bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative genomics using Fugu reveals insights into regulatory subfunctionalization
Authors: Woolfe Adam , Elgar Greg
Published: April 2007

Background

A major mechanism for the preservation of gene duplicates in the genome is thought to be mediated via loss or modification of cis-regulatory subfunctions between paralogs following duplication (a process known as regulatory subfunctionalization). Despite a number of gene expression studies that support this mechanism, no comprehensive analysis of regulatory subfunctionalization has been undertaken at the level of the distal cis-regulatory modules involved. We have exploited fish-mammal genomic alignments to identify and compare more than 800 conserved non-coding elements (CNEs) that associate with genes that have undergone fish-specific duplication and retention.

Results

Using the abundance of duplicated genes within the Fugu genome, we selected seven pairs of teleost-specific paralogs involved in early vertebrate development, each containing clusters of CNEs in their vicinity. CNEs present around each Fugu duplicated gene were identified using multiple alignments of orthologous regions between single-copy mammalian orthologs (representing the ancestral locus) and each fish duplicated region in turn. Comparative analysis reveals a pattern of element retention and loss between paralogs indicative of subfunctionalization, the extent of which differs between duplicate pairs. In addition to complete loss of specific regulatory elements, a number of CNEs have been retained in both regions but may be responsible for more subtle levels of subfunctionalization through sequence divergence.

Conclusion

Comparative analysis of conserved elements between duplicated genes provides a powerful approach for studying regulatory subfunctionalization at the level of the regulatory elements involved.
The innate immune repertoire in Cnidaria - ancestral complexity and stochastic gene loss
Authors: Miller David J , Hemmrich Georg , Ball Eldon E , Hayward David C , Khalturin Konstantin , Funayama Noriko , Agata Kiyokazu , Bosch Thomas CG
Published: April 2007

Background

Characterization of the innate immune repertoire of extant cnidarians is of both fundamental and applied interest - it not only provides insights into the basic immunological 'tool kit' of the common ancestor of all animals, but is also likely to be important in understanding the global decline of coral reefs that is presently occurring. Recently, whole genome sequences became available for two cnidarians, Hydra magnipapillata and Nematostella vectensis, and large expressed sequence tag (EST) datasets are available for these and for the coral Acropora millepora.

Results

To better understand the basis of innate immunity in cnidarians, we scanned the available EST and genomic resources for some of the key components of the vertebrate innate immune repertoire, focusing on the Toll/Toll-like receptor (TLR) and complement pathways. A canonical Toll/TLR pathway is present in representatives of the basal cnidarian class Anthozoa, but neither a classic Toll/TLR receptor nor a conventional nuclear factor (NF)-κB could be identified in the anthozoan Hydra. Moreover, the detection of complement C3 and several membrane attack complex/perforin domain (MAC/PF) proteins suggests that a prototypic complement effector pathway may exist in anthozoans, but not in hydrozoans. Together with data for several other gene families, this implies that Hydra may have undergone substantial secondary gene loss during evolution. Such losses are not confined to Hydra, however, and at least one MAC/PF gene appears to have been lost from Nematostella.

Conclusion

Consideration of these patterns of gene distribution underscores the likely significance of gene loss during animal evolution whilst indicating ancient origins for many components of the vertebrate innate immune system.
On the functions of the h subunit of eukaryotic initiation factor 3 in late stages of translation initiation
Authors: Kim Byung-Hoon , Cai Xue , Vaughn Justin N , von Arnim Albrecht G
Published: April 2007

Background

The eukaryotic translation initiation factor 3 (eIF3) has multiple roles during the initiation of translation of cytoplasmic mRNAs. How individual subunits of eIF3 contribute to the translation of specific mRNAs remains poorly understood, however. This is true in particular for those subunits that are not conserved in budding yeast, such as eIF3h.

Results

Working with stable reporter transgenes in Arabidopsis thaliana mutants, it was demonstrated that the h subunit of eIF3 contributes to the efficient translation initiation of mRNAs harboring upstream open reading frames (uORFs) in their 5' leader sequence. uORFs, which can function as devices for translational regulation, are present in over 30% of Arabidopsis mRNAs, and are enriched among mRNAs for transcriptional regulators and protein modifying enzymes. Microarray comparisons of polysome loading in wild-type and eif3h mutant seedlings revealed that eIF3h generally helps to maintain efficient polysome loading of mRNAs harboring multiple uORFs. In addition, however, eIF3h also boosted the polysome loading of mRNAs with long leaders or coding sequences. Moreover, the relative polysome loading of certain functional groups of mRNAs, including ribosomal proteins, was actually increased in the eif3h mutant, suggesting that regulons of translational control can be revealed by mutations in generic translation initiation factors.

Conclusion

The intact eIF3h protein contributes to efficient translation initiation on 5' leader sequences harboring multiple uORFs, although mRNA features independent of uORFs are also implicated.
Evolutionary conservation of sequence and secondary structures in CRISPR repeats
Authors: Kunin Victor , Sorek Rotem , Hugenholtz Philip
Published: April 2007

Background

Clustered regularly interspaced short palindromic repeats (CRISPRs) are a novel class of direct repeats, separated by unique spacer sequences of similar length, that are present in approximately 40% of bacterial and most archaeal genomes analyzed to date. More than 40 gene families, called CRISPR-associated sequences (CASs), appear in conjunction with these repeats and are thought to be involved in the propagation and functioning of CRISPRs. It has been recently shown that CRISPR provides acquired resistance against viruses in prokaryotes.

Results

Here we analyze CRISPR repeats identified in 195 microbial genomes and show that they can be organized into multiple clusters based on sequence similarity. Some of the clusters present stable, highly conserved RNA secondary structures, while others lack detectable structures. Stable secondary structures exhibit multiple compensatory base changes in the stem region, indicating evolutionary and functional conservation.

Conclusion

We show that the repeat-based classification corresponds to, and expands upon, a previously reported CAS gene-based classification, including specific relationships between CRISPR and CAS subtypes.
Discovery of tissue-specific exons using comprehensive human exon microarrays
Authors: Clark Tyson A , Schweitzer Anthony C , Chen Tina X , Staples Michelle K , Lu Gang , Wang Hui , Williams Alan , Blume John E
Published: April 2007

Background

Higher eukaryotes express a diverse population of messenger RNAs generated by alternative splicing. Large-scale methods for monitoring gene expression must adapt in order to accurately detect the transcript variation generated by this splicing.

Results

We have designed a high-density oligonucleotide microarray with probesets for more than one million annotated and predicted exons in the human genome. Using these arrays and a simple algorithm that normalizes exon signal to signal from the gene as a whole, we have identified tissue-specific exons from a panel of 16 different normal adult tissues. RT-PCR validation confirms approximately 86% of the predicted tissue-enriched probesets. Pair-wise comparisons between the tissues suggest that as many as 73% of detected genes are differentially alternatively spliced. We also demonstrate how an inclusive exon microarray can be used to discover novel alternative splicing events. As examples, 17 new tissue-specific exons from 11 genes were validated by RT-PCR and sequencing.

Conclusion

In conjunction with a conceptually simple algorithm, comprehensive exon microarrays can detect tissue-specific alternative splicing events. Our data suggest significant expression outside of known exons and well annotated genes and a high frequency of alternative splicing events. In addition, we identified and validated a number of novel exons with tissue-specific splicing patterns. The tissue map data will likely serve as a valuable source of information on the regulation of alternative splicing.
Growth control of the eukaryote cell: a systems biology study in yeast
Authors: Castrillo Juan I , Zeef Leo A , Hoyle David C , Zhang Nianshu , Hayes Andrew , Gardner David CJ , Cornell Michael J , Petty June , Hakes Luke , Wardleworth Leanne , Rash Bharat , Brown Marie , Dunn Warwick B , Broadhurst David , O'Donoghue Kerry , Hester Svenja S , Dunkley Tom PJ , Hart Sarah R , Swainston Neil , Li Peter , Gaskell Simon J , Paton Norman W , Lilley Kathryn S , Kell Douglas B , Oliver Stephen G
Published: April 2007

Background

Cell growth underlies many key cellular and developmental processes, yet a limited number of studies have been carried out on cell-growth regulation. Comprehensive studies at the transcriptional, proteomic and metabolic levels under defined controlled conditions are currently lacking.

Results

Metabolic control analysis is being exploited in a systems biology study of the eukaryotic cell. Using chemostat culture, we have measured the impact of changes in flux (growth rate) on the transcriptome, proteome, endometabolome and exometabolome of the yeast Saccharomyces cerevisiae. Each functional genomic level shows clear growth-rate-associated trends and discriminates between carbon-sufficient and carbon-limited conditions. Genes consistently and significantly upregulated with increasing growth rate are frequently essential and encode evolutionarily conserved proteins of known function that participate in many protein-protein interactions. In contrast, more unknown, and fewer essential, genes are downregulated with increasing growth rate; their protein products rarely interact with one another. A large proportion of yeast genes under positive growth-rate control share orthologs with other eukaryotes, including humans. Significantly, transcription of genes encoding components of the TOR complex (a major controller of eukaryotic cell growth) is not subject to growth-rate regulation. Moreover, integrative studies reveal the extent and importance of post-transcriptional control, patterns of control of metabolic fluxes at the level of enzyme synthesis, and the relevance of specific enzymatic reactions in the control of metabolic fluxes during cell growth.

Conclusion

This work constitutes a first comprehensive systems biology study on growth-rate control in the eukaryotic cell. The results have direct implications for advanced studies on cell growth, in vivo regulation of metabolic fluxes for comprehensive metabolic engineering, and for the design of genome-scale systems biology models of the eukaryotic cell.
Anabolic androgenic steroids: what the psychiatrist needs to know
Authors: Rashid Harry , Ormerod Sara , Day Ed
Published: April 2007

Anabolic androgenic steroids (commonly known as anabolic steroids) are synthetic derivatives of the hormone testosterone. They are being increasingly used by professional and recreational athletes to enhance performance, and by men and women to improve physical appearance. This article discusses the characteristics of such steroid ‘misusers’ and the techniques of use. It highlights the psychiatric complications associated with these steroids, including increased risk of aggression, personality disorders, psychosis and mood disorders, particularly manic symptoms. Medical complications of steroid use are common and frequently reversible. Use is associated with an increased risk of injury, cardiovascular events, gastrointestinal complications, virilisation in women, and gynaecomastia and testicular atrophy in men. Whether addiction to these steroids can occur is debatable, but there is evidence for dependence and a withdrawal syndrome. Steroid use may be a ‘gateway’ to other addictions. Users are often reluctant to seek treatment and the psychiatrist's role in the recognition and management of use is presented.
Fabrication and induction of illness in children: the psychopathology of abuse
Authors: Bass Christopher , Adshead Gwen
Published: April 2007

Fabricating or inducing illness in children (previously called Munchhausen syndrome by proxy) is a form of child abuse in which a caregiver falsifies illness in a child by fabricating or producing symptoms and presenting the child for medical care disclaiming knowledge of the cause of the problem. The behaviour has attracted considerable interest and controversy, and some have questioned its existence. In this article, we assess the prevalence of the behaviour, describing behaviours that have been reported and identified, and discuss its psychopathology. We consider the role of psychiatric expertise in the investigation of such behaviour and in the assessment of those who carry it out, based on what is known to date about their psychopathology. We also outline an approach to management with special reference to the characteristics in the mother that may allow for reunification with the child after the abuse has been established.
Repeated self-injury from a liaison psychiatry perspective
Authors: Broadhurst Mark , Gill Paul
Published: April 2007

Self-injury (self-harm) occurs frequently and is familiar in the accident and emergency departments and surgical and medical wards of ‘acute hospitals’. Despite its common presentation, there are frequent and authoritative reports that patients' experiences of emergency hospital treatment for self-harm are often negative. There is compelling evidence for the need to improve delivery of care for patients who self-harm, and to improve the training, supervision, support and coordination of the staff groups delivering that care.
Debt and mental health: the role of psychiatrists
Authors: Fitch Chris , Chaplin Robert , Trend Colin , Collard Sharon
Published: April 2007

One in four people with mental health problems in Britain report debt or arrears, which is nearly three times the rate among individuals without similar conditions. Although health professionals commonly encounter debt among patients, some report that they lack basic knowledge to effectively intervene and that patient debt is often not acted on until a crisis emerges. Our aim in this article is to improve psychiatrists' knowledge and confidence in dealing with patient debt. We provide basic definitions of debt and problem debt; outline the impact that debt can have on patients' health, social and financial well-being; identify the stages and signs that a patient may be accruing problem debt; describe how psychiatrists should respond; and review the instruments available to assess patients' mental capacity to make financial decisions. We do not expect psychiatrists to become ‘debt experts’, but provide working knowledge for engaging more effectively with this problem.
Persistent violent offending: what do we know?
Authors: Hodgins Sheilagh
Published: April 2007

A great deal is known about men who display a stable pattern of antisocial behaviour since childhood. However, more research is needed to identify subtypes within this population so as to further understanding of the causal processes that initiate and maintain violent behaviours and to identify interventions that specifically target the deficits presented by each subtype. Evidence-based practice means not only using treatments proven to be effective but also basing conceptualisations of disorders on scientific evidence.
Precision of actuarial risk assessment instruments
Authors: Hart Stephen D. , Michie Christine , Cooke David J.
Published: April 2007

Background

Actuarial risk assessment instruments (ARAIs) estimate the probability that individuals will engage in future violence.

Aims

To evaluate the ‘margins of error’ at the group and individual level for risk estimates made using ARAIs.

Method

An established statistical method was used to construct 95% CI for group and individual risk estimates made using two popular ARAIs.

Results

The 95% CI were large for risk estimates at the group level; at the individual level, they were so high as to render risk estimates virtually meaningless.

Conclusions

The ARAIs cannot be used to estimate an individual's risk for future violence with any reasonable degree of certainty and should be used with great caution or not at all. In theory, reasonably precise group estimates could be made using ARAIs if developers used very large construction samples and if the tests included few score categories with extreme risk estimates.
Collecting service use data for economic evaluation in DSPD populations
Authors: Barrett Barbara , Byford Sarah
Published: April 2007

Background

Economic evaluation of the Dangerous and Severe Personality Disorder Programme is essential to ensure value for money. The collection of individual-level service use information is crucial to any such evaluation, but the best way to collect these data in secure facilities is unclear.

Aims

To develop a method for the collection of individual-level service use information for prisoners/patients in secure facilities.

Methods

Services provided within secure facilities were identified through examination of facility and policy literature, and discussions with managerial and clinical staff. Appropriate methods of measuring the quantities of services used were then explored and a new research tool capable of capturing all relevant services was developed and pilot tested.

Results

The Secure Facilities Service Use Schedule (SF–SUS) records service use information from records and is capable of capturing data on the use of all individual-level services provided within a secure facility plus external services commonly accessed by occupants.

Discussion

The SF–SUS is able to collect meaningful individual-level service use information for the economic evaluation of services provided within secure facilities.
Personality disorder and impaired functioning from adolescence to adulthood
Authors: Skodol Andrew E. , Johnson Jeffrey G. , Cohen Patricia , Sneed Joel R. , Crawford Thomas N.
Published: April 2007

Background

Little is currently known about functioning and impairment during adulthood associated with the course of personality disorders.

Aims

To investigate the association of personality disorder stability from adolescence through middle adulthood with measures of global functioning and impairment, using prospective epidemiological data.

Method

A community-based sample of 658 individuals was interviewed at mean ages 14, 16, 22 and 33 years.

Results

Individuals with persistent personality disorder had markedly poorer functioning and greater impairment at mean age 33 years than did those who had never been identified as having such disorder or who had a personality disorder that was in remission, after co-occurring Axis I disorders at age 33 years were taken into account. Remitted disorder was associated with mild long-term impairment. Adult-onset personality disorders, however, were also associated with significant impairment.

Conclusions

Persistent and adult-onset personality disorders are associated with functional impairment among adults in the community. These effects are independent of co-occurring Axis 1 disorders.
Cognitive remediation therapy in schizophrenia
Authors: Wykes Til , Reeder Clare , Landau Sabine , Everitt Brian , Knapp Martin , Patel Anita , Romeo Renee
Published: April 2007

Background

Cognitive difficulties are prevalent in people with a diagnosis of schizophrenia and are associated with poor long-term functioning.

Aims

To evaluate the effectiveness of cognitive remediation therapy on cognitive difficulties experienced by people with schizophrenia.

Method

Participants with a diagnosis of schizophrenia, a social behaviour problem and a cognitive difficulty (n=85) were randomised to 40 sessions of cognitive remediation or treatment as usual in a single-blind randomised controlled trial. Working memory, cognitive flexibility and planning, were measured at weeks 0, 14 and 40.

Results

There were durable improvements in working memory (advantage 1.33 points, 95% CI 0.43–2.16, standardised effect size 0.34) as well as an indication of improvement in cognitive flexibility. Memory improvement predicted improvement in social functioning. Costs were lower in the cognitive remediation group following therapy but rose at follow-up. However, cost-effectiveness analyses showed that improvements in memory were achieved at little additional cost.

Conclusions

Cognitive remediation therapy is associated with durable improvements in memory, which in turn are associated with social functioning improvements in people with severe mental illness.
Chinese herbal medicine for schizophrenia
Authors: Rathbone John , Zhang Lan , Zhang Mingming , Xia Jun , Liu Xiehe , Yang Yanchun , Adams Clive Elliott
Published: April 2007

Background

Chinese herbal medicine has been used to treat millions of people with schizophrenia for thousands of years.

Aims

To evaluate Chinese herbal medicine as a treatment for schizophrenia.

Method

A systematic review of randomised controlled trials (RCTs).

Results

Seven trials were included. Most studies evaluated Chinese herbal medicine in combination with Western antipsychotic drugs; in these trials results tended to favour combination treatment compared with antipsychotic alone (Clinical Global Impression ‘not improved/worse’ n= 123, RR=0.19, 95% CI 0.1-0.6, NNT=6,95% CI 5–11; n=109, Brief Psychiatric Rating Scale ‘not improved/worse’ RR=0.78,95% CI 0.5-1.2; n=109, Scale for the Assessment of Negative Symptoms ‘not improved/worse’ RR=0.87,95% CI 0.7-1.2; n= 109, Scale for the Assessment of Positive Symptoms ‘not improved/worse’ RR=0.69,95% CI 0.5-1.0, NNT=6 95% CI 4-162). Medium-term study attrition was significantly less for people allocated the herbal/antipsychotic mix (n=897, four RCTs, RR=0.34,95% CI 0.2–0.7, NNT=23,95% CI 18-43).

Conclusions

Results suggest that combining Chinese herbal medicine with antipsychotics is beneficial.
Prison mental health inreach services
Authors: Steel Julie , Thornicroft Graham , Birmingham Luke , Brooker Charlie , Mills Alice , Harty Mari , Shaw Jenny
Published: April 2007

Prison mental health inreach teams have been established nationwide in England and Wales over the past 3 years to identify and treat mental disorders among prisoners. This paper summarises the policy content and what has been achieved thus far, and poses challenges that these teams face if they are to become a clear and effective component in the overall system of forensic mental healthcare.
Acute in-patient psychiatry: how patients spend their time on acute psychiatric wards
Authors: Radcliffe Jonathan , Smith Roger
Published: April 2007

Aims and Method

We observed levels of social interaction and activity among in-patients on 16 acute psychiatric wards in 6 hospitals in a large mental health trust. Each ward was observed for 1 week and attendance at organised activities was audited over 3-week periods.

Results

At any time during the day 84% of in-patients were socially disengaged and mainly inactive. On average only 4% of in-patients' time was spent in an organised group activity, with many in-patients opting out altogether. Provision and take-up of group activity programmes varied widely between wards.

Clinical Implications

Provision of organised activity needs to be a higher priority in acute services, and there should be national and local standards for what should be provided. Concerted organisational strategies and assertive approaches by staff are needed to engage in-patients in group activity programmes.
Basic competency testing to meet Clinical Negligence Scheme for Trusts standards
Authors: Kloer Mary , Mynors-Wallis Laurence , Cope Denise
Published: April 2007

Aims and Method

In order to meet revised (2005) Clinical Negligence Scheme for Trusts standards, tests of competency in key clinical skills were set for psychiatric senior house officers (SHOs) at the start of their posts.

Results

The assessment of basic competencies demonstrated that 9 out of 14 SHOs met the required standards in tests of key clinical skills (overall competency rate of 64%). Senior house officers were generally in agreement with the principles behind the assessments.

Clinical Implications

Competency testing is becoming important at all stages of training and within all medical specialties. The recommended methods combine assessment of both knowledge-based competencies and clinical performance in the workplace.
Effects of a crisis resolution and home treatment team on in-patient admissions
Authors: Jethwa Krishma , Galappathie Nuwan , Hewson Paul
Published: April 2007

Aims and Method

To evaluate the effects of a crisis resolution and home-based treatment team upon in-patient admission rates. We collected data for 2 years prior and 1 year post-implementation of such a service in Leeds. The chosen time frame allowed the new service to settle in and controlled for seasonal variations.

Results

There were 4353 admissions during the period of the study, with 3325 in the 2 years prior to the service and 1028 in the year after. Generalised linear analysis found a 37.5% reduction in monthly admissions after the introduction of the team (P < 0.0001).

Clinical Implications

This study shows that in everyday clinical practice crisis resolution and home treatment teams lead to a sustained reduction in in-patient admission rates.
The Molecular Biology of SARS Coronavirus
Authors: SATIJA NAMITA , LAL SUNIL K.
Published: April 2007

Abstract:  Severe acute respiratory syndrome (SARS) is the first emerging infectious disease of the 21st century that has been highly transmissible and fatal and was caused by a previously unknown coronavirus (SARS‐CoV). The SARS epidemic in 2003 resulted in more than 8400 SARS cases and approximately 800 deaths. Existing in non‐identified animal reservoirs, SARS‐CoV continues to represent a threat to humans although more than four years have passed since a large outbreak of SARS, and no new cases have been reported. However, we cannot exclude the possibility of reemergence of SARS. It is hence necessary to understand the biology of the SARS‐CoV to deal adequately with the next outbreak, whenever it happens. The SARS‐CoV is a novel coronavirus with a large (∼30 thousand nucleotides) positive‐sense, single‐stranded RNA containing 14 functional open reading frames (ORFs) of which 2 large ORFs constitute the replicase gene which encodes proteins required for viral RNA syntheses. The remaining 12 ORFs encode the 4 structural proteins: spike, membrane, nucleocapsid and envelope; and eight accessory proteins. The viral genome and its expression within the host cell undergoes extensive translational and enzymatic processing to form the 4 structural, 8 accessory and 16 nonstructural proteins. In an effort to understand the molecular mechanisms or capsid assembly and viral pathogenesis, laboratories around the world have adopted a variety of approaches to answering these trivial questions. It has been our effort to consolidate all information known to date about the molecular mechanisms of the SARS‐CoV into this chapter to update our readership on the current status of research.
Signal Transduction in SARS‐CoV‐Infected Cells
Authors: MIZUTANI T.
Published: April 2007

Abstract:  Severe acute respiratory syndrome (SARS) is a newly found infectious disease that is caused by a novel human coronavirus, SARS coronavirus (SARS‐CoV). Because the mortality rate of SARS patients is very high, understanding the pathological mechanisms of SARS not only in vivo but in vitro is important for the prevention of SARS. Activation of signaling pathways caused by SARS‐CoV infection leads to the phosphorylation and activation of downstream molecules. Two conflicting cellular programs, apoptosis to eliminate virus‐infected cells and survival to delay apoptosis by producing antiviral cytokines, occur in SARS patients. Recent studies regarding SARS and SARS‐CoV have clarified that activation of mitogen‐activated protein kinases (MAPKs) plays important roles in upregulation of cytokine expression and apoptosis both in vitro and in vivo. Both Akt and p38 MAPK are keys for determination of cell survival or death in SARS‐CoV‐infected cells in vitro. Agents being developed to target these signaling cascades may be important for the design of anti‐SARS‐CoV drugs. This review highlights recent progress regarding SARS‐CoV biology, especially signal transduction in SARS‐CoV‐infected cells.
Bioproduction of Therapeutic Proteins in the 21st Century and the Role of Plants and Plant Cells as Production Platforms
Authors: BOEHM ROBERT
Published: April 2007

Abstract:  In the last decade, the technique to genetically modify crop plants has gained more and more interest in terms of bioproduction of heterologous proteins. Plants have been discovered as a possible source for large amounts of cost effective recombinant protein. Main application fields are therapeutics for use in animal and human health, diagnostics, and technical enzymes. This review is focused on the recent progress in this field of molecular farming. After a comparison with hitherto established protein production systems, the advantages of plants as an alternative production system are discussed. An overview about the different host plants and possible expression strategies is given and the progress in commercialization of the techniques is highlighted. Finally, the role of plant cell cultures for the production of recombinant proteins is discussed.
Correlation of Computed Tomography and Positron Emission Tomography in Patients With Metastatic Gastrointestinal Stromal Tumor Treated at a Single Institution With Imatinib Mesylate: Proposal of New Computed Tomography Response Criteria
Authors: Choi Haesun , Charnsangavej Chuslip , Faria Silvana C. , Macapinlac Homer A. , Burgess Michael A. , Patel Shreyaskumar R. , Chen Lei L. , Podoloff Donald A. , Benjamin Robert S.
Published: April 2007

Purpose

Response Evaluation Criteria in Solid Tumors (RECIST) are insensitive in evaluating gastrointestinal stromal tumors (GISTs) treated with imatinib. This study evaluates whether computed tomography (CT) findings of GIST after imatinib treatment correlate with tumor responses by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and develops reliable, quantitative, CT response criteria.

Patients and Methods

A total of 172 lesions selected by RECIST were evaluated in 40 patients with metastatic GISTs treated with imatinib. All patients had pretreatment and 2-month follow-up CTs and FDG-PETs. Multivariate analysis was performed using tumor size and density (Hounsfield unit [HU]) on CT and maximum standardized uptake value (SUVmax) on FDG-PET. Patients were observed up to 28 months.

Results

Mean baseline tumor size and density on CT were 5.3 cm and 72.8 HU, respectively, and mean baseline SUVmax on FDG-PET was 5.8. Thirty-three patients had good response on FDG-PET. A decrease in tumor size of more than 10% or a decrease in tumor density of more than 15% on CT had a sensitivity of 97% and a specificity of 100% in identifying PET responders versus 52% and 100% by RECIST. Good responders on CT at 2 months had significantly longer time to progression than those who did not respond (P = .01).

Conclusion

Small changes in tumor size or density on CT are sensitive and specific methods of assessing the response of GISTs. If the prognostic value of our proposed CT response criteria can be confirmed prospectively, the criteria should be employed in future studies of patients with GIST.
Death in Patients With Recurrent Prostate Cancer After Radical Prostatectomy: Prostate-Specific Antigen Doubling Time Subgroups and Their Associated Contributions to All-Cause Mortality
Authors: Freedland Stephen J. , Humphreys Elizabeth B. , Mangold Leslie A. , Eisenberger Mario , Dorey Frederick J. , Walsh Patrick C. , Partin Alan W.
Published: April 2007

Purpose

Among patients with biochemical recurrence after radical prostatectomy, we found previously that postoperative prostate-specific antigen doubling time (PSADT) was associated with risk of prostate cancer death. However, given the small number of patients in the highest risk PSADT subgroup, it is unclear which PSADT subgroups contribute the greatest to prostate cancer–specific death and how this influences all-cause mortality.

Patients and Methods

This study was a retrospective analysis of 379 patients treated with radical prostatectomy between 1982 and 2000 who had a biochemical recurrence and PSADT data available. Mean and median follow-up after surgery was 11.4 (standard deviation, 5.4) and 11.0 years, respectively (range, 1.6 to 23.0 years).

Results

Shorter PSADT was significantly associated with prostate cancer–specific and all-cause mortality (P < .001). Although patients with a PSADT less than 3 months were at the greatest risk of death, because of the limited number of patients in this group, they accounted for only 13% of prostate cancer deaths at 15 years after biochemical recurrence, whereas patients with an intermediate PSADT (3.0 to 8.9 months) accounted for 58% of all prostate cancer deaths. Among patients with a PSADT less than 15 months, prostate cancer accounted for 90% of all deaths. Only patients in the slowest PSADT subgroup (≥ 15 months) had a greater risk of competing-causes mortality compared with that from prostate cancer.

Conclusion

Among a select cohort of young, healthy patients with PSA recurrence after radical prostatectomy and a PSADT less than 15 months, prostate cancer accounted for an estimated 90% of all deaths by 15 years after recurrence. The majority of prostate cancer deaths occurred among patients with an intermediate PSADT (3.0 to 8.9 months).
Phase I Trial of Imexon in Patients With Advanced Malignancy
Authors: Dragovich Tomislav , Gordon Michael , Mendelson David , Wong Lucas , Modiano Manuel , Chow H.-H. Sherry , Samulitis Betty , O'Day Steven , Grenier Kathryn , Hersh Evan , Dorr Robert
Published: April 2007

Purpose

Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers.

Patients and Methods

Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays.

Results

There were 13 dose levels evaluated, from 20 mg/m2/d to 1,000 mg/m2/d. The MTD recommended for phase II studies was 875 mg/m2/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m2/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve–dependent decrease in cystine levels 8 hours after dosing at ≥ 750 mg/m2/d.

Conclusion

The phase II recommended dose of imexon is 875 mg/m2/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.
Phase III Trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With Infusional Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) As First-Line Treatment for Metastatic Colorectal Cancer: The Gruppo Oncologico Nord Ovest
Authors: Falcone Alfredo , Ricci Sergio , Brunetti Isa , Pfanner Elisabetta , Allegrini Giacomo , Barbara Cecilia , Crinò Lucio , Benedetti Giovanni , Evangelista Walter , Fanchini Laura , Cortesi Enrico , Picone Vincenzo , Vitello Stefano , Chiara Silvana , Granetto Cristina , Porcile Gianfranco , Fioretto Luisa , Orlandini Cinzia , Andreuccetti Michele , Masi Gianluca
Published: April 2007

Purpose

The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI).

Methods

Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR).

Results

A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032).

Conclusion

The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.
Optimizing Treatment of Desmoid Tumors
Authors: Lev Dina , Kotilingam Dhanasekaran , Wei Caimiao , Ballo Matthew T. , Zagars Gunar K. , Pisters Peter W.T. , Lazar Alexander A. , Patel Shreyaskumar R. , Benjamin Robert S. , Pollock Raphael E.
Published: April 2007

Purpose

This study compared a large series of desmoid patients treated at a single institution to a previously published series from the same institution to determine if patient population characteristics, treatment approaches, and clinical outcomes had undergone change over the two study periods.

Materials and Methods

Data from a prospective soft tissue tumor database was used to analyze clinical courses of 189 desmoid patients treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) from 1995 to 2005 as compared with 189 UTMDACC desmoid patients treated between 1965 and 1994.

Results

A nearly three-fold increase in annualized UTMDACC desmoid referral volume with significantly higher percentages and numbers of primary desmoid tumor referrals to UTMDACC was observed in the most recent study period. Significantly increased systemic therapy use and decreased reliance on surgery alone was observed more recently. While the recent series patients had higher rates of macroscopic residual disease and equivalent rates of positive microscopic margins after definitive surgery, the estimated 5-year local recurrence rate of 20% was improved compared with the 30% rate observed in the earlier series.

Conclusion

Increased awareness of the complex multidisciplinary management needed for desmoid tumor control may underlie significantly increased numbers of referrals to UTMDACC, especially primary untreated desmoids. Increased neoadjuvant treatments may be associated with improved desmoid patient outcomes. These trends should be supported, particularly if personalized molecular-based therapies are to be rapidly and effectively deployed for the benefit of those afflicted by this rare and potentially debilitating disease.
Mitotic spindle orientation distinguishes stem cell and terminal modes of neuron production in the early spinal cord
Authors: Wilcock Arwen C. , Swedlow Jason R. , Storey Kate G.
Published: April 2007

Despite great insight into the molecular mechanisms that specify neuronal cell type in the spinal cord, cell behaviour underlying neuron production in this tissue is largely unknown. In other neuroepithelia, divisions with a perpendicular cleavage plane at the apical surface generate symmetrical cell fates, whereas a parallel cleavage plane generates asymmetric daughters, a neuron and a progenitor in a stem cell mode, and has been linked to the acquisition of neuron-generating ability. Using a novel long-term imaging assay, we have monitored single cells in chick spinal cord as they transit mitosis and daughter cells become neurons or divide again. We reveal new morphologies accompanying neuron birth and show that neurons are generated concurrently by asymmetric and terminal symmetric divisions. Strikingly,divisions that generate two progenitors or a progenitor and a neuron both exhibit a wide range of cleavage plane orientations and only divisions that produce two neurons have an exclusively perpendicular orientation. Neuron-generating progenitors are also distinguished by lengthening cell cycle times, a finding supported by cell cycle acceleration on exposure to fibroblast growth factor (FGF), an inhibitor of neuronal differentiation. This study provides a novel, dynamic view of spinal cord neurogenesis and supports a model in which cleavage plane orientation/mitotic spindle position does not assign neuron-generating ability, but functions subsequent to this step to distinguish stem cell and terminal modes of neuron production.
Adhesion of Precision Welded Lead-Free Electrical Interconnects Formed by Molten Droplet Deposition
Authors: Webb D P , Liu C , Sarvar F , Conway P P , Williams K
Published: April 2007

An existing process, droplet welding, has been proposed for the production of precision, high-temperature, lead-free electrical joints. A modified metal inert gas (MIG) welding plasma is used to produce molten metal droplets, which then fall on a part to make an electrical joint. The subject of the present paper is an investigation of the factors affecting successful welded joint formation for a given droplet material and target, with the goal of providing the basis of a computer model to enable rapid process set-up on a production line. It is found that a parameter space can be identified for good adhesion of a droplet to a target, characterized by droplet temperature and target thickness, for each droplet material/target material combination. Essentially adhesion can be viewed as determined by competition between the delivery of thermal energy from the droplet to the target immediately underneath the droplet, and the removal of the energy from the interface region to the rest of the target, with no role played by the droplet kinetics after impact. It is therefore concluded that a relatively simple thermal model could be used by production-line engineers to identify the parameter space for rapid process set-up with new material combinations and products. The conclusion is supported by evidence from high-speed video images of droplet impact. Such a simple thermal model is proposed and is found to be capable of predicting adhesion between droplet and target. The results are discussed in the context of the extensive literature on molten droplet impact and solidification.
Determining the Suitability of Low Carbon Steel Wire for the Dieless Drawing Process
Authors: Tiernan P , Comerford P
Published: April 2007

Dieless wire drawing is the process of causing a reduction in a wire or bar diameter, without the use of conventional wire drawing dies. In this process, the dies are replaced by a heat source, e.g. an induction coil. The wire is pulled through the heat source to allow local stretching of the metal, in the heated zone. The current paper investigates an experimental elevated tensile test model in an attempt to assess the suitability of low carbon steel to the dieless drawing process. The tests were completed on two grades of low carbon steel at various deformation rates at temperatures up to 800 °C. The tensile tests were carried out on a modified Hounsfield tensile testing machine. The tensile strength and the percent elongation of each sample were recorded after each test. Stress-strain data were obtained from each experiment and these results were evaluated to determine the change in mechanical properties of each sample at the various temperatures. X-ray powder diffraction (XRD) was performed on the samples to determine the extent and composition of the oxide layer, which formed on the surface of the samples at the various test temperatures. Photomicrographs were taken of the deformation zone to examine the grain structure after the specimens were tested.
Macromodel for Ultrasonic Machining of Titanium and its Alloys: Designed Experiments
Authors: Singh R , Khamba J S
Published: April 2007

Titanium and its alloys have many potential engineering applications. There has been a critical need for cost-effective machining processes for titanium and its alloys. Not much work hitherto has been reported on the machining of tough materials like titanium by the ultrasonic machining process. An approach to macromodelling of the material removal rate, the tool wear rate, and surface roughness during ultrasonic machining of titanium and its alloys has been proposed and applied. Relationships between material removal rate (MMR), tool wear rate (TWR), surface roughness (SR), and other controllable machining parameters have been deduced by using Taguchi technique L18 orthogonal arrays. The comparison with experimental results will also serve as future validation of the model.
Fabrication and Characterization of Microparts by Mechanical Micromachining: Precision and Cost Estimation
Authors: Kang Hyuk-Jin , Ahn Sung-Hoon
Published: April 2007

The demands of mechanical micromachining technology have been increased in the manufacturing of micro-scale precision shapes and parts. Mechanical micromachining with microcutting tools has great advantages in productivity, usability, and economical efficiency compared with microelectromechanical system (MEMS) techniques. The main purpose of the present research is to verify the precision and cost efficiency of the mechanical micromachining. In order to measure the precision and feasibility of mechanical micromachining, various microfeatures were machined. Aluminium moulds were machined by the three-axis microstage in order to fabricate a microchip with a 200 μm wide channel for capillary electrophoresis; then the microchips were made by injection moulding with a tolerance of 5 μm. To evaluate the cost efficiency of various micromanufacturing processes, cost estimation for mechanical micromachining was conducted, and costs of microchips fabricated by mechanical micromachining, injection moulding, and MEMS were compared. As a result, it is proved that injection moulding has about 15 times lower cost than the MEMS method in the fabrication of the microchip. Mechanical micromachining is a simple, rapid, and cost-effective method to fabricate the metal master for polymer microchips, which would be suitable for prototypes of microchips.