilysin. Using CLiPS technology, the specificity of karilysin was found to be similar to that of MMPs with preference for Leu/Tyr/Met at P1′ and Pro/Ala at P3. This specificity and the ability to degrade elastin, fibrinogen and fibronectin may contribute to the pathogenicity of periodontitis.
Grammar and Interaction: Reported Discourse and Subjunctive in German
Authors: Golato Andrea 
Published: November 2009

Abstract
The present study investigates the relationship between grammar and interaction, specifically, the forms and interactional functions of direct and indirect discourse in spoken German. The study demonstrates that quotatives and the grammatical form of quotes are context-sensitive; that is, depending on the current actions (either providing background information, telling stories, telling troubles, or giving explanations), interactants select different quotation formats. The use of the subjunctive or Konjunktiv is only one of several quotation formats used by speakers in interaction for very specific social purposes; these social purposes are oriented to as such by coparticipants.