bluuebunny/crossref_metadata_2025 huggingface dataset:
Transplantation of selected or transgenic blood stem cells – a future treatment for HIV/AIDS?
Authors: Hütter Gero , Schneider Thomas , Thiel Eckhard
Published: June 2009

Interaction with the chemokine receptor, CCR5, is a necessary precondition for maintaining HIV‐1 infection. Individuals with the CCR5‐delta32 deletion who lack this receptor are highly resistant to infection by the most common forms of HIV‐1. We recently reported on the successful transplantation in an HIV‐1‐positive patient of allogeneic stem cells homozygous for the CCR5‐delta32 allele, which stopped viral replication for more than 27 months without antiretroviral therapy.

Here, we report on the results of a meeting regarding the potential implications and future directions of stem cell‐targeted HIV treatments. The meeting drew together an international panel of hematologists, immunologists, HIV specialists and representatives from bone marrow donor registries.

The meeting came to an agreement to support further attempts to use CCR5‐delta32 deleted stem cells, for example, prescreened cord blood stem cells, to treat probable HIV‐1‐positive patients with malignancies. Furthermore, improvement of HIV‐1 therapy that interferes with the entry mechanism seems to be a promising approach in HIV‐1‐infected patients with no matching CCR5‐delta32 deleted donor.
Refractory lympho-epithelial carcinoma of the nasopharynx: a case report illustrating a protracted clinical course
Authors: Wu Frederick Y , Yang Eddy S , Willey Christopher D , Ely Kim , Garrett Gaelyn , Cmelak Anthony J
Published: June 2009

Nasopharyngeal carcinoma is an uncommon cancer in North America. Its clinical course is typified by locally advanced disease at diagnosis and has a high propensity for both regional and distant spread. It is, therefore, typically treated with a combination of radiation and chemotherapy. This report describes our 10-year clinical and radiological findings in a 48-year-old Vietnamese male patient with locally-advanced T4N1M0 lympho-epithelial carcinoma of the nasopharynx. Despite a long remission period after his initial course of aggressive chemoradiation, his tumor recurred locally after 4 years. Thereafter, throughout a period of over 10 years, he has been treated with multiple courses of re-irradiation and three different trials of chemotherapy. He was ultimately provided with over 30 months of progression-free tumor control with the epidermal growth factor receptor (EGFR)-inhibitor cetuximab. This case illustrates the commonly protracted course of this disease and its responsiveness to multiple treatment modalities.
Frequent loss of endothelin-3 (EDN3) expression due to epigenetic inactivation in human breast cancer
Authors: Wiesmann Frank , Veeck Jürgen , Galm Oliver , Hartmann Arndt , Esteller Manel , Knüchel Ruth , Dahl Edgar
Published: June 2009

Introduction

Endothelin (EDN) signalling plays a crucial role in cell differentiation, proliferation and migration processes. There is compelling evidence that altered EDN signalling is involved in carcinogenesis by modulating cell survival and promoting invasiveness. To date, most reports have focused on the oncogenic potential of EDN1 and EDN2, both of which are overexpressed in various tumour entities. Here, we aimed at a first comprehensive analysis on EDN3 expression and its implication in human breast cancer.

Methods

EDN3 mRNA expression was assessed by Northern blotting in normal human tissues (n = 9) as well as in matched pairs of normal and tumourous tissues from breast specimens (n = 50). EDN3 mRNA expression in breast cancer was further validated by real-time polymerase chain reaction (PCR) (n = 77). A tissue microarray was used to study EDN3 protein expression in breast carcinoma (n = 150) and normal breast epithelium (n = 44). EDN3 promoter methylation was analysed by methylation-specific PCR in breast cell lines (n = 6) before and after demethylating treatment, normal breast tissues (n = 17) and primary breast carcinomas (n = 128). EDN3 expression and methylation data were statistically correlated with clinical patient characteristics and patient outcome.

Results

Loss of EDN3 mRNA expression in breast cancer, as initially detected by array-based expression profiling, could be confirmed by Northern blot analysis (> 2-fold loss in 96%) and real-time PCR (> 2-fold loss in 78%). Attenuated EDN3 expression in breast carcinoma was also evident at the protein level (45%) in association with adverse patient outcome in univariate (P = 0.022) and multivariate (hazard ratio 2.0; P = 0.025) analyses. Hypermethylation of the EDN3 promoter could be identified as the predominant mechanism leading to gene silencing. Reversion of the epigenetic lock by 5-aza-2'-deoxycytidine and trichostatin A resulted in EDN3 mRNA re-expression in vitro. Furthermore, EDN3 promoter hypermethylation was detected in 70% of primary breast carcinomas with significant association to loss of EDN3 mRNA expression (P = 0.005), whilst normal matched breast tissues revealed no EDN3 promoter methylation.

Conclusions

EDN3 is a frequent target of epigenetic inactivation in human breast cancer, potentially contributing to imbalanced EDN signalling commonly found in this disease. The clinical implication supports the view that EDN3, in contrast to EDN1 and EDN2, may act as natural tumour suppressor in the human mammary gland.
Genomic linkage map of the human blood fluke Schistosoma mansoni
Authors: Criscione Charles D , Valentim Claudia LL , Hirai Hirohisa , LoVerde Philip T , Anderson Timothy JC
Published: June 2009

Background

Schistosoma mansoni is a blood fluke that infects approximately 90 million people. The complete life cycle of this parasite can be maintained in the laboratory, making this one of the few experimentally tractable human helminth infections, and a rich literature reveals heritable variation in important biomedical traits such as virulence, host-specificity, transmission and drug resistance. However, there is a current lack of tools needed to study S. mansoni's molecular, quantitative, and population genetics. Our goal was to construct a genetic linkage map for S. mansoni, and thus provide a new resource that will help stimulate research on this neglected pathogen.

Results

We genotyped grandparents, parents and 88 progeny to construct a 5.6 cM linkage map containing 243 microsatellites positioned on 203 of the largest scaffolds in the genome sequence. The map allows 70% of the estimated 300 Mb genome to be ordered on chromosomes, and highlights where scaffolds have been incorrectly assembled. The markers fall into eight main linkage groups, consistent with seven pairs of autosomes and one pair of sex chromosomes, and we were able to anchor linkage groups to chromosomes using fluorescent in situ hybridization. The genome measures 1,228.6 cM. Marker segregation reveals higher female recombination, confirms ZW inheritance patterns, and identifies recombination hotspots and regions of segregation distortion.

Conclusions

The genetic linkage map presented here is the first for S. mansoni and the first for a species in the phylum Platyhelminthes. The map provides the critical tool necessary for quantitative genetic analysis, aids genome assembly, and furnishes a framework for comparative flatworm genomics and field-based molecular epidemiological studies.
Epac inhibits apoptosis of human leukocytes
Authors: Grandoch M , Bujok V , Fleckenstein D , Schmidt M , Fischer J W , Weber A A
Published: June 2009

Selective activation of Epac proteins inhibits apoptosis in U937, HL-60, and primary human mononuclear cells.

cAMP is known to participate in the regulation of apoptosis in leukocytes. Depending on the cell type, pro- and antiapoptotic effects of cAMP have been described. Thus far, most of the cAMP-dependent effects have been attributed to the activation of PKA. However, Epac proteins (direct cAMP targets and guanine nucleotide exchange factors for Ras-like GTPases) have been shown recently to contribute to cAMP-dependent regulation of apoptosis. Therefore, we investigated the effects of the selective Epac activators 8-pCPT and Sp on apoptosis in human leukocytic cells (U937, HL-60, primary human mononuclear cells). We report here that Epac activation inhibits leukocyte apoptosis significantly.
The functional significance behind expressing two IL–8 receptor types on PMN
Authors: Stillie RoseMarie , Farooq Shukkur Muhammed , Gordon John R , Stadnyk Andrew W
Published: June 2009

The presence of two CXCL8 receptor types combined with the inflammatory roles of PMN has led to interest in whether each receptor type contributes to unique functions.

PMN are critical to innate immunity and are fundamental to antibacterial defense. To localize to sites of infection, PMN possess receptors that detect chemoattractant stimuli elicited at the site, such as chemokines, complement split products, or bioactive lipids. Signaling through these receptors stimulates chemotaxis toward the site of infection but also activates a number of biochemical processes, with the result that PMN kill invading bacteria. PMN possess two receptors, CXCR1 and CXCR2, for the N–terminal ELR motif–containing CXC chemokines, although only two chemokine members bind both receptors and the remainder binding only CXCR2. This peculiar pattern in receptor specificity has drawn considerable interest and investigation into whether signaling through each receptor might impart unique properties on the PMN. Indeed, at first glance, CXCR1 and CXCR2 appear to be functionally redundant; however, there are differences. Considering these proinflammatory activities of activating PMN through chemokine receptors, there has been great interest in the possibility that blocking CXCR1 and CXCR2 on PMN will provide a therapeutic benefit. The literature examining CXCR1 and CXCR2 in PMN function during human and modeled diseases will be reviewed, asking whether the functional differences can be perceived based on alterations in the role PMN play in these processes.
DAMPs and inflammatory processes: the role of redox in the different outcomes
Authors: Carta Sonia , Castellani Patrizia , Delfino Laura , Tassi Sara , Venè Roberta , Rubartelli Anna
Published: June 2009

Extracellular redox changes are relevant to the start, progress, and resolution of different acute or chronic inflammatory processes, with emphasis on the modulation of DAMP activity.

Inflammation is deeply entangled with redox modulation. Triggering of PRRs on inflammatory cells induces ROS generation. As a consequence, activated cells mount antioxidant responses to counteract the possible harmful effects of oxidation. Therefore, when repair is completed, homeostasis is restored. Here, we describe some recent results showing that an exuberant antioxidant response to pro–oxidant inflammatory stimuli modifies not only the intra– but also the extracellular redox and contributes to the outcome of the inflammatory process. In particular, the role of redox modulation in IL–1β secretion, in B lymphocyte differentiation to plasma cells, and in tumor progression will be discussed, and the potential consequences of extracellular redox alterations on DAMP activity will be considered.
Optimal experiment design for time-lapse traveltime tomography
Authors: Ajo-Franklin Jonathan B.
Published: June 2009

Geophysical monitoring techniques offer the only noninvasive approach capable of assessing the spatial and temporal dynamics of subsurface fluid processes. Increasingly, permanent sensor arrays in boreholes and on the ocean floor are being deployed to improve the repeatability and increase the temporal sampling of monitoring surveys. Because permanent arrays require a large up-front capital investment and are difficult (or impossible) to reconfigure once installed, a premium is placed on selecting a geometry capable of imaging the desired target at minimum cost. We have taken a simple approach to optimizing downhole sensor configurations for monitoring experiments making use of differential seismic traveltimes. We used a design quality metric based on the accuracy of tomographic reconstructions for a suite of imaging targets. By not requiring an explicit singular value decomposition of the forward operator, evaluation of this objective function scaled to problems with a large numberof unknowns. We restricted the design problem by recasting the array geometry into a low-dimensional form more suitable for optimization at a reasonable computational cost. We tested two search algorithms on the design problem: the Nelder-Mead downhill simplex method and the multilevel coordinate search algorithm. The algorithm was tested for four crosswell acquisition scenarios relevant to continuous seismic monitoring, a two-parameter array optimization, several scenarios involving four-parameter length/offset optimizations, and a comparison of optimal multisource designs. In the last case, we also examined trade-offs between source sparsity and the quality of tomographic reconstructions. Asymmetrical array lengths improved localized image quality in crosswell experiments with a small number of sources and a large number of receivers. Preliminary results also suggested that high-quality differential images could be generated using only a small number of optimally positioned sources in tandem with a more extensive receiver array.
Antiglucocorticoids in psychiatry
Authors: McIsaac Sean A. , Westrin Åsa , Young Allan H.
Published: June 2009

Significant evidence has accrued suggesting that the hypothalamic–pituitary–adrenal (HPA) axis plays a role in some psychiatric disorders. This article reviews the physiology of the HPA axis, evidence of dysfunction in this axis in psychiatric illnesses and the role that this dysfunction might play in pharmacological treatment resistance. Future therapeutic strategies that may potentially arise from these researches are briefly outlined.
The future of specialised alcohol treatment services: a matter of policy?
Authors: Rao Harish , Luty Jason
Published: June 2009

Around 7.1 million people in England drink hazardously or harmfully and a further 1.1 million are dependent on alcohol. Motivational interviewing is widely used to treat people with alcohol problems and is probably the best described example of a brief intervention. However, some recent trials have been disappointing. Specialised alcohol treatment services have also suffered from weakness in the evidence base. Investment in treating alcohol misuse has fallen far behind that for drug misuse. The Department of Health's Alcohol Harm Reduction Strategy for England embraces policies that are high-profile and cheap but are ineffective and ignore many effective measures. It recommends stepped care for alcohol treatment, but unlike the equivalent for drugs treatment, it sets no targets and leaves the small (7%) increase in funding to the discretion of local purchasers. UK spending on specialised treatment for drug misuse is estimated to be around £600 million for 2007 – around three times the estimated cost of treatment for alcohol misuse.
Reasons to be cheerful?
Authors: Rice Peter
Published: June 2009

Alcohol policy varies in different jurisdictions and is subject to change. Understanding policy development requires an international perspective. Current models of alcohol treatment systems require an understanding of the different impacts of interventions on different patient groups and clarity in the description of interventions and populations. Several systematic reviews have evaluated the outcome of alcohol treatment favourably and shown it to be highly cost-effective.
Beyond ADHD and narcolepsy: psychostimulants in general psychiatry
Authors: Ng Bradley , O'Brien Angela
Published: June 2009

Psychostimulants (dexamphetamine, methylphenidate, modafinil) reduce fatigue, promote alertness and wakefulness, and have possible mood-enhancing properties. In modern psychiatric practice, their use has been limited to attention-deficit hyperactivity disorder and sleep disorders such as narcolepsy. Despite this, research has continued into psychostimulant use in general psychiatry, especially in the treatment of depression and fatigue. This article reviews the recent literature regarding psychostimulant use in general and consultation-liaison psychiatry. Although psychostimulants continue to attract clinical research, there is currently not enough evidence to recommend their routine use for general psychiatric conditions.
Anger and depression
Authors: Busch Fredric N.
Published: June 2009

A series of psychoanalytic theorists and clinicians have suggested that conflicts about anger play a central role in the development of depression. Research data have supported the notion that patients struggle with the experience and expression of angry feelings. Anger in people with depression often stems from narcissistic vulnerability, a sensitivity to perceived or actual loss or rejection. These angry reactions cause intrapsychic conflicts through the onset of guilt and the fear that angry feelings will disrupt relationships. These conflicts lead to anger being directed inwards, further lowering self-esteem, creating a vicious cycle. Defence mechanisms that are triggered, including passive aggression, reaction formation, denial and identification with the aggressor, are ineffective at managing these conflicts and further prevent the appropriate expression of anger. This article discusses how to identify and detoxify angry feelings and fantasies using a psychodynamic approach.
Mood disorders and violence: a new focus
Authors: Oakley Clare , Hynes Fiona , Clark Tom
Published: June 2009

Violent behaviour in people with a psychiatric disorder causes great public concern and leads to stigma for people with mental illness. There is good evidence for a correlation between schizophrenia and increased rates of violence but any association between mood disorders and violence has been comparatively overlooked. It appears that there may be more evidence relating mood disorders and violence than many clinicians realise. This article highlights the difficulties in assessing this, summarises what is known and discusses what this means for clinical practice.
Targeting the HPA axis in major depression: does it work?
Authors: Claes Stephan
Published: June 2009

In the search for antidepressant drugs with enhanced efficacy, targeting the hypothalamic–pituitary–adrenal (HPA) axis is a valid strategy. This commentary critically summarises the evidence for the efficacy of antidepressant drugs targeting the HPA axis, and concludes that the available clinical trials do not support claims that this class of drugs is superior to existing treatments.
Patterns of neurocognitive impairment in first-episode bipolar
disorder and schizophrenia
Authors: Barrett Suzanne L. , Mulholland Ciaran C. , Cooper Stephen J. , Rushe Teresa M.
Published: June 2009

Background

Researching psychotic disorders in unison rather than as separate
diagnostic groups is widely advocated, but the viability of such an
approach requires careful consideration from a neurocognitive
perspective.

Aims

To describe cognition in people with bipolar disorder and schizophrenia
and to examine how known causes of variability in individual's
performance contribute to any observed diagnostic differences.

Method

Neurocognitive functioning in people with bipolar disorder
(n = 32), schizophrenia (n = 46) and
healthy controls (n = 67) was compared using analysis of
covariance on data from the Northern Ireland First Episode Psychosis
Study.

Results

The bipolar disorder and schizophrenia groups were most impaired on tests
of memory, executive functioning and language. The bipolar group
performed significantly better on tests of response inhibition, verbal
fluency and callosal functioning. Between-group differences could be
explained by the greater proclivity of individuals with schizophrenia to
experience global cognitive impairment and negative symptoms.

Conclusions

Particular impairments are common to people with psychosis and may prove
useful as endophenotypic markers. Considering the degree of individuals'
global cognitive impairment is critical when attempting to understand
patterns of selective impairment both within and between these diagnostic
groups.
Research as part of the career of a psychiatrist entering clinical practice
Authors: Fogel Joshua
Published: June 2009

This article reviews the literature on research as part of the career of a psychiatrist. Many of the reviewed articles emphasised an interest among psychiatry trainees for conducting psychiatric research. A number of reviewed articles discussed the aspects of research training experiences that lead to a career with a major research emphasis. A few articles described the percentage of time dedicated to research by academic psychiatrists. for those trainees completing their training and who plan to pursue a career as a clinician, there are still ways to incorporate research into clinical practice and continue to maintain some of the research skills that were learned as a psychiatry trainee.
Service user perspectives on the content of the undergraduate curriculum in psychiatry
Authors: Dogra Nisha , Cavendish Sue , Anderson Jill , Edwards Ruth
Published: June 2009

Aims and Method

To explore user perspectives on the content and delivery of the undergraduate curriculum in psychiatry. the study design was qualitative and used focus groups. Four focus groups were run with a total of 28 participants.

Results

The key finding was that participants were clearer about the attitudes they felt students should convey than they were about the skills and knowledge required.

Clinical Implications

Service user perspectives on the content of the undergraduate psychiatry curriculum need to be considered as curricula are developed.
Losing participants before the trial ends erodes credibility of findings
Authors: Xia Jun , Adams Clive , Bhagat Nishant , Bhagat Vinaya , Bhoopathi Paranthaman , El-Sayeh Hany , Pinfold Vanessa , Takriti Yahya
Published: June 2009

Aims and Method

To estimate the proportion of attrition at which results of drug trials for people with schizophrenia lose enough credibility to become mistrusted by relevant groups of stakeholders. A piloted questionnaire was sent to 128 local clinicians, 100 relevant researchers and 104 service users and carers.

Results

We received the biggest number of responses from the service user and carer group (n=81, 76%); 43% of clinicians and 32% of researchers responded. All three groups suggested that the follow-up rate for a 12-week schizophrenia drug trial should be around 70–75% for the trial to be credible.

Clinical Implications

This survey suggests that relevant stakeholders, including researchers, fundamentally mistrust results of the majority of drug trials in schizophrenia. Adopting a more pragmatic trial design can help address this.
Attitudes and practice in relation to first-episode psychosis: a survey of child and adult psychiatrists
Authors: Tiffin Paul A. , Gasparyan Ana
Published: June 2009

Aims and Method

Early intervention in psychosis services serving the 14–35 age range often receive input from psychiatrists from both child and adolescent as well as adult mental health services. Differences in staff attitudes or practices could potentially affect the experience of care that an individual with first-episode psychosis receives on the basis of their age. In order to investigate such potential variation a questionnaire-based survey was conducted targeting the relevant psychiatrists working in a large mental health trust in north-east England.

Results

Only subtle differences in attitudes between the two staff groups were noted. However, a number of significant differences in prescribing preferences were reported.

Clinical Implications

Attitudes towards first-episode psychosis show marked variation between psychiatrists but may not be especially associated with sub-specialty. Further national guidance should be drawn up, disseminated and implemented to help ensure that service users across the age range receive the safest and most effective medications for an episode of psychotic illness, regardless of age.
Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer
Authors: Schlumberger Martin J. , Elisei Rossella , Bastholt Lars , Wirth Lori J. , Martins Renato G. , Locati Laura D. , Jarzab Barbara , Pacini Furio , Daumerie Chantal , Droz Jean-Pierre , Eschenberg Michael J. , Sun Yu-Nien , Juan Todd , Stepan Daniel E. , Sherman Steven I.
Published: June 2009

Purpose

This phase II study investigated the efficacy and tolerability of motesanib, an investigational, highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit in advanced medullary thyroid cancer (MTC).

Patients and Methods

Patients with locally advanced or metastatic, progressive or symptomatic MTC received motesanib 125 mg/d orally for up to 48 weeks or until unacceptable toxicity or disease progression. The primary end point was objective response by independent review. Other end points included duration of response, progression-free survival, safety, pharmacokinetics, and changes in tumor markers.

Results

Of 91 enrolled patients who received motesanib, two (2%) achieved objective response (95% CI, 0.3% to 7.7%); their duration of response was 32 weeks (censored) and 21 weeks (disease progressed). Eighty-one percent of patients had stable disease (48% had durable stable disease ≥ 24 weeks), 8% had disease progression as best response, and 9% were not evaluated; 76% experienced a decrease from baseline in target lesion measurement. Median progression-free survival was 48 weeks (95% CI, 43 to 56 weeks). Among patients with tumor marker analysis, 69 (83%) of 83 and 63 (75%) of 84 had decreased serum calcitonin and carcinoembryonic antigen during treatment, respectively, compared with baseline. The most common treatment-related adverse events were diarrhea (41%), fatigue (41%), hypothyroidism (29%), hypertension (27%), and anorexia (27%). In pharmacokinetic analyses, motesanib trough concentrations were lower compared with differentiated thyroid cancer patients from the same study.

Conclusion

Although the objective response rate was low, a significant proportion of MTC patients (81%) achieved stable disease while receiving motesanib.
Insulin Resistance and Risk Factors for Cardiovascular Disease in Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia
Authors: Oeffinger Kevin C. , Adams-Huet Beverley , Victor Ronald G. , Church Timothy S. , Snell Peter G. , Dunn Andrea L. , Eshelman-Kent Debra A. , Ross Robert , Janiszewski Peter M. , Turoff Alicia J. , Brooks Sandra , Vega Gloria Lena
Published: June 2009

Purpose

To determine the prevalence of insulin resistance and other risk factors for cardiovascular disease (CVD) in young adult survivors of childhood acute lymphoblastic leukemia (ALL).

Patients and Methods

In this cross-sectional evaluation of 118 survivors of childhood ALL (median age, 23.0 years; range, 18 to 37 years), insulin resistance was estimated using the homeostasis model for assessment of insulin resistance (HOMA-IR). Sex-specific comparisons were made with a cohort of 30- to 37-year-old individuals from the same region participating in the Dallas Heart Study (DHS, N = 782). ALL survivors were stratified by treatment with and without cranial radiotherapy (CRT).

Results

Female ALL survivors had a significantly higher HOMA-IR (CRT, mean 4.6, 95% CI, 3.6 to 5.7; no CRT, mean 3.3, 95% CI, 2.8 to 3.8) in comparison with DHS women (mean 2.4, 95% CI, 2.2 to 2.7). Eighty percent of women treated with CRT had at least three of six CVD risk factors, and they were significantly more likely to have three or more risk factors compared with DHS women (odds ratio [OR], 5.96; 95% CI, 2.15 to 16.47). Male ALL survivors had a significantly higher HOMA-IR (CRT, mean 4.0, 95% CI, 2.8 to 5.6; no CRT, mean 3.4, 95% CI, 2.9 to 3.9) in comparison with DHS men (mean 2.3, 95% CI, 2.1 to 2.6), but were not more likely to have multiple CVD risk factors.

Conclusion

ALL survivors had an increased prevalence of insulin resistance in comparison with a cohort of older individuals from the same community. Importantly, women treated with CRT seem to have an increased prevalence of multiple CVD risk factors, warranting close monitoring and risk-reducing strategies.
Sensitivity to First-Line Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers
Authors: Kriege Mieke , Seynaeve Caroline , Meijers-Heijboer Hanne , Collee J. Margriet , Menke-Pluymers Marian B.E. , Bartels Carina C.M. , Tilanus-Linthorst Madeleine M.A. , Blom Jannet , Huijskens Elisabeth , Jager Agnes , van den Ouweland Ans , van Geel Bert , Hooning Maartje J. , Brekelmans Cecile T.M. , Klijn Jan G.M.
Published: June 2009

Purpose

Preclinical as well as a few small retrospective, neoadjuvant studies suggest that breast cancer (cells) without functional BRCA1 or BRCA2 protein have an increased sensitivity to some chemotherapeutic agents causing double-strand DNA breaks. In this study we assessed the sensitivity to standard first-line chemotherapy of metastatic BRCA1/2-associated breast cancer, compared with sporadic breast cancer patients.

Patients and Methods

From the Family Cancer Clinic database, we selected 93 BRCA1- and 28 BRCA2-associated breast cancer patients treated with chemotherapy for metastatic disease before January 1, 2007. Objective response (OR), progression-free survival (PFS), and overall survival (OS) after start of first-line chemotherapy were compared with those of sporadic patients, matched for year of birth, age at diagnosis of primary breast cancer, and year of detection of metastatic disease.

Results

The chemotherapy regimens most frequently used were anthracycline-based (n = 147) and cyclophosphamide, methotrexate, and fluorouracil (CMF)/CMF like (n = 68). As compared to sporadic patients, BRCA2-associated patients had a significantly higher OR (89% v 50%; P = .001), a longer PFS (hazard ratio multivariate [HRmult] 0.64; P = .04) and a prolonged OS (HRmult, 0.53; P = .005) after start of first-line chemotherapy for metastatic breast cancer. For BRCA1-associated patients, a nonsignificant trend for an increased OR (66% v 50%; P = .07), and a longer PFS (HRmult, 0.79; P = .14) after first-line chemotherapy for metastatic breast cancer was observed, but not for OS.

Conclusion

BRCA2-associated breast cancer is more sensitive to standard first-line chemotherapy for metastatic breast cancer in comparison with sporadic breast cancer, especially to anthracyclines. For BRCA1-associated breast cancer no statistically significant higher sensitivity was observed.
Building a Protocol Expressway: The Case of Mayo Clinic Cancer Center
Authors: McJoynt Terre A. , Hirzallah Muhanad A. , Satele Daniel V. , Pitzen Jason H. , Alberts Steven R. , Rajkumar S. Vincent
Published: June 2009

Purpose

Inconsistencies and errors resulting from nonstandard processes, together with redundancies, rework, and excess workload, lead to extended time frames for clinical trial protocol development. This results in dissatisfaction among sponsors, investigators, and staff and restricts the availability of novel treatment options for patients.

Methods

A team of experts from Mayo Clinic formed, including Protocol Development Unit staff and management from the three Mayo Clinic campuses (Florida, Minnesota, and Arizona), a systems and procedures analyst, a quality office analyst, and two physician members to address the identified deficiencies. The current-state process was intensively reviewed, and improvement steps were taken to accelerate the development and approval of cancer-related clinical trials. The primary goal was to decrease the time from receipt of a new protocol through submission to an approving authority, such as the National Cancer Institute or institutional review board.

Results

Using the Define, Measure, Analyze, Improve, Control (DMAIC) framework infused with Lean waste-reduction methodologies, areas were identified for improvement, including enhancing first-time quality and processing new studies on a first-in/first-out basis. The project was successful in improving the mean turnaround time for internally authored protocols (P < .001) from 25.00 weeks (n = 41; range, 3.43 to 94.14 weeks) to 10.15 weeks (n = 14; range, 4.00 to 22.14 weeks). The mean turnaround time for externally authored protocols was improved (P < .001) from 20.61 weeks (n = 85; range, 3.29 to 108.57 weeks) to 7.79 weeks (n = 50; range, 2.00 to 20.86 weeks).

Conclusion

DMAIC framework combined with Lean methodologies is an effective tool to structure the definition, planning, analysis, and implementation of significant process changes.
Improving the Methodologic and Ethical Validity of Best Supportive Care Studies in Oncology: Lessons From a Systematic Review
Authors: Cherny Nathan I. , Abernethy Amy P. , Strasser Florian , Sapir Rama , Currow David , Zafar S. Yousuf
Published: June 2009

Purpose

To systematically review the best supportive care (BSC) literature and to evaluate the ethical and methodologic validity issues by using widely acknowledged criteria.

Methods

Two search strings that included both cancer and supportive as terms (with random article type, or review or meta-analysis) explored databases from 1966 to 2008. Citations, abstracts, and papers were reviewed for inclusion criteria, and relevant data were extracted by two independent researchers. Data were validated for accuracy. Ethical and methodologic validity were evaluated by using the criteria derived from the Helsinki Requirements of the WMA; CONSORT statements for the evaluation of reports of randomized, controlled trials; and the universal requirements for ethical clinical research.

Results

Forty-three published papers were identified that described 32 studies, 20 of which incorporated the design of treatment plus supportive care (SC) versus SC alone, and 12 of which incorporated the design of treatment versus SC. Most of the studies had poor compliance to critical Helsinki requirements, to methodologic precautions derived from the CONSORT statement for studies involving a nonpharmacologic arm, and to four of seven universal requirements for ethical clinical research.

Conclusion

Lack of rigor in BSC studies has contributed to a generation of research with widespread ethical and methodologic shortcomings. Ad hoc SC and lack of standardization of SC delivery may be sources of systematic bias or error in BSC trials. Rectifying these shortcomings in future studies demands greater vigilance toward these issues by researchers, institutional review boards, editors, and peer reviewers. Given the prevalence of overlooked problems that are later identified, currently open BSC studies should be reevaluated by institutional review boards and researchers to check for ethical and methodologic validity, and identified shortcomings should be addressed.
Integrated model for supplier evaluation: Taking the machine tool industry as an example
Authors: Yu K-T , Shen C-Y , Huang D-K
Published: June 2009

An important consideration for a manufacturer is how to select, evaluate, observe, and finally create a cooperative relationship with existing or new suppliers. Previous research in this area indicates that most enterprises tend to evaluate their suppliers mainly based on quality, delivery performance, and cost. However, it is ineffective for an enterprise to only consider one of these factors when faced with an all-round competitive environment. An analysis tool that can simultaneously integrate numerical decision criteria would be more useful, especially for the machine tool industry with its high proportion of outsourcing operations, short lead times, multiple component categories, and small batches. In an effort to meet this need, an integrated performance evaluation model, using multiple indices that construct a suppliers’ integrated evaluation chart (SIEC), is presented in this study. This model can aid managers to understand the problems encountered by their suppliers and lead them to solutions for these problems that are mutually beneficial. Finally, this study offers an illustration of a Taiwanese machine tool manufacturer's use of the SIEC in a practical application.
Manufacturing performance optimization: The simulation—expert mechanism approach
Authors: Mebrahtu H , Walker R , Dionysopoulos T , Mileham T
Published: June 2009

This paper presents an expert mechanism approach to manufacturing performance optimization using simulation as the base tool. The expert mechanism is integrated to the back end of a manufacturing simulator to interpret manufacturing simulation results, assess performance, and then, consistent with set constraints, to effect changes on controllable variables prior to the next run to improve performance. The expert mechanism has a knowledge base that includes proven operations management performance-enhancing methods. In contrast, existing commercial simulation-optimization methods use meta-heuristics in which a near-optimum value is searched from a population of alternative solutions, which can be inefficient in terms of time and cost. The findings of a real case study from a world-class manufacturing company are discussed to demonstrate the expert mechanism and compare it with one of the widely used commercial simulation optimizers.
Combining tolerance design and monitoring process capability in a design-manufacturing integration procedure
Authors: Yu K-T , Shen C-Y
Published: June 2009

Traditionally, tolerance design and process capability control for new product development belong to the design and manufacturing stages respectively. In fact, they determine the finished product's cost, function, and quality, and should be considered concurrently. This paper provides a design—manufacturing integration procedure to enhance the efficiency of new product development. The procedure includes a total cost analysis, process capability indices, and an altered Ix - Iy monitoring chart. In particular, the process capability indices are considered in the total cost function in order to establish the relationship between quality variability and tolerance design. The use of this procedure should help designers to determine the optimum tolerance when considering not only the total cost but also the level of process capability that a manufacturer can supply. Similarly, it also can help manufacturers to simply and accurately indicate the status of their production in meeting the required tolerance levels. Finally, the proposed procedure is applied to an assembly study to illustrate how the proposed procedure can be employed in practice.
An experimental investigation of chatter effects on tool life
Authors: Kayhan M , Budak E
Published: June 2009

Tool wear is one of the most important considerations in machining operations, as it affects surface quality and integrity, productivity, and cost. The most commonly used model for tool life analysis is the one proposed by F. W. Taylor about a century ago. Although the extended form of this equation includes the effects of important cutting conditions on tool wear, tool life studies are mostly performed under stable cutting conditions where the effect of chatter vibrations are not considered. This paper presents an empirical attempt to understand tool life under vibratory cutting conditions. Tool wear data are collected in turning and milling on different work materials under stable and chatter conditions. The effects of cutting conditions as well as severity of chatter on tool life are analysed. The results indicate significant reduction in tool life on account of chatter, as expected. They also show that the severity of chatter, and thus the vibration amplitude, greatly reduce the life of cutting tools. These results can be useful in evaluating the real cost of chatter by including the reduced tool life. They can also be useful in justifying the cost of chatter suppression and more rigid machining systems.
The effects of geometric offsets on the dynamic responses of a Scott—Russell amplifying mechanism with flexible hinges
Authors: Chen C-M , Fung R-F
Published: June 2009

The dynamic equations of a micro-positioning Scott—Russell (SR) mechanism associated with two flexible hinges and an offset are developed to calculate output responses. Both rigid and flexible hinges are considered to explore the results. The main features in the kinematics of the SR mechanism are its displacement amplification and straight-line motion, which are widely needed in practical industries. The manufacturing inaccuracy of the SR mechanism definitely causes geometric offsets of flexure hinges, and affects displacement amplification and straight-line output motion. Analytical models based on kinematics and Hamilton's principle are derived to explore the variation of linearity ratio, magnification factor, and deviation factor due to various offsets and link lengths. From numerical simulations for the SR mechanism with various offsets of flexible hinges in the conditions of different link lengths, it is found that offsets of flexure hinges obviously affect the amplifying factor and linearity ratio, and appear to dominate the changes of magnification factors. Moreover, an analytical model is also used to predict magnification factors due to various offsets. Finally, some conclusions concerning the effects of offset on the performance of the SR mechanism are drawn.
A generalized theory for shaft—hub couplings
Authors: Croccolo D , Vincenzi N
Published: June 2009

The design of compression-fit joints, based on the theory of thick-walled cylinders, is usually referred to shaft—hub couplings carried out between two elements that have an axial symmetric shape. The stress distributions both inside the elements and on the contact surfaces can be defined by the equilibrium and by the compatibility formulae once the total radial interference and the internal and external pressure (the boundary conditions) are known. The complete tensile state of the coupling is defined by two principal stresses: the radial and the hoop tensions.

The present article aims at extending the analytic calculation valid for two elements to a number of n elements by means of a sequential solution of the governing equation system. The elements in contact can rotate at a generic angular velocity and can, also, be made of different materials. The overall solution has been derived starting from the hypothesis of the simultaneous presence of axial symmetric geometries and axial symmetric loads. The mathematical model has been verified by comparing the theoretical results with some finite-element analysis calculations performed on the same coupled elements.
The effect of chitosan content on the crystallinity, thermal stability, and mechanical properties of bacterial cellulose—chitosan composites
Authors: Cai Z , Chen P , Jin H-J , Kim J
Published: June 2009

A bacterial cellulose—chitosan (BC—Chi) composite has been successfully prepared by immersing wet BC pellicle in chitosan acetic acid solution followed by freeze-drying. By changing chitosan concentration and immersion time, a foam-like structure is made with the chitosan content in the range of 12—45 per cent. Scanning electron microscope images show that chitosan molecules can penetrate into BC forming a multi-layer structure. This foam has a very well interconnected porous network structure. The X-ray diffraction patterns indicate that with the increase in chitosan content, the crystalline structure is not changed but the crystallinity index tends to decrease. The thermal degradation temperature increases from 263 to 366 °C with the chitosan content increasing from 12 to 45 per cent. The tensile test results show that the tensile strength and Young's modulus of BC—Chi composites tend to decrease with the increase in chitosan content but the value is much higher than that of pure chitosan. This improved elasticity of the BC—Chi composites is important for biomedical applications.
Measuring fracture toughness from machining tests
Authors: Patel Y , Blackman B R K , Williams J G
Published: June 2009

An analysis of the forces involved in orthogonal cutting or machining is presented in which yielding on a shear plane is assumed. The fracture toughness Gc is included and it is observed that Gc may be determined by measuring the cutting and transverse forces together with the chip thickness for a range of cutting depths. This latter measurement enabled the shear plane angle ϕ to be determined experimentally. A simplified version of the analysis is also given in which ϕ is predicted by a cutting force minimization scheme. Neither scheme requires any details of the friction condition to be known since the transverse force is sufficient information for any type to be included in the analysis. A friction model including a coefficient of friction and an adhesion toughness is also utilized. Data for both polymer and metal cutting are taken from the literature and Gc is determined. In some datasets the tool rake angle α is also varied and the values of Gc and the yield stress σY are found to be independent of α. The force minimization method gives a good estimate of ϕ for most polymers. For metals (aluminium alloy, steel, and brass) the method worked well. For aluminium alloy Gc was independent of α and the predicted and measured ϕ values agreed. For steel and brass this was not so. Gc was mostly independent of α except at low values where high values of Gc were observed. A constant value of the coefficient of friction was observed for each α value but values for both the coefficient of friction and the adhesion toughness varied significantly with increasing rake angle.
Analysis of bonded finite wedges with an interfacial crack under antiplane shear loading
Authors: Shahani A R , Ghadiri M
Published: June 2009

Antiplane shear deformation of bonded finite wedges with an interface crack is studied in this article. The traction-free condition is imposed on the circular segment of the wedge. Boundary conditions on the radial edges are considered as traction—traction. In order to solve this problem a novel mathematical technique has been employed. This technique consists of the use of some recently proposed finite complex transforms, which have complex analogies to the standard finite Mellin transforms of the first and second kinds. However, for the problem of bonded wedges with an interfacial crack, first it is necessary to express the traction-free condition of the crack faces in the form of a singular integral equation, which is done in this article by describing an exact analytical method. The resultant singular integral equations are then solved numerically and the obtained results including the stress intensity factors at the crack tips are plotted. Comparison of the results in the special cases shows a complete agreement with those cited in the literature.
Laboratory investigation of drillstring vibrations
Authors: Khulief Y A , Al-Sulaiman F A
Published: June 2009

Experimental investigations of drillstring dynamics are essential to complement the theoretical studies and to alleviate the complexity of such dynamic models. This article presents an experimental investigation using a specially designed drilling test rig. The test rig can simulate the drillstring vibrational response because of various excitation mechanisms, including stick-slip, well—borehole contact, and drilling fluid interaction. The test rig is driven by a variable speed motor that allows for testing different drilling speeds, while a magnetic tension brake is used to simulated stick-slip. In addition, a shaker is employed to excite the drillstring axially in order to simulate the weight-on-bit. The drillstring is instrumented for vibration measurements. The experimental measurements in conjunction with the finite-element mathematical model of the drillstring are used to characterize and tune some modelling parameters. Comparisons with published data demonstrate the reliability of the developed scheme for prediction of drillstring vibrations.