bluuebunny/crossref_metadata_2025 huggingface dataset:
Constructing common cohorts from trials with overlapping eligibility criteria: implications for comparing effect sizes between trials
Authors: Mount David L , Feeney Patricia , Fabricatore Anthony N , Coday Mace , Bahnson Judy , Byington Robert , Phelan Suzanne , Wilmoth Sharon , Knowler William C , Hramiak Irene , Osei Kwame , Sweeney Mary Ellen , Espeland Mark A
Published: September 2009

Background Comparing findings from separate trials is necessary to choose among treatment options, however differences among study cohorts may impede these comparisons.

Purpose As a case study, to examine the overlap of study cohorts in two large randomized controlled clinical trials that assess interventions to reduce risk of major cardiovascular disease events in adults with type 2 diabetes in order to explore the feasibility of cross-trial comparisons

Methods The Action for Health in Diabetes (Look AHEAD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials enrolled 5145 and 10,251 adults with type 2 diabetes, respectively. Look AHEAD assesses the efficacy of an intensive lifestyle intervention designed to produce weight loss; ACCORD tests pharmacological therapies for control of glycemia, hyperlipidemia, and hypertension. Incidence of major cardiovascular disease events is the primary outcome for both trials. A sample was constructed to include participants from each trial who appeared to meet eligibility criteria and be appropriate candidates for the other trial’s interventions. Demographic characteristics, health status, and outcomes of members and nonmembers of this constructed sample were compared.

Results Nearly 80% of Look AHEAD participants were projected to be ineligible for ACCORD; ineligibility was primarily due to better glycemic control or no early history of cardiovascular disease. Approximately 30% of ACCORD participants were projected to be ineligible for Look AHEAD, often for reasons linked to poorer health. The characteristics of participants projected to be jointly eligible for both trials continued to reflect differences between trials according to factors likely linked to retention, adherence, and study outcomes.

Limitations Accurate ascertainment of cross-trial eligibility was hampered by differences between protocols.

Conclusions Despite several similarities, the Look AHEAD and ACCORD cohorts represent distinct populations. Even within the subsets of participants who appear to be eligible and appropriate candidates for trials of both modes of intervention, differences remained. Direct comparisons of results from separate trials of lifestyle and pharmacologic interventions are compromised by marked differences in enrolled cohorts. Clinical Trials 2009; 6: 416—429. http://ctj.sagepub.com
Linear and loglinear structural mean models to evaluate the benefits of an on-demand dosing regimen
Authors: Comté Laetitia , Vansteelandt Stijn , Tousset Eric , Baxter Garth , Vrijens Bernard
Published: September 2009

Background Structural mean models can be used to estimate treatment efficacy when drug exposure varies. We applied stuctural mean model to evaluate the clinical benefits of a proton pump inhibitor prescribed to be taken as needed to alleviate epigastric pain. We also investigated a new diagnostic approach to evaluate model assumptions.

Methods All patients were suffering from nonerosive reflux disease or functional ulcer-like dyspepsia and were prescribed a proton pump inhibitor to be taken as needed for relief of epigastric pain. The primary endpoint was a score variable that expresses the magnitude of gastro-intestinal symptoms at 8 weeks after randomization. We developed linear and loglinear versions of the structural mean models to derive an unbiased estimator of the reduction in symptom score as a function of exposure to the test drug. Semi-parametric models based on splines and corresponding simultaneous confidence bands identified the presence of potential interactions between drug exposure and baseline covariates.

Results The on-demand dosing regimen generated a wide range of drug exposure. Application of SMM showed that the potential treatment-induced reduction in symptom score was much greater than the average treatment reduction observed in this population of patients. Our diagnostic tool was useful for detecting the interaction between drug exposure and baseline covariates. Limitations Analysis could only be performed over the first 2 months after randomization because, afterwards, many patients dropped out from the placebo group. Conclusions The structural mean model approach allows one to estimate treatment efficacy in the presence of variable drug exposure. Similar results were obtained using linear and loglinear structural mean model. Clinical Trials 2009; 6: 403—415. http://ctj.sagepub.com
Fibronectin maintains survival of mouse natural killer (NK) cells via CD11b/Src/β-catenin pathway
Authors: Zhang Ting , Liu Shuxun , Yang Pengyuan , Han Chaofeng , Wang Jianli , Liu Juan , Han Yanmei , Yu Yizhi , Cao Xuetao
Published: September 2009

Tissue microenvironment and stroma-derived extracellular matrix (ECM) molecules play important roles in the survival and differentiation of cells. Mouse natural killer (NK) cells usually die within 24 hours once isolated ex vivo. Exogenous cytokines such as interleukin-12 (IL-12) and IL-15 are required to maintain the survival and activity of mouse NK cells cultured in vitro. Whether and how ECM molecules such as fibronectin can support the survival of NK cells remain unknown. We demonstrate that fibronectin, just like IL-15, can maintain survival of mouse NK cells in vitro. Furthermore, we show that fibronectin binds to the CD11b on NK cells, and then CD11b recruits and activates Src. Src can directly interact with β-catenin and trigger nuclear translocation of β-catenin. The activation of β-catenin promotes extracellular signal-related kinase (ERK) phosphorylation, resulting in the increased expression of antiapoptotic protein B-cell leukemia 2 (Bcl-2), which may contribute to the maintenance of NK-cell survival. Consistently, fibronectin cannot maintain the survival of CD11b− NK cells and β-catenin–deficient NK cells in vitro, and the number of NK cells is dramatically decreased in the β-catenin–deficient mice. Therefore, fibronectin can maintain survival of mouse NK cells by activating ERK and up-regulating Bcl-2 expression via CD11b/Src/β-catenin pathway.
Differential expression of follistatin and FLRG in human breast proliferative disorders
Authors: Bloise Enrrico , Couto Henrique L , Massai Lauretta , Ciarmela Pasquapina , Mencarelli Marzia , Borges Lavinia E , Muscettola Michela , Grasso Giovanni , Amaral Vania F , Cassali Geovanni D , Petraglia Felice , Reis Fernando M
Published: September 2009

Background

Activins are growth factors acting on cell growth and differentiation. Activins are expressed in high grade breast tumors and they display an antiproliferative effect inducing G0/G1 cell cycle arrest in breast cancer cell lines. Follistatin and follistatin- related gene (FLRG) bind and neutralize activins. In order to establish if these activin binding proteins are involved in breast tumor progression, the present study evaluated follistatin and FLRG pattern of mRNA and protein expression in normal human breast tissue and in different breast proliferative diseases.

Methods

Paraffin embedded specimens of normal breast (NB - n = 8); florid hyperplasia without atypia (FH - n = 17); fibroadenoma (FIB - n = 17); ductal carcinoma in situ (DCIS - n = 10) and infiltrating ductal carcinoma (IDC - n = 15) were processed for follistatin and FLRG immunohistochemistry and in situ hybridization. The area and intensity of chromogen epithelial and stromal staining were analyzed semi-quantitatively.

Results

Follistatin and FLRG were expressed both in normal tissue and in all the breast diseases investigated. Follistatin staining was detected in the epithelial cytoplasm and nucleus in normal, benign and malignant breast tissue, with a stronger staining intensity in the peri-alveolar stromal cells of FIB at both mRNA and protein levels. Conversely, FLRG area and intensity of mRNA and protein staining were higher both in the cytoplasm and in the nucleus of IDC epithelial cells when compared to NB, while no significant changes in the stromal intensity were observed in all the proliferative diseases analyzed.

Conclusion

The present findings suggest a role for follistatin in breast benign disease, particularly in FIB, where its expression was increased in stromal cells. The up regulation of FLRG in IDC suggests a role for this protein in the progression of breast malignancy. As activin displays an anti-proliferative effect in human mammary cells, the present findings indicate that an increased FST and FLRG expression in breast proliferative diseases might counteract the anti-proliferative effects of activin in human breast cancer.
NC2213: a novel methionine aminopeptidase 2 inhibitor in human colon cancer HT29 cells
Authors: Selvakumar Ponniah , Lakshmikuttyamma Ashakumary , Das Umashankar , Pati Hari N , Dimmock Jonathan R , Sharma Rajendra K
Published: September 2009

Methionine aminopeptidase 2 (MetAP2) is a bifunctional protein that plays a critical role in the regulation of post-translational processing and protein synthesis. MetAP2 is overexpressed in human colon cancer. In this report we screened various MetAP2 inhibitors and treated HT29 cells with various concentrations of compounds. We evaluated the expression of MetAP2 and pp60c-src expressions in HT29 cells. In addition we also carried out the cell proliferation and cell cycle analysis in the MetAP2 inhibitor-treated HT29 cells. The cell cycle analysis of HT29 treated with 1.0 μM of NC2213 showed an arrest in the G2 phase followed by an induction in the percentage of cells undergoing apoptosis in the sub-G1 phase. Western blot analysis revealed that the MetAP2 expression was dose-dependently decreased when the HT29 cells were treated with the 3,5-bis(benzylidene)-4-piperidone derivative (NC2213). In addition, phosphorylation of Src, a myristoylated oncoprotein was significantly decreased by 1.0 μM of NC2213 as revealed by Western blot analysis. Furthermore, NC2213 also inhibits the expression of pp60c-src in HT29 cells. Interestingly, this compound also inhibits the phosphorylation at Tyr416 of pp60c-src while increasing the phosphorylation at Tyr527 of pp60c-src. NC2213 inhibits the growth of HT29 cells by inducing apoptosis and might be useful for the treatment of human colon cancer.
Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years
Authors: van der Heijde Désirée , Salonen David , Weissman Barbara N , Landewé Robert , Maksymowych Walter P , Kupper Hartmut , Ballal Shaila , Gibson Eric , Wong Robert ,   the Canadian (M03-606) study group and the ATLAS study group
Published: September 2009

Introduction

Ankylosing spondylitis (AS) is a chronic rheumatic disease associated with spinal inflammation that subsequently leads to progression of structural damage and loss of function. The fully human anti-tumor necrosis factor (anti-TNF) antibody adalimumab reduces the signs and symptoms and improves overall quality of life in patients with active AS; these benefits have been maintained through 2 years of treatment. Our objective was to compare the progression of structural damage in the spine in patients with AS treated with adalimumab for up to 2 years versus patients who had not received TNF antagonist therapy.

Methods

Radiographs from patients with AS who received adalimumab 40 mg every other week subcutaneously were pooled from the Adalimumab Trial Evaluating Long-Term Efficacy and Safety for Ankylosing Spondylitis (ATLAS) study and a Canadian AS study (M03-606). Radiographic progression from baseline to 2 years in the spine of adalimumab-treated patients from these two studies (adalimumab cohort, n = 307) was compared with an historic anti-TNF-naïve cohort (Outcome in AS International Study [OASIS], n = 169) using the modified Stoke AS Spine Score (mSASSS) method.

Results

mSASSS results were not significantly different between the adalimumab cohort and the OASIS cohort, based on baseline and 2-year radiographs. Mean changes in mSASSS from baseline to 2 years were 0.9 for the OASIS cohort and 0.8 for the adalimumab cohort (P = 0.771), indicating similar radiographic progression in both groups. When results for patients in the OASIS cohort who met the baseline disease activity criteria for the ATLAS and Canadian studies (OASIS-Eligible cohort) were analyzed, there was no significant difference in mean change in mSASSS from baseline to 2 years between OASIS-Eligible patients and adalimumab-treated patients; the mean changes in mSASSS were 0.9 for the OASIS-Eligible cohort and 0.8 for the adalimumab cohort (P = 0.744).

Conclusions

Two years of treatment with adalimumab did not slow radiographic progression in patients with AS, as assessed by the mSASSS scoring system, when compared with radiographic data from patients naïve to TNF antagonist therapy.

Trial registration

Canadian study (M03-606) ClinicalTrials.gov identifier: NCT00195819; ATLAS study (M03-607) ClinicalTrials.gov identifier: NCT00085644.
VX-166: a novel potent small molecule caspase inhibitor as a potential therapy for sepsis
Authors: Weber Peter , Wang Ping , Maddens Stephane , Wang Paul SH , Wu Rongqian , Miksa Michael , Dong Weifeng , Mortimore Michael , Golec Julian MC , Charlton Peter
Published: September 2009

Introduction

Prevention of lymphocyte apoptosis by caspase inhibition has been proposed as a novel treatment approach in sepsis. However, it has not been clearly demonstrated that caspase inhibitors improve survival in sepsis models when dosed post-insult. Also, there are concerns that caspase inhibitors might suppress the immune response. Here we characterize VX-166, a broad caspase inhibitor, as a novel potential treatment for sepsis.

Methods

VX-166 was studied in a number of enzymatic and cellular assays. The compound was then tested in a murine model of endotoxic shock (lipopolysaccharide (LPS), 20 mg/kg IV) and a 10 d rat model of polymicrobial sepsis by caecal ligation and puncture (CLP).

Results

VX-166 showed potent anti-apoptotic activity in vitro and inhibited the release of interleukin (IL)-1beta and IL-18. In the LPS model, VX-166 administered 0, 4, 8 and 12 h post-LPS significantly improved survival in a dose-dependent fashion (P < 0.0028). In the CLP model, VX-166 continuously administered by mini-osmotic pump significantly improved survival when dosed 3 h after insult, (40% to 92%, P = 0.009). When dosed 8 h post-CLP, VX-166 improved survival from 40% to 66% (P = 0.19). Mode of action studies in the CLP model confirmed that VX-166 significantly inhibited thymic atrophy and lymphocyte apoptosis as determined by flow cytometry (P < 0.01). VX-166 reduced plasma endotoxin levels (P < 0.05), suggesting an improved clearance of bacteria from the bloodstream. Release of IL-1beta in vivo or T-cell activation in vitro were moderately affected.

Conclusions

Our studies enhance the case for the use of caspase inhibitors in sepsis. VX-166 itself has promise as a therapy for the treatment of sepsis in man.
Rotterdam Criteria for Sentinel Node (SN) Tumor Burden and the Accuracy of Ultrasound (US) -Guided Fine-Needle Aspiration Cytology (FNAC): Can US-Guided FNAC Replace SN Staging in Patients With Melanoma?
Authors: Voit Christiane A. , van Akkooi Alexander C.J. , Schäfer-Hesterberg Gregor , Schoengen Alfred , Schmitz Paul I.M. , Sterry Wolfram , Eggermont Alexander M.M.
Published: September 2009

Purpose

Sentinel node (SN) status is the most important prognostic factor for overall survival (OS) for patients with stage I/II melanoma, and the role of the SN procedure as a staging procedure has long been established. However, a less invasive procedure, such as ultrasound (US) -guided fine-needle aspiration cytology (FNAC), would be preferred. The aim of this study was to evaluate the accuracy of US-guided FNAC and compare the results with histology after SN surgery was performed in all patients.

Patients and Methods

Four hundred consecutive patients who underwent lymphoscintigraphy subsequently underwent a US examination before the SN procedure. When the US examination showed a suspicious or malignant pattern, patients underwent an FNAC. Median Breslow thickness was 1.8 mm; mean follow-up was 42 months (range, 4 to 82 months). We considered the US-guided FNAC positive if either US and/or FNAC were positive. If US was suggestive of abnormality, but FNAC was negative, the US-guided FNAC was considered negative.

Results

US-guided FNAC identified 51 (65%) of 79 SN metastases. Specificity was 99% (317 of 321), with a positive predictive value of 93% and negative predictive value of 92%. SN-positive identification rate by US-guided FNAC increased from 40% in stage pT1a/b disease to 79% in stage pT4a/b disease. US-guided FNAC detected SN tumors more than 1.0 mm in 86% of cases, SN tumors of 0.1 to 1.0 mm in 46% of cases, and SN tumors less than 0.1 mm in 23% of cases. Estimated 5-year OS rates were 92% for patients with negative US-guided FNAC results and 51% for patients with positive results.

Conclusion

US-guided FNAC of SNs is highly accurate. Up to 65% of the patients with SN-positive results in our institution could have been spared an SN procedure.
Risk of Fracture After Single Fraction Image-Guided Intensity-Modulated Radiation Therapy to Spinal Metastases
Authors: Rose Peter S. , Laufer Ilya , Boland Patrick J. , Hanover Andrew , Bilsky Mark H. , Yamada Josh , Lis Eric
Published: September 2009

Purpose

Single-fraction image-guided intensity-modulated radiation therapy (IG-IMRT) allows for tumoricidal treatment of traditionally radioresistant cancers while sparing critical adjacent structures. Risk of vertebral fracture after IG-IMRT for spinal metastases has not been defined.

Patients and Methods

We evaluated 62 consecutive patients undergoing single fraction IG-IMRT at 71 sites for solid organ metastases. A neuroradiologist and three spine surgeons evaluated prospectively obtained magnetic resonance/computed tomography (CT) imaging studies for post-treatment fracture development and tumor recurrence.

Results

Fracture progression was noted in 27 vertebrae (39%). Multivariate logistic regression analysis showed that CT appearance, lesion location, and percent vertebral body involvement independently predicted fracture progression. Lesions located between T10 and the sacrum were 4.6 times more likely to fracture than were lesions above T10 (95% CI, 1.1 to 19.7). Lytic lesions were 6.8 times more likely to fracture than were sclerotic and mixed lesions (95% CI, 1.4 to 33.3). As percent vertebral body involvement increased, odds of fracture also increased. Patients with fracture progression had significantly higher narcotic use, change in Karnofsky performance score, and a strong trend toward higher pain scores. Local tumor progression occurred in seven patients and contributed to one fracture. Obesity, posterior element involvement, bisphosphonate use, and local kyphosis did not confer increased risk.

Conclusion

Vertebral fracture is common after single fraction IG-IMRT for metastatic spine lesions. Lytic disease involving more than 40% of the vertebral body and location at or below T10 confer a high risk of fracture, the presence of which yields significantly poorer clinical outcomes. These results may help clinicians identify high-risk patients who would benefit from prophylactic vertebro- or kyphoplasty.
Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients With Advanced Cancers
Authors: Lewis Nancy L. , Lewis Lionel D. , Eder Joseph P. , Reddy Nandi J. , Guo Feng , Pierce Kristen J. , Olszanski Anthony J. , Cohen Roger B.
Published: September 2009

Purpose

This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596.

Patients and Methods

Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups.

Results

Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased γ-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months).

Conclusion

CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.
Safety of Bevacizumab in Patients With Non–Small-Cell Lung Cancer and Brain Metastases
Authors: Socinski Mark A. , Langer Corey J. , Huang Jane E. , Kolb Margaret M. , Compton Peter , Wang Lisa , Akerley Wallace
Published: September 2009

Purpose

Patients with non–small-cell lung cancer (NSCLC) and brain metastases have previously been excluded from trials of bevacizumab because of suspected risk of CNS hemorrhage. This phase II trial, AVF3752g (PASSPORT), specifically addressed bevacizumab safety (incidence of grade ≥ 2 CNS hemorrhage) in patients with NSCLC and previously treated brain metastases.

Patients and Methods

This open-label multicenter trial for first- and second-line treatment of nonsquamous NSCLC enrolled patients with treated brain metastases. First-line patients received bevacizumab (15 mg/kg) every 3 weeks with platinum-based doublet therapy or erlotinib (at physician's decision), and second-line patients received bevacizumab with single-agent chemotherapy or erlotinib, until disease progression or death.

Results

Of the 115 enrolled patients, 66 of 76 first-line patients received carboplatin-based chemotherapy; 22 of 39 second-line patients received pemetrexed, and nine of 39 received erlotinib. As of the June 23, 2008 data cut, among 106 safety-evaluable patients, median on-study duration was 6.3 months (range, 0 to 22 months), with a median of five bevacizumab cycles (range, one to 17), and no reported episodes of grade ≥ 2 CNS hemorrhage (95% CI, 0.0% to 3.3%). Of the bevacizumab-targeted adverse events reported, two were grade 5. Both were pulmonary hemorrhages, one occurring during treatment and the other occurring 6 weeks after the data cut; there was also one grade 4, nonpulmonary/non-CNS hemorrhage. Twenty-six patients (24.5%) discontinued study treatment as a result of an adverse event, and 37 (34.9%) discontinued because of disease progression.

Conclusion

Addition of bevacizumab to various chemotherapy agents or erlotinib in patients with NSCLC and treated brain metastases seems to be safe and is associated with a low incidence of CNS hemorrhage.
Perineural Invasion Is an Independent Predictor of Outcome in Colorectal Cancer
Authors: Liebig Catherine , Ayala Gustavo , Wilks Jonathan , Verstovsek Gordana , Liu Hao , Agarwal Neeti , Berger David H. , Albo Daniel
Published: September 2009

Purpose

Perineural invasion (PNI) is associated with decreased survival in several malignancies, but its significance in colorectal cancer (CRC) remains to be clearly defined. We evaluated PNI as a potential prognostic indicator in CRC, focusing on its significance in node-negative patients.

Patients and Methods

We identified 269 consecutive patients who had CRC resected at our institution. Tumors were rereviewed for PNI by a pathologist blinded to the patients' outcomes. Overall and disease-free survivals were determined using the Kaplan-Meier method, with differences determined by multivariate analysis using the Cox multiple hazards model. Results were compared using the log-rank test.

Results

PNI was identified in less than 0.5% of the initial pathology reports. On rereview, 22% of tumors in our series were found to be PNI positive. The 5-year disease-free survival rate was four-fold greater for patients with PNI-negative tumors versus those with PNI-positive tumors (65% v 16%, respectively; P < .0001). The 5-year overall survival rate was 72% for PNI-negative tumors versus 25% for PNI-positive tumors. On multivariate analysis, PNI was an independent prognostic factor for both cancer-specific overall and disease-free survival. In a subset analysis comparing patients with node-negative disease with patients with stage III disease, the 5-year disease-free survival rate was 56% for stage III patients versus 29% for patients with node-negative, PNI-positive tumors (P = .0002). Similar results were seen for overall survival.

Conclusion

PNI is grossly underreported in CRC and could serve as an independent prognostic factor of outcomes in these patients. PNI should be considered when stratifying CRC patients for adjuvant treatment.
Randomized Comparison of the Stanford V Regimen and ABVD in the Treatment of Advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244
Authors: Hoskin Peter J. , Lowry Lisa , Horwich Alan , Jack Andrew , Mead Ben , Hancock Barry W. , Smith Paul , Qian Wendi , Patrick Philippa , Popova Bilyana , Pettitt Andrew , Cunningham David , Pettengell Ruth , Sweetenham John , Linch David , Johnson Peter W.M.
Published: September 2009

Purpose

This multicenter, prospective, randomized controlled trial compared the efficacy and toxicity of two chemotherapy regimens in advanced Hodgkin's lymphoma (HL): the weekly alternating Stanford V and the standard, twice-weekly regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).

Patients and Methods

Patients had stage IIB, III, or IV disease or had stages I to IIA disease with bulky disease or other adverse features. Radiotherapy was administered in both arms to sites of previous bulk (> 5 cm) and to splenic deposits, although this was omitted in the latter part of the trial for patients achieving complete remission (CR) in the ABVD arm. A total of 520 patients were randomly assigned and were assessed for the primary outcome measure of progression-free survival (PFS). Five hundred patients received protocol treatment, and radiotherapy was administered to 73% in the Stanford V arm and to 53% in the ABVD arm.

Results

The overall response rates after completion of all treatment were 91% for Stanford V and 92% for ABVD. During a median follow-up of 4.3 years, there was no evidence of a difference in projected 5-year PFS and overall survival (OS) rates (76% and 90%, respectively, for ABVD; 74% and 92%, respectively, for Stanford V). More pulmonary toxicity was reported for ABVD, whereas other toxicities were more frequent with Stanford V.

Conclusion

In a large, randomized trial, the efficacies of Stanford V and ABVD were comparable when given in combination with appropriate radiotherapy.
New Antithrombotic Drugs: Potential for Use in Oncology
Authors: Levine Mark N.
Published: September 2009

For more than 50 years, heparin and vitamin K antagonists (VKAs) have been the anticoagulant drugs used to prevent and treat thrombosis. Low molecular weight heparins (LMWHs) are more recent and have been available for approximately 20 years. Patients with cancer are members of a unique patient population because of their high risk for thrombosis and the risk of anticoagulant-related bleeding. With the currently available antithrombotic agents, patients with cancer still have unmet needs in terms of the prevention and treatment of thrombosis. Although long-term LMWH is the treatment of choice for patients with cancer who have acute, symptomatic venous thromboembolism (VTE), some patients still experience recurrent VTE. More effective antithrombotic agents are needed for such patients. Convenient (ie, oral and with no laboratory monitoring), effective, and safe agents are needed to prevent thrombosis in patients taking chemotherapy and antiangiogenic drugs and in patients with central vein catheters. There are a number of new antithrombotic agents that have been studied in recent years and will soon be available for certain diseases. They target either activated factor X (ie, factor Xa) or activated thrombin, and some of them have potential therapeutic value in patients with cancer. In this article, the clinical research model used for the development of a new antithrombotic agent is discussed along with the results of recent trials that evaluate these new agents in high-risk populations.
Inhibitors of the V0 subunit of the vacuolar H+-ATPase prevent segregation of lysosomal- and secretory-pathway proteins
Authors: Sobota Jacqueline A. , Bäck Nils , Eipper Betty A. , Mains Richard E.
Published: September 2009

The vacuolar H+-ATPase (V-ATPase) establishes pH gradients along secretory and endocytic pathways. Progressive acidification is essential for proteolytic processing of prohormones and aggregation of soluble content proteins. The V-ATPase V0 subunit is thought to have a separate role in budding and fusion events. Prolonged treatment of professional secretory cells with selective V-ATPase inhibitors (bafilomycin A1, concanamycin A) was used to investigate its role in secretory-granule biogenesis. As expected, these inhibitors eliminated regulated secretion and blocked prohormone processing. Drug treatment caused the formation of large, mixed organelles, with components of immature granules and lysosomes and some markers of autophagy. Markers of the trans-Golgi network and earlier secretory pathway were unaffected. Ammonium chloride and methylamine treatment blocked acidification to a similar extent as the V-ATPase inhibitors without producing mixed organelles. Newly synthesized granule content proteins appeared in mixed organelles, whereas mature secretory granules were spared. Following concanamycin treatment, selected membrane proteins enter tubulovesicular structures budding into the interior of mixed organelles. shRNA-mediated knockdown of the proteolipid subunit of V0 also caused vesiculation of immature granules. Thus, V-ATPase has a role in protein sorting in immature granules that is distinct from its role in acidification.
Aneuploidy in mitosis of PtK1 cells is generated by random loss and nondisjunction of individual chromosomes
Authors: Torosantucci Liliana , De Santis Puzzonia Marco , Cenciarelli Chiara , Rens Willem , Degrassi Francesca
Published: September 2009

Chromosome lagging at anaphase and migration of both sister chromatids to the same pole, i.e. nondisjunction, are two chromosome-segregation errors producing aneuploid cell progeny. Here, we developed an assay for the simultaneous detection of both chromosome-segregation errors in the marsupial PtK1 cell line by using multiplex fluorescence in situ hybridization with specific painting probes obtained by chromosome flow sorting. No differential susceptibility of the six PtK1 chromosomes to undergo nondisjunction and/or chromosome loss was observed in ana-telophase cells recovering from a nocodazole- or a monastrol-induced mitotic arrest, suggesting that the recurrent presence of specific chromosomes in several cancer types reflects selection effects rather than differential propensities of specific chromosomes to undergo missegregation. Experiments prolonging metaphase duration during drug recovery and inhibiting Aurora-B kinase activity on metaphase-aligned chromosomes provided evidence that some type of merotelic orientations was involved in the origin of both chromosome-segregation errors. Visualization of mero-syntelic kinetochore-microtubule attachments (a merotelic kinetochore in which the thicker microtubule bundle is attached to the same pole to which the sister kinetochore is connected) identified a peculiar malorientation that might participate in the generation of nondisjunction. Our findings imply random missegregation of chromosomes as the initial event in the generation of aneuploidy in mammalian somatic cells.
Neurofilament cross-bridging competes with kinesin-dependent association of neurofilaments with microtubules
Authors: Kushkuley Jacob , Chan Walter K. H. , Lee Sangmook , Eyer Joel , Leterrier Jean-Francois , Letournel Franck , Shea Thomas B.
Published: September 2009

The phosphorylation of neurofilaments (NFs) has long been considered to regulate their axonal transport rate and in doing so to provide stability to mature axons. Axons contain a centrally situated `bundle' of closely opposed phospho-NFs that display a high degree of NF-NF associations and phospho-epitopes, surrounded by less phosphorylated `individual' NFs that are often associated with kinesin and microtubules (MTs). Bundled NFs transport substantially slower than the surrounding individual NFs and might represent a resident population that stabilizes axons and undergoes replacement by individual NFs. To examine this possibility, fractions enriched in bundled NFs and individual NFs were generated from mice and NB2a/d1 cells by sedimentation of cytoskeletons over a sucrose cushion. More kinesin was recovered within individual versus bundled NF fractions. Individual but not bundled NFs aligned with purified MTs under cell-free conditions. The percentage of NFs that aligned with MTs was increased by the addition of kinesin, and inhibited by anti-kinesin antibodies. Bundles dissociated following incubation with EGTA or alkaline phosphatase, generating individual NFs that retained or were depleted of phospho-epitopes, respectively. These dissociated NFs aligned with MTs at a level identical to those originally isolated as individual NFs regardless of phosphorylation state. EGTA-mediated dissociation of bundles was prevented and reversed by excess Ca2+, whereas individual NFs did not associate in the presence of excess Ca2+. These findings confirm that bundling competes with NF-MT association, and provide a mechanism by which C-terminal NF phosphorylation might indirectly contribute to the observed slowing in axonal transport of phospho-NFs
Specimen size and shape effect in split Hopkinson pressure bar testing
Authors: Pankow M , Attard C , Waas A M
Published: September 2009

The results from an experimental and computational study on the effects of specimen size and shape on split Hopkinson pressure bar (SHPB) testing are presented. The effects of the L/ D ratio (length L divided by diameter D) along with specimen shape (cylindrical versus square prismatic) were investigated. Even though specimens having a circular cylindrical cross-section are traditionally used in SHPB testing, a square cross-section specimen has advantages associated with in situ imaging of the specimen side surfaces during stress wave propagation. The results presented here show a strong correlation in specimen response between the two types of specimens. Different ranges of L/ D ratios are recommended for obtaining stiffness and strength data at near constant strain rates.
Contact stresses within a split ring inserted into a circular housing
Authors: Strozzi A , Baldini A , Giacopini M , Rosi R , Bertocchi E
Published: September 2009

The contact problem between a split ring and a circular housing is mechanically examined. This contact is revisited in terms of receding contact, the zones along which the ring beds over the housing are investigated, and normalizing design parameters are evidenced. The split ring is modelled in terms of a straight, purely flexural beam as well as of a curved, shear-elastic beam; for both models, analytical solutions are obtained. Various easy accessible design diagrams, useful for estimating the maximum elastic stresses within the split ring and the axial insertion force, have been prepared with the aid of these two beam models and using finite elements. The mechanical response of the split ring when its angular width is appreciably lower than π is clarified.
Aeronautics and astronautics: Recent progress and future trends
Authors: Martinez-Val R , Perez E
Published: September 2009

Aeronautics and astronautics are two closely related disciplines, sometimes found under the joint term aerospace, that have progressed at a formidable pace during the 20th century. Their impact on society is overwhelming. For example, the aeroplane, the core of aeronautics, has been identified as one of the three major inventions of that century. On its turn, satellites have paved the way for modern globalization. Major drivers leading this progress have changed from the classical motto ‘higher, further, faster’ to the current ‘more affordable, cleaner, quieter’, but safety has always been kept the undisputed number one. The underlying key factors for progress have been and still are excellence and co-operation. Both aeronautics and astronautics are multidisciplinary in nature and, accordingly, this review summarizes relevant advances and trends in pertinent fields: aerodynamics, structures, propulsion, and so on. All these fields are still very healthy and the 21st century will witness again a new era of astonishing aerospace developments.
A novel shock isolator for heavy structure installation
Authors: Zhang L-J , Zhu C-M , Shi X , Zhang P
Published: September 2009

During the heavy structure installation process, any external disturbance may result in a huge impact on the substructure due to the extremely large mass involved, which may damage the whole structure permanently. Therefore, a reliable shock isolator for the installation interface is very important in such applications. In this study, a novel shock isolator based on a hydraulic damper is presented. It has been designed with an optimized throttling orifice to dissipate the energy efficiently and with air bags to store energy. Considering the maximal relative travel range of the isolator within a specified physical limit, the design is formulated as an optimization problem to minimize the peak acceleration during the impact and finalized as a constant force isolator. A mathematical model of the isolator is established and a prediction of its performance is obtained through some simulations. Experiments are performed to evaluate the theoretical model and it is found that the experimental data agree with the theoretical prediction very well, and thus validates the design. The influence of initial oil pressure and the material of elastic impact head are also investigated. The results show that higher initial oil pressure increases the peak acceleration, while the material of the elastic impact head has no significant effect on that.
Singularities within the workspace of spatial parallel mechanisms with symmetric structures
Authors: Zhao J-S , Chu F , Feng Z-J
Published: September 2009

This article addresses the symmetry similarities between the singularity distributions within the reachable workspaces of spatial parallel mechanisms and the mechanism structures. The symmetry similarities between the workspace and the mechanism architecture are also fit for interpreting the relationship between the singularities within the workspace and the architecture. Further, this research reveals that the symmetry group of the workspace must be a subgroup of the symmetry group of the distribution of singularities within the reachable workspace, which is rigorously proved in theory. Mechanism examples also demonstrate these similarities of symmetries between the singularities, the reachable workspace, and the mechanism structure. The novelty of this work in engineering applications is that the searching range for the singularities in the reachable workspace can be reduced greatly.
On the forced vibration of carbon nanotubes via a non-local Euler—Bernoulli beam model
Authors: Karaoglu P , Aydogdu M
Published: September 2009

This article studies the forced vibration of the carbon nanotubes (CNTs) using the local and the non-local Euler—Bernoulli beam theory. Amplitude ratios for the local and the non-local Euler—Bernoulli beam models are given for single- and double-walled CNTs. It is found that the non-local models give higher amplitudes when compared with the local Euler—Bernoulli beam models. The non-local Euler—Bernoulli beam model predicts lower resonance frequencies.
Flow measurements across an automotive catalyst monolith situated downstream of a planar wide-angled diffuser
Authors: Quadri S S , Benjamin S F , Roberts C A
Published: September 2009

Flow measurements are presented across an automotive catalyst monolith situated downstream of a planar wide-angled diffuser. Particle image velocimetry measurements were obtained in the diffuser and the flow distribution within the monolith was obtained from hot wire anemometry at the monolith exit. Flow separation at the diffuser inlet resulted in the formation of a jet that traversed the diffuser before spreading just prior to entering the monolith. The jet featured a potential core and saddle-type velocity profiles. A free shear layer separated the jet core from two large recirculation regions that developed in the diffuser narrowing the potential core. The flow field in the main body of the diffuser was observed to be independent of Re in contrast to that within the monolith. Increasing monolith length gave greater flow uniformity in the monolith as a consequence of jet spreading. Comparing the axial velocity flow profiles ∼ 3 mm upstream of the monolith to that downstream showed that significant flow redistribution occurred as the flow entered the monolith, resulting in more flow entering peripheral channels. It is inferred that pressure loss arising from oblique entry into monolith channels significantly affects the flow distribution within the monolith.
Geometry, specification, and drilling performance of a plane rake faced drill point design
Authors: Zhang Q , Wang J
Published: September 2009

A study of a modified drill point design with plane rake faces is presented. The critical geometries that uniquely define the drill point design are analysed based on the international standard. The study shows that the modified drill design yields positive normal rake angle on the entire lips and point relieving in the chisel edge region. An experimental study of drilling a high tensile steel using 7–13 mm high-speed steel (HSS) drills with titanium nitride (TiN) coatings has been carried out to assess the new drill point design. It shows that the modified plane rake faced (PRF) drills can reduce the thrust force by as much as 46.9 per cent with an average of 23.8 per cent, as compared to the conventional twist drills under the corresponding cutting conditions, while the reduction in torque is also significant with the maximum of 24.9 per cent. These drilling performance improvements are comparable to those from using the multi-facet drills that were claimed as one of the most heartening drill developments in several decades for drilling force reduction, while the PRF drills can be easily sharpened using the conventional twist drill grinders. The drill-life tests amply demonstrate the superiority of the PRF drills over the conventional twist drills.
Parametric study of tip cooling injection in an axial turbine cascade: Influences of injection circumferential angle
Authors: Niu M , Zang S
Published: September 2009

This article presents a parametric investigation of an innovative tip-clearance control method. Cooling air is injected into the tip clearance to obstruct tip clearance flow, from the blade tip surface through a row of 11 equidistant holes. In order to demonstrate the influences of injection circumferential angle, four different test cases are performed and compared with the baseline case without air injection. The results indicate that injection circumferential angle plays an important role in the redistribution of secondary flow within the cascade passage. Injection at a smaller circumferential angle performs better in reducing tip clearance mass flow and its associated losses. However, it also intensifies the tip passage vortex much more, because of the reduced restraint deriving from the weaker tip clearance vortex. It can also be found that flow under-turning caused by the tip clearance vortex can be reduced greatly with a smaller circumferential angle. But the heat transfer condition is worse than that when cooling air is injected perpendicularly to the blade tip surface. Besides that, a modified tip clearance loss model is observed to be able to perform well in predicting the losses induced by tip clearance flow at all the conditions considered in this article.
Simplified approximations for the accumulation value and time constant for an evaporator system in drum-type boilers
Authors: Dharmalingam S , Sivakumar L , Anil Kumar K K
Published: September 2009

The storage capacity of the evaporator system of a boiler helps in minimizing the steam pressure fluctuations during load changes even before the combustion control comes into play. The quantitative representation of the storage capacity is usually expressed as an index known as the accumulation value and it quantifies the steam that can be additionally drawn for unit pressure drop. Further, the time constant of the evaporator system can be calculated using the accumulation value. The time constants calculated for varying load clearly indicates non-linear behaviour of the evaporator system. The time constant forms the basis for designing suitable controllers. The simplified approximate relationships for the calculation of the accumulation value of the evaporator of a boiler as a function of drum operating pressure, and of the time constant as a function of varying load, are given for different ratings of the boiler.
An application of Bayesian networks for the optimization of a bridge layout
Authors: Garrè L , Perassi A , Raffetti A , Rizzuto E
Published: September 2009

Advantages in the adoption of integrated systems on a ship's bridge are quantified with respect to a more traditional bridge layout. The study is performed by modelling the causation factor for a ship-to-ship collision scenario. The assessment is provided in terms of the probability distribution of the time required to the officer on the watch (OOW) to complete a foreseen procedure aimed at avoiding a collision with another ship. The time needed to identify and agree the evasive manoeuvre with the second ship is evaluated for the two layouts, considering also a probabilistic occurrence of disturbances distracting and delaying the OOW during the procedure. Bayesian networks are employed to model the scenario. A general increment of the reactivity of the OOW in the integrated bridge is seen, represented by a shorter time to complete the procedure and by a reduced probability of being interrupted. The overall effect is an increase in the time available to put into practice the manoeuvre itself and, eventually, to avoid the collision.
Recognition of Mismatched Base Pairs in DNA
Authors: Nakatani Kazuhiko
Published: September 2009

Mismatch binding ligand (MBL) selectively binds to mismatched base pairs with discrimination of the nucleotide bases composing the mismatch. This review focuses on the inside story regarding the molecular design of MBL and its function, and potential application in genomic science.