bluuebunny/crossref_metadata_2025 huggingface dataset:
Which data residual norm for robust elastic frequency-domain full waveform inversion?
Authors: Brossier Romain , Operto Stéphane , Virieux Jean
Published: April 2010

Elastic full-waveform inversion is an ill-posed data-fitting procedure that is sensitive to noise, inaccuracies of the starting model, definition of multiparameter classes, and inaccurate modeling of wavefield amplitudes. We have investigated the performance of different minimization functionals as the least-squares norm [Formula: see text], the least-absolute-values norm [Formula: see text], and combinations of both (the Huber and so-called hybrid criteria) with reference to two noisy offshore (Valhall model) and onshore (overthrust model) synthetic data sets. The four minimization functionals were implemented in 2D elastic frequency-domain full-waveform inversion (FWI), where efficient multiscale strategies were designed by successive inversions of a few increasing frequencies. For the offshore and onshore case studies, the [Formula: see text]-norm provided the most reliable models for P- and S-wave velocities ([Formula: see text] and[Formula: see text]), even when strongly decimated data sets that correspond to few frequencies were used in the inversion and when outliers polluted the data. The [Formula: see text]-norm can provide reliable results in the presence of uniform white noise for [Formula: see text] and [Formula: see text] if the data redundancy is increased by refining the frequency sampling interval in the inversion at the expense of computational efficiency. The [Formula: see text]-norm and the Huber and hybrid criteria, unlike the [Formula: see text]-norm, allow for successful imaging of the [Formula: see text] model from noisy data in a soft-seabed environment, where the P-to-S-waves have a small footprint in the data. However, the Huber and hybrid criteria are sensitive to a threshold criterion that controls the transition between the criteria and that requires tedious trial-and-error investigations for reliable estimation. The [Formula: see text]-norm provides a robust alternative to the [Formula: see text]-norm for inverting decimated data sets in the framework of efficient frequency-domain FWI.
Prestack phase-shift migration of separate offsets in laterally inhomogeneous media
Authors: Alkhalifah Tariq
Published: April 2010

Using the stationary-phase method, prestack phase-shift migration is implemented one offset at a time. This separate-offset implementation allows for a Fourier (reasonably fast) wave-equation-type migration on data with irregular offset sampling. However, the separate-offset phase-shift migration, like its zero-offset counterpart, handles only vertically inhomogeneous media. Using the combination of the split-step and phase-shift-plus-interpolation (PSPI) approaches, the separate-offset phase-shift migration is extended to handle laterally inhomogeneous media. The cost of the separate-offset implementation is practically equivalent to that of the conventional zero-offset version. However, due to the lack of exact source and receiver ray-trajectory information in the separate-offset implementation, the combined split-step and PSPI handles only smooth lateral inhomogeneity. Specifically, it produces images equivalent to those resulting from smoothing the velocity model laterally over a window equal to the half offset. Thus, for zero-offset or laterally homogeneous media, the separate-offset migration is equivalent to any wave-equation-based migration. Errors might occur for finite-offset data in laterally inhomogeneous media. Such errors depend primarily on the strength of lateral inhomogeneity. Using this separate-offset phase-shift migration, accurate images of synthetic data of a model with large reflector dips and good images from real data from offshore Trinidad are obtained.
A laboratory study of the effect of Fe(II)-bearing minerals on nuclear magnetic resonance (NMR) relaxation measurements
Authors: Keating Kristina , Knight Rosemary
Published: April 2010

A laboratory study was conducted to measure the effect of the mineralogic form and concentration of iron(II) [Fe(II)] minerals on nuclear magnetic resonance (NMR) relaxation rates of water-saturated sand mixtures. We measured mixtures of quartz sand and three common Fe(II)-bearing minerals in granular form: siderite [Formula: see text], pyrite [Formula: see text], and pyrrhotite ([Formula: see text]; [Formula: see text]) at two concentrations of iron by weight. The NMR response of these samples was used to calculate four transverse relaxation rates for each Fe(II) mineral mixture: total mean log, bulk fluid, diffusion, and surface relaxation rates. The surface area of the samples was used to calculate the surface relaxivity of the sample and the magnetically active surface. For each iron mineral, the mean log and surface relaxation rates were greater for samples with higher Fe(II) concentration. For the siderite,pyrrhotite, and high-concentration pyrite mixtures, surface relaxation was the dominant relaxation mechanism. Bulk fluid relaxation contributed significantly to the total relaxation for the siderite and pyrite mixtures; for the low-concentration pyrite mixtures, bulk fluid relaxation was the dominant relaxation mechanism. For the pyrrhotite mixtures, the diffusion relaxation rate was nonzero and slower than the surface relaxation rate; for the siderite and pyrite mixtures, the diffusion relaxation rate was zero. Surface relaxivity calculations revealed that, for the pyrite mixtures, relaxation occurred in the fast diffusion regime; for the siderite and pyrrhotite mixtures, relaxation did not occur in the fast diffusion regime. The range of surface relaxivity values calculated depends on mineralogic form. We conclude that Fe(II) concentration and mineralogic form are important factors in determining relaxation rate.
Successful Treatment of Childhood High-Risk Hepatoblastoma With Dose-Intensive Multiagent Chemotherapy and Surgery: Final Results of the SIOPEL-3HR Study
Authors: Zsíros József , Maibach Rudolf , Shafford Elizabeth , Brugieres Laurence , Brock Penelope , Czauderna Piotr , Roebuck Derek , Childs Margaret , Zimmermann Arthur , Laithier Veronique , Otte Jean-Bernard , de Camargo Beatriz , MacKinlay Gordon , Scopinaro Marcelo , Aronson Daniel , Plaschkes Jack , Perilongo Giorgio
Published: April 2010

Purpose

The primary objective was to determine the efficacy of a newly designed preoperative chemotherapy regimen in an attempt to improve the cure rate of children with high-risk hepatoblastoma.

Patients and Methods

High risk was defined as follows: tumor in all liver sections (ie, Pretreatment Extension IV [PRETEXT-IV]), or vascular invasion (portal vein [P+], three hepatic veins [V+]), or intra-abdominal extrahepatic extension (E+), or metastatic disease, or α-fetoprotein less than 100 ng/mL at diagnosis. Patients were treated with alternating cycles of cisplatin and carboplatin plus doxorubicin (preoperatively, n = 7; postoperatively, n = 3) and delayed tumor resection.

Results

Of the 151 patients (150 evaluable for response) 118 (78.7%) achieved a partial response to chemotherapy. Complete resection of the liver tumor could be achieved in 115 patients (76.2%) either by partial hepatectomy (55.6%) or by liver transplantation (20.6%). In 106 children (70.2%), complete resection of all tumor lesions (including metastases) was achieved. Among the patients with initial lung metastases, 52.2% achieved complete remission of the lung lesions with chemotherapy alone. In half of the patients with initial PRETEXT-IV tumor as the only high-risk feature, the tumor could be completely resected with partial hepatectomy. Event-free (EFS) and overall survival (OS) estimates at 3 years were 65% (95% CI, 57% to 73%) and 69% (95% CI, 62% to 77%) for the whole group. EFS and OS for all patients with PRETEXT-IV tumor were 68% and 69%, respectively, and they were 56% and 62%, respectively, for patients with metastasis.

Conclusion

The applied treatment rendered a great proportion of tumors resectable, and, in comparison with previously published results, led to an improved survival in patients with high-risk hepatoblastoma.
Conditional Survival and the Choice of Conditioning Set for Patients With Colon Cancer: An Analysis of NSABP Trials C-03 Through C-07
Authors: Zamboni Beth A. , Yothers Greg , Choi Mehee , Fuller Clifton D. , Dignam James J. , Raich Peter C. , Thomas Charles R. , O'Connell Michael J. , Wolmark Norman , Wang Samuel J.
Published: April 2010

Purpose

Colon cancer overall survival (OS) is usually computed from the time of diagnosis. Survival gives the initial prognosis but does not reflect how prognosis changes with changing hazard rates over time. Conditional survival (probability of surviving y additional years given they have survived x years [CS or OS|OS]) is an alternative measure that accounts for elapsed time since diagnosis, providing more relevant prognostic information. We extend the concept of CS to condition on the set of patients alive, recurrence-free, and second primary cancer-free (disease-free survival [OS|DFS]).

Patients and Methods

Using data from National Surgical Adjuvant Breast and Bowel Project trials C-03 through C-07, 5-year OS|DFS was calculated on patients who were disease free up to 5 years after diagnosis, stratified by age, stage, nodal status, and performance status (PS).

Results

For stage II, OS|DFS improved from 87% to 92% at 5 years. For stage III, OS|DFS improved from 69% to 88%. Patients younger than 50 years showed OS|DFS improvement from 79% to 95%; those older than 70 years showed no sustained increase in OS|DFS. Node-negative patients with ≥ 12 nodes resected showed little change (89% to 94%); those with more than four positive nodes showed an improvement (57% to 86%). Patients with a PS of 0 or 1 demonstrated a small improvement; those with a PS of 2 did not (64% to 58%).

Conclusion

Prognosis improves over time for almost all groups of patients with colon cancer, especially those with positive nodes. OS|DFS is a more relevant measure of prognosis for those who have already survived disease free a period of time after diagnosis.
Clinical Utility of Microarray-Based Gene Expression Profiling in the Diagnosis and Subclassification of Leukemia: Report From the International Microarray Innovations in Leukemia Study Group
Authors: Haferlach Torsten , Kohlmann Alexander , Wieczorek Lothar , Basso Giuseppe , Kronnie Geertruy Te , Béné Marie-Christine , De Vos John , Hernández Jesus M. , Hofmann Wolf-Karsten , Mills Ken I. , Gilkes Amanda , Chiaretti Sabina , Shurtleff Sheila A. , Kipps Thomas J. , Rassenti Laura Z. , Yeoh Allen E. , Papenhausen Peter R. , Liu Wei-min , Williams P. Mickey , Foà Robin
Published: April 2010

Purpose

The Microarray Innovations in Leukemia study assessed the clinical utility of gene expression profiling as a single test to subtype leukemias into conventional categories of myeloid and lymphoid malignancies.

Methods

The investigation was performed in 11 laboratories across three continents and included 3,334 patients. An exploratory retrospective stage I study was designed for biomarker discovery and generated whole-genome expression profiles from 2,143 patients with leukemias and myelodysplastic syndromes. The gene expression profiling–based diagnostic accuracy was further validated in a prospective second study stage of an independent cohort of 1,191 patients.

Results

On the basis of 2,096 samples, the stage I study achieved 92.2% classification accuracy for all 18 distinct classes investigated (median specificity of 99.7%). In a second cohort of 1,152 prospectively collected patients, a classification scheme reached 95.6% median sensitivity and 99.8% median specificity for 14 standard subtypes of acute leukemia (eight acute lymphoblastic leukemia and six acute myeloid leukemia classes, n = 693). In 29 (57%) of 51 discrepant cases, the microarray results had outperformed routine diagnostic methods.

Conclusion

Gene expression profiling is a robust technology for the diagnosis of hematologic malignancies with high accuracy. It may complement current diagnostic algorithms and could offer a reliable platform for patients who lack access to today's state-of-the-art diagnostic work-up. Our comprehensive gene expression data set will be submitted to the public domain to foster research focusing on the molecular understanding of leukemias.
Surgery and Adjuvant Chemotherapy Use Among Veterans With Colon Cancer: Insights From a California Study
Authors: Hynes Denise M. , Tarlov Elizabeth , Durazo-Arvizu Ramon , Perrin Ruth , Zhang Qiuying , Weichle Thomas , Ferreira M. Rosario , Lee Todd , Benson Al B. , Bhoopalam Nirmala , Bennett Charles L.
Published: April 2010

Purpose

US veterans have been shown to be a vulnerable population with high cancer rates, and cancer care quality in Veterans Affairs (VA) hospitals is the focus of a congressionally mandated review. We examined rates of surgery and chemotherapy use among veterans with colon cancer at VA and non-VA facilities in California to gain insight into factors associated with quality of cancer care.

Methods

A retrospective cohort of incident colon cancer patients from the California Cancer Registry, who were ≥ 66 years old and eligible to use VA and Medicare between 1999 and 2001, were observed for 6 months after diagnosis.

Results

Among 601 veterans with colon cancer, 72% were initially diagnosed and treated in non-VA facilities. Among veterans with stage I to III cancer, those diagnosed and initially treated in VA facilities experienced similar colectomy rates as those at non-VA facilities. Stage III patients diagnosed and initially treated in VA versus non-VA facilities had similar odds of receiving adjuvant chemotherapy. In both settings, older patients had lower odds of receiving chemotherapy than their younger counterparts even when race and comorbidity were considered (age 76 to 85 years: odds ratio [OR] = 0.18; 95% CI, 0.07 to 0.46; age ≥ 86 years: OR = 0.17; 95% CI, 0.04 to 0.73).

Conclusion

In California, older veterans with colon cancer used both VA and non-VA facilities for cancer treatment, and odds of receiving cancer-directed surgery and chemotherapy were similar in both systems. Among stage III patients, older age lowered odds of receiving adjuvant chemotherapy in both systems. Further studies should continue to explore potential health system effects on quality of colon cancer care across the United States.
Clinical Relevance of Conditional Survival of Cancer Patients in Europe: Age-Specific Analyses of 13 Cancers
Authors: Janssen-Heijnen Maryska L.G. , Gondos Adam , Bray Freddie , Hakulinen Timo , Brewster David H. , Brenner Hermann , Coebergh Jan-Willem W.
Published: April 2010

Purpose

When cancer survivors wish to receive accurate information on their current prognosis during follow-up, conditional 5-year relative survival may be most suitable. We have estimated conditional 5-year relative survival for 13 cancers using a large European database—European Network for Indicators on Cancer (EUNICE)—of 10 dedicated long-standing cancer registries across Europe.

Patients and Methods

Patients age 15 years and older diagnosed between 1985 and 2004 were included. Conditional 5-year relative survival for each age group was computed for every additional year survived up to 10 years. Period analysis with follow-up period 2000 to 2004 was used.

Results

All patients with cutaneous melanoma or colorectal, endometrial, or testis cancer and younger patients with stomach, glottis, cervix, ovary, or thyroid cancer or non-Hodgkin's lymphoma exhibited hardly any excess mortality (conditional 5-year relative survival > 95%) given that they were alive at a defined time point within 10 years of initial diagnosis. However, patients with supraglottis, lung, breast, and kidney cancer, as well as older patients with most cancers exhibited substantial excess mortality (conditional 5-year relative survival < 90%). Initial differences in relative survival at diagnosis between age groups largely disappeared with time since initial diagnosis for melanoma, or stomach, colorectal, corpus uteri, or testicular cancer but persisted for patients diagnosed with other tumors. Differences between stage groups became smaller over time or disappeared.

Conclusion

Conditional relative survival shows clinically relevant variations according to time since diagnosis, type of cancer, and age, and can help serve as a guide for cancer survivors in planning for their future and for doctors in planning schedules for surveillance.
Associations Among Cancer Survivorship Discussions, Patient and Physician Expectations, and Receipt of Follow-Up Care
Authors: Cheung Winson Y. , Neville Bridget A. , Earle Craig C.
Published: April 2010

Purpose

To explore the associations among cancer survivorship discussions, patient-physician expectations, and receipt of follow-up care in cancer survivors.

Patients and Methods

We surveyed cancer survivors about various aspects of their care, including expectations of their providers' roles, whether discussions with a physician had occurred, and self-reported patterns of follow-up. Primary care providers (PCPs) and oncologists were also surveyed for their own perceived roles. We developed a scoring system to evaluate the level of agreement in expectations between patients and physicians and between PCPs and oncologists (where 0 = most discordant and 4 = most concordant). Regression and stratified analyses were conducted to examine the relationships among expectations, discussions, and follow-up.

Results

In total, 535 patients (54%) and 378 physicians (62%) responded. Survivorship care expectations were most discrepant between PCPs and oncologists (mean score, 1.78), moderate between patients and oncologists (mean score, 1.97), and most similar between patients and PCPs (mean score, 2.82). Having a conversation specifically about cancer follow-up was associated with better concordance between patients and oncologists, but not for patients and their PCPs or between physicians. Better concordance in patient-oncologist expectations also correlated with greater odds of receiving certain aspects of follow-up care, such as influenza vaccinations and physical examinations, but only if a discussion about cancer follow-up had occurred.

Conclusion

A discussion about cancer follow-up may affect survivorship care through its primary influence on patient-oncologist expectations. Further work is required to clarify the aspects of survivorship discussions that are important for optimal cancer survivorship care planning.
Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval
Authors: Fong Peter C. , Yap Timothy A. , Boss David S. , Carden Craig P. , Mergui-Roelvink Marja , Gourley Charlie , De Greve Jacques , Lubinski Jan , Shanley Susan , Messiou Christina , A'Hern Roger , Tutt Andrew , Ashworth Alan , Stone John , Carmichael James , Schellens Jan H.M. , de Bono Johann S. , Kaye Stan B.
Published: April 2010

Purpose

Selective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers.

Patients and Methods

Patients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity.

Results

Fifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002).

Conclusion

Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.
Future of Personalized Medicine in Oncology: A Systems Biology Approach
Authors: Gonzalez-Angulo Ana Maria , Hennessy Bryan T.J. , Mills Gordon B.
Published: April 2010

The development of cost-effective technologies able to comprehensively assess DNA, RNA, protein, and metabolites in patient tumors has fueled efforts to tailor medical care. Indeed validated molecular tests assessing tumor tissue or patient germline DNA already drive therapeutic decision making. However, many theoretical and regulatory challenges must still be overcome before fully realizing the promise of personalized molecular medicine. The masses of data generated by high-throughput technologies are challenging to manage, visualize, and convert to the knowledge required to improve patient outcomes. Systems biology integrates engineering, physics, and mathematical approaches with biologic and medical insights in an iterative process to visualize the interconnected events within a cell that determine how inputs from the environment and the network rewiring that occurs due to the genomic aberrations acquired by patient tumors determines cellular behavior and patient outcomes. A cross-disciplinary systems biology effort will be necessary to convert the information contained in multidimensional data sets into useful biomarkers that can classify patient tumors by prognosis and response to therapeutic modalities and to identify the drivers of tumor behavior that are optimal targets for therapy. An understanding of the effects of targeted therapeutics on signaling networks and homeostatic regulatory loops will be necessary to prevent inadvertent effects as well as to develop rational combinatorial therapies. Systems biology approaches identifying molecular drivers and biomarkers will lead to the implementation of smaller, shorter, cheaper, and individualized clinical trials that will increase the success rate and hasten the implementation of effective therapies into the clinical armamentarium.
Ethics of Mandatory Research Biopsy for Correlative End Points Within Clinical Trials in Oncology
Authors: Peppercorn Jeffrey , Shapira Iuliana , Collyar Deborah , Deshields Teresa , Lin Nancy , Krop Ian , Grunwald Hans , Friedman Paula , Partridge Ann H. , Schilsky Richard L. , Bertagnolli Monica M.
Published: April 2010

Clinical investigators in oncology are increasingly interested in using molecular analysis of cancer tissue to understand the biologic bases of response or resistance to novel interventions and to develop prognostic and predictive biomarkers that will guide clinical decision making. Some scientific questions of this nature can only be addressed, or may best be addressed, through the conduct of a clinical trial in which research biopsies are obtained from all participants. However, trial designs with mandatory research biopsies have raised ethical concerns related to the risk of harm to participants, the adequacy of voluntary informed consent, and the potential for misunderstanding among research participants when access to an experimental intervention is linked to the requirement to undergo a research biopsy. In consideration of the ethical and scientific issues at stake in this debate, the Cancer and Leukemia Group B Ethics Committee proposes guidelines for clinical trials involving mandatory research biopsies. Any cancer clinical trial that requires research biopsies of participants must be well designed to address the scientific question, obtain the biopsy in a way that minimizes risk, and ensure that research participants are fully informed of the risks, rationale, and requirements of the study, as well as of treatment alternatives. Further guidelines and discussions of this issue are specified in this position paper. We feel that if these principles are respected, an informed adult with cancer can both understand and voluntarily consent to participation in a clinical trial involving mandatory research biopsy for scientific end points.
Phase II Study of Asparagine-Glycine-Arginine–Human Tumor Necrosis Factor α, a Selective Vascular Targeting Agent, in Previously Treated Patients With Malignant Pleural Mesothelioma
Authors: Gregorc Vanesa , Zucali Paolo A. , Santoro Armando , Ceresoli Giovanni L. , Citterio Giovanni , De Pas Tommaso M. , Zilembo Nicoletta , De Vincenzo Fabio , Simonelli Matteo , Rossoni Gilda , Spreafico Anna , Grazia Viganò Maria , Fontana Floriana , De Braud Filippo G. , Bajetta Emilio , Caligaris-Cappio Federico , Bruzzi Paolo , Lambiase Antonio , Bordignon Claudio
Published: April 2010

Purpose

NGR-hTNF consists of human tumor necrosis factor α (hTNF-α) fused to the tumor-homing peptide asparagine-glycine-arginine (NGR) able to selectively bind an aminopeptidase N isoform overexpressed on tumor blood vessels. Hypervascularity is a prominent and poor-prognosis feature of malignant pleural mesothelioma (MPM). Currently, there are no standard options for patients with MPM who are failing a front-line pemetrexed-based regimen. We explored safety and efficacy of NGR-hTNF in this setting.

Patients and Methods

Eligible patients had radiologically documented tumor progression and performance status ≤ 2. Primary study aim was progression-free survival (PFS). NGR-hTNF 0.8 μg/m2was given intravenously every 3 weeks. A subsequent cohort of patients received 0.8 μg/m2on a weekly basis.

Results

In the triweekly cohort (n = 43), only one grade 3 drug-related toxicity was noted, and the most common grades 1 to 2 were short-lived chills (71%). The median PFS was 2.8 months (95% CI, 2.3 to 3.3 months). Nineteen patients (44%) had disease control (one had partial response, and 18 had stable diseases) and experienced a median progression-free time of 4.4 months. In the weekly cohort (n = 14), there was no higher toxicity, and median PFS was 3.0 months (95% CI, 1.9 to 4.1 months). Seven patients (50%) had disease control (all stable diseases) and had a median progression-free interval of 9.1 months. In the overall study population (N = 57), median PFS was 2.8 months. Median progression-free time was 4.7 months in twenty-six patients (46%) who achieved disease control. Median survival was 12.1 months.

Conclusion

The tolerability and disease control of NGR-hTNF 0.8 μg/m2weekly warrant additional evaluation in patients with advanced MPM.
Equipoise Lost: Ethics, Costs, and the Regulation of Cancer Clinical Research
Authors: Stewart David J. , Whitney Simon N. , Kurzrock Razelle
Published: April 2010

Cancer is the leading cause of death in Americans younger than 85 years of age and kills one American every 56 seconds. Advances in understanding of cancer biology have given us the potential to develop new, effective targeted therapies. However, progress is slowed by suboptimal/outdated clinical trial design paradigms and by regulatory complexity and rigidity. For instance, simulations suggest that restricting randomized trials to patients expressing drug target, instead of using unselected patient populations, could substantially reduce patient numbers required to demonstrate efficacy. High response rates that are achievable when patients and drugs are matched on the basis of molecular profiles may also make some randomized trials unnecessary or unjustifiable. Moreover, increasing the regulatory rigidity of clinical trials (regulatory fundamentalism) augments trial complexity and costs while slowing progress without demonstrating meaningful safety benefits. Time from drug discovery to marketing increased from 8 years in 1960 to 12 to 15 years currently. Toxic death rates on phase I trials have decreased from 0.8% in 1979 to 0.5% by 2002, but the estimated cost per life-year gained by tighter regulations is $2,700,000 (far higher than costs of other health measures), and simulations suggest that regulatory delays in development of effective therapies result in tens to hundreds of thousands of life-years lost, whereas stringent regulations save extremely few. Dysregulation is also a major disincentive to patient and clinician participation in clinical research. In summary, current approaches squander research resources and discourage research participation, and the marked imbalance between potential life-years lost versus saved renders the regulatory burden potentially unethical. We outline suggested solutions.
PAK4: a pluripotent kinase that regulates prostate cancer cell adhesion
Authors: Wells Claire M. , Whale Andrew D. , Parsons Maddy , Masters John R. W. , Jones Gareth E.
Published: April 2010

Hepatocyte growth factor (HGF) is associated with tumour progression and increases the invasiveness of prostate carcinoma cells. Migration and invasion require coordinated reorganisation of the actin cytoskeleton and regulation of cell-adhesion dynamics. Rho-family GTPases orchestrate both of these cellular processes. p21-activated kinase 4 (PAK4), a specific effector of the Rho GTPase Cdc42, is activated by HGF, and we have previously shown that activated PAK4 induces a loss of both actin stress fibres and focal adhesions. We now report that DU145 human prostate cancer cells with reduced levels of PAK4 expression are unable to successfully migrate in response to HGF, have prominent actin stress fibres, and an increase in the size and number of focal adhesions. Moreover, these cells have a concomitant reduction in cell-adhesion turnover rates. We find that PAK4 is localised at focal adhesions, is immunoprecipitated with paxillin and phosphorylates paxillin on serine 272. Furthermore, we demonstrate that PAK4 can regulate RhoA activity via GEF-H1. Our results suggest that PAK4 is a pluripotent kinase that can regulate both actin cytoskeletal rearrangement and focal-adhesion dynamics.
ERMES-mediated ER-mitochondria contacts: molecular hubs for the regulation of mitochondrial biology
Authors: Kornmann Benoît , Walter Peter
Published: April 2010

Organelles are separate yet interdependent units of eukaryotic cells. They provide an appropriate milieu for the catalysis of many biochemical reactions, and they must establish physical links to communicate and exchange metabolites throughout the cell. Interorganelle communication is an important, yet still poorly understood, aspect of cell biology. We recently identified a protein complex that we refer to as ERMES [endoplasmic reticulum (ER)-mitochondria encounter structure], the main function of which is to provide a tethering force between the ER and the mitochondria. This complex, composed of both ER and mitochondrial transmembrane proteins, is located at the interface of the two organelles and serves to zipper them together. Previous work had implicated several ERMES components in many different physiological processes. The identification of ERMES as an interorganelle tether allows us to re-examine the amply documented phenotypic consequences of the loss of this complex in the light of this new function, thus providing a unique opportunity to assess the physiological relevance of ER-mitochondria junctions. These phenotypes hint at a broad role for ER-mitochondria connections in regulating mitochondrial and cell physiology. In this Hypothesis, we speculate on the potential role of ER-mitochondria connections as hubs in regulating several aspects of mitochondrial biology, including the regulation of mitochondrial membrane biosynthesis, genome replication, Ca2+ signaling and protein import. Finally, we discuss how cells might use ER-mitochondria communication to fine-tune these processes according to their metabolic needs.
Drosophila twinfilin is required for cell migration and synaptic endocytosis
Authors: Wang Dan , Zhang Lijun , Zhao Guoli , Wahlström Gudrun , Heino Tapio I. , Chen Jiong , Zhang Yong Q.
Published: April 2010

Precise actin regulation is essential for diverse cellular processes such as axonal growth, cell migration and endocytosis. twinfilin (twf) encodes a protein that sequesters actin monomers, but its in vivo functions are unclear. In this study, we characterized twf-null mutants in a metazoan for the first time and found that Drosophila twf negatively regulates F-actin formation in subcellular regions of rapid actin turnover in three different systems, namely postsynaptic neuromuscular junction (NMJ) synapses, migratory border cells and epithelial follicle cells. Loss of twf function results in defects in axonal growth in the brain and border cell migration in the ovary. Additionally, we found that the actin-dependent postsynaptic localization of glutamate receptor GluRIIA, but not GluRIIB, was specifically reduced in twf mutants. More importantly, we showed that twf mutations caused significantly reduced presynaptic endocytosis at NMJ synapses, as detected using the fluorescent dye FM1-43 uptake assay. Furthermore, electrophysiological analysis under high-frequency stimulation showed compromised neurotransmission in twf mutant synapses, confirming an insufficient replenishment of synaptic vesicles. Together, our results reveal that twinfilin promotes actin turnover in multiple cellular processes that are highly dependent on actin dynamics.
C3 peptide enhances recovery from spinal cord injury by improved regenerative growth of descending fiber tracts
Authors: Boato Francesco , Hendrix Sven , Huelsenbeck Stefanie C. , Hofmann Fred , Große Gisela , Djalali Susann , Klimaschewski Lars , Auer Maria , Just Ingo , Ahnert-Hilger Gudrun , Höltje Markus
Published: April 2010

Functional recovery and regeneration of corticospinal tract (CST) fibers following spinal cord injury by compression or dorsal hemisection in mice was monitored after application of the enzyme-deficient Clostridium botulinum C3-protein-derived 29-amino-acid fragment C3bot154-182. This peptide significantly improved locomotor restoration in both injury models as assessed by the open-field Basso Mouse Scale for locomotion test and Rotarod treadmill experiments. These data were supported by tracing studies showing an enhanced regenerative growth of CST fibers in treated animals as visualized by anterograde tracing. Additionally, C3bot154-182 stimulated regenerative growth of raphespinal fibers and improved serotonergic input to lumbar α-motoneurons. These in vivo data were confirmed by in vitro data, showing an enhanced axon outgrowth of α-motoneurons and hippocampal neurons cultivated on normal or growth-inhibitory substrates after application of C3bot154-182. The observed effects were probably caused by a non-enzymatic downregulation of active RhoA by the C3 peptide as indicated by pull-down experiments. By contrast, C3bot154-182 did not induce neurite outgrowth in primary cultures of dorsal root ganglion cells. In conclusion, C3bot154-182 represents a novel, promising tool to foster axonal protection and/or repair, as well as functional recovery after traumatic CNS injury.
MidA is a putative methyltransferase that is required for mitochondrial complex I function
Authors: Carilla-Latorre Sergio , Gallardo M. Esther , Annesley Sarah J. , Calvo-Garrido Javier , Graña Osvaldo , Accari Sandra L. , Smith Paige K. , Valencia Alfonso , Garesse Rafael , Fisher Paul R. , Escalante Ricardo
Published: April 2010

Dictyostelium and human MidA are homologous proteins that belong to a family of proteins of unknown function called DUF185. Using yeast two-hybrid screening and pull-down experiments, we showed that both proteins interact with the mitochondrial complex I subunit NDUFS2. Consistent with this, Dictyostelium cells lacking MidA showed a specific defect in complex I activity, and knockdown of human MidA in HEK293T cells resulted in reduced levels of assembled complex I. These results indicate a role for MidA in complex I assembly or stability. A structural bioinformatics analysis suggested the presence of a methyltransferase domain; this was further supported by site-directed mutagenesis of specific residues from the putative catalytic site. Interestingly, this complex I deficiency in a Dictyostelium midA− mutant causes a complex phenotypic outcome, which includes phototaxis and thermotaxis defects. We found that these aspects of the phenotype are mediated by a chronic activation of AMPK, revealing a possible role of AMPK signaling in complex I cytopathology.
Serum testosterone levels measured by isotope dilution-liquid chromatography–tandem mass spectrometry in postmenopausal women versus those in women who underwent bilateral oophorectomy
Authors: Bui Hong N , Struys Eduard A , Martens Frans , de Ronde Willem , Thienpont Linda M , Kenemans Peter , Verhoeven Marieke O , Jakobs Cornelis , Dijstelbloem Hilde M , Blankenstein Marinus A
Published: April 2010

Background

Differentiation between subtle changes in low serum testosterone concentrations, common in women and children, is not possible with current commercially available assays. The objectives of the study were to develop a method based on stable isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) with adequate sensitivity and specificity and to investigate the applicability of this assay in serum samples from pre- and postmenopausal women.

Methods

For 16 women, testosterone levels were measured in blood samples drawn two years before and after physiological menopause, and for eight women in samples drawn before and after bilateral oophorectomy. Testosterone was extracted from serum, derivatized and analysed on an LC-MS/MS.

Results

The developed ID-LC-MS/MS method allowed for specific and reproducible measurement of testosterone. Comparison with stable isotope dilution-gas chromatography coupled to mass spectrometry detection by Deming regression analysis gave a slope of 1.025 and an intercept of 0.055 nmol/L ( r = 0.9998). A significant decrease was found in testosterone concentrations before and after bilateral oophorectomy ( P = 0.02), whereas no significant difference was found before and after natural menopause ( P = 0.4).

Conclusions

The ID-LC-MS/MS assay measures serum testosterone with acceptable accuracy and is useful in female samples, supporting the conclusion that the postmenopausal ovary contributes to circulating testosterone. To our knowledge, our analytical method compares favourably to similar published methods in terms of sensitivity. The sensitivity and specificity of this method comply with the reference method for measurement of testosterone in serum samples of women, children and men suffering from hypogonadism and can also be used for men with testosterone in the reference range.
Fatal ammonia toxicity in an adult due to an undiagnosed urea cycle defect: under-recognition of ornithine transcarbamylase deficiency
Authors: Thurlow Vanessa R , Asafu-Adjaye Michelle , Agalou Stamatina , Rahman Yusof
Published: April 2010

There is a lack of awareness of acutely presenting inborn errors of metabolism in adults, of which the X-linked urea cycle defect ornithine transcarbamylase (OTC) deficiency is an example, many comparatively mild mutations having been identified. In male hemizygotes clinical manifestations and age at presentation vary and depend on the mutation. In female heterozygotes the clinical spectrum depends on the extent to which the abnormal gene is expressed. Milder versions of the defect may not cause clear clinical symptoms and may remain unrecognized until the person is subjected to an unusually high nitrogen load when they develop severe hyperammonaemia. During acute episodes liver enzymes may be normal or only slightly elevated and occasionally accompanied by coagulopathy, but the key finding is hyperammonaemia. Boys with these milder forms may exhibit abnormal behaviour and be diagnosed with attention deficit hyperactivity disorder. This case illustrates how late presentation of OTC deficiency in a non-specialist centre can be difficult to differentiate from drug abuse, psychiatric illness or encephalopathy. Failure to measure blood ammonia in adults with unexplained key symptoms – particularly prolonged vomiting without diarrhoea and altered mental state/hallucinations, or to recognize the significance of elevated blood ammonia without evidence of liver decompensation can lead to delayed or missed diagnosis.
Falsely elevated troponin I results due to outliers indicate a lack of analytical robustness
Authors: Ungerer Jacobus P J , Pretorius Carel J , Dimeski Goce , O'Rourke Peter K , Tyack Shirley A
Published: April 2010

Aims

Troponin (Tn) is the preferred biochemical marker for the diagnosis of acute coronary syndrome. Spurious false Tn results (outliers) may cause significant problems with clinical management. We investigated the occurrence of outliers and whether this phenomenon could be explained by analytical imprecision.

Methods and results

Troponin I (TnI) was measured in duplicate with Beckman AccuTnI reagent if the first TnI result was ≥0.04 μg/L ( n = 5265). All TnI requests were performed in duplicate in a subset of samples for one calendar month ( n = 881). A total of 13,178 TnI requests were received during the study period. Variables were sample type, centrifugation speed and analyser. Results were identified as outliers when the difference between two results exceeded a critical difference (CD) limit defined by CD = z × √2 × SDAnalytical. Outliers at the 0.0005 probability level were detected in 102 of 5265 duplicate observations (1.94 ± 0.37%). This translated into an outlier rate of 0.55 ± 0.13% for all TnI results and 1.37 ± 0.31% for results above 0.04 μg/L. Outliers resulted only in falsely elevated TnI values and were not dependent on the analyser, centrifugation speed or sample type.

Conclusion

TnI outliers occurred more frequently than anticipated, could not be explained by analytical imprecision and indicated a lack of robustness in the assay. The high rate and the magnitude of the errors will complicate clinical management and carry a risk of detrimental patient outcome. The outlier rate is a useful parameter to define the robustness of assays.
Clinical accuracy of midnight salivary cortisol measured by automated electrochemiluminescence immunoassay method in Cushing's syndrome
Authors: Carrozza Cinzia , Corsello Salvatore Maria , Paragliola Rosa Maria , Ingraudo Francesca , Palumbo Sara , Locantore Pietro , Sferrazza Antonella , Pontecorvi Alfredo , Zuppi Cecilia
Published: April 2010

Background

The diagnosis of Cushing's syndrome (CS) represents a challenge for endocrinologists. Several screening tests are used, but none of them seems to be the gold standard for the diagnosis. The aim of this study was to confirm the diagnostic value of salivary cortisol (SC) as a first-level screening test and to evaluate the clinical performance of a electrochemiluminescence immunoassay (ECLIA) method.

Methods

In 33 patients with a strong clinical suspicion of CS, we evaluated urinary free cortisol, circadian rhythm plasma cortisol (PC) and morning PC after low-dose dexamethasone suppression test (LDDST). At the same sampling times, we evaluated SC analysed by the same automated method. Correlation studies were evaluated by Spearman index (significance P < 0.05).

Results

On the basis of biochemical results CS was confirmed in 21/33. SC was significantly correlated to PC at 12:00 and 23:00. Thus, we chose 8.3 nmol/L as midnight SC cut-off value with 100% sensitivity and 97.4% specificity. The cut-off chosen after LDDST was 1.7 nmol/L (100% sensitivity and 72% specificity).

Conclusion

SC assay showed a good clinical accuracy and the ECLIA method can be used in clinical routine to obtain fast results easily.
A variant of the KLK4 gene is expressed as a cis sense–antisense chimeric transcript in prostate cancer cells
Authors: Lai John , Lehman Melanie L. , Dinger Marcel E. , Hendy Stephen C. , Mercer Tim R. , Seim Inge , Lawrence Mitchell G. , Mattick John S. , Clements Judith A. , Nelson Colleen C.
Published: April 2010

In humans, more than 30,000 chimeric transcripts originating from 23,686 genes have been identified. The mechanisms and association of chimeric transcripts arising from chromosomal rearrangements with cancer are well established, but much remains unknown regarding the biogenesis and importance of other chimeric transcripts that arise from nongenomic alterations. Recently, a SLC45A3–ELK4 chimera has been shown to be androgen-regulated, and is overexpressed in metastatic or high-grade prostate tumors relative to local prostate cancers. Here, we characterize the expression of a KLK4 cis sense–antisense chimeric transcript, and show other examples in prostate cancer. Using non-protein-coding microarray analyses, we initially identified an androgen-regulated antisense transcript within the 3′ untranslated region of the KLK4 gene in LNCaP cells. The KLK4 cis-NAT was validated by strand-specific linker-mediated RT-PCR and Northern blotting. Characterization of the KLK4 cis-NAT by 5′ and 3′ rapid amplification of cDNA ends (RACE) revealed that this transcript forms multiple fusions with the KLK4 sense transcript. Lack of KLK4 antisense promoter activity using reporter assays suggests that these transcripts are unlikely to arise from a trans-splicing mechanism. 5′ RACE and analyses of deep sequencing data from LNCaP cells treated ±androgens revealed six high-confidence sense–antisense chimeras of which three were supported by the cDNA databases. In this study, we have shown complex gene expression at the KLK4 locus that might be a hallmark of cis sense–antisense chimeric transcription.
Synthesis of carbon nanotubes by plasma-enhanced chemical vapor deposition in an atmospheric-pressure microwave torch
Authors: Zajíčková Lenka , Jašek Ondrej , Eliáš Marek , Synek Petr , Lazar Lukáš , Schneeweiss Oldřich , Hanzlíková Renáta
Published: April 2010

There are many different techniques for the synthesis of carbon nanotubes (CNTs), and plasma technologies experience a significant competitor in thermal chemical vapor deposition (CVD) processes. A particular process is, therefore, selected according to the specific requirements of an application, which clearly differ for the development of composites as compared to nanoelectronics, field emission, displays, sensors, and the like. This paper discusses the method for the synthesis of CNTs using an atmospheric-pressure microwave (MW) torch. It was successfully applied in the fast deposition of multiwalled nanotubes (MWNTs) on a substrate without the necessity of any vacuum or heating equipment. Dense straight-standing nanotubes were prepared on Si substrates with and also without barrier SiO
x
layer. Therefore, it was possible to produce CNTs directly on conductive Si and to use them as an electron-emitting electrode of the gas pressure sensor. The CNTs grown in MW torch were also used to create a gas sensor based on the changes of electrical resistance measured between two planar electrodes connected by the CNTs.
Liquid-phase laser ablation
Authors: Sasaki Koichi , Takada Noriharu
Published: April 2010

The irradiation of an intense laser pulse onto a solid target immersed in liquid produces dense plasma. The plasma produced by liquid-phase laser ablation has unique features at high pressure and temperature, which are never realized by liquid-phase discharges. Another unique characteristic of liquid-phase laser ablation is the formation of a cavitation bubble. This article reports the fundamental aspects of liquid-phase laser-ablation plasmas, cavitation bubbles, and the formation processes of nanoparticles, together with some applications of liquid-phase laser ablation.