bluuebunny/crossref_metadata_2025 huggingface dataset:
A method to determine spatial access to specialized palliative care services using GIS
Authors: Cinnamon Jonathan , Schuurman Nadine , Crooks Valorie A
Published: July 2008

Background

Providing palliative care is a growing priority for health service administrators worldwide as the populations of many nations continue to age rapidly. In many countries, palliative care services are presently inadequate and this problem will be exacerbated in the coming years. The provision of palliative care, moreover, has been piecemeal in many jurisdictions and there is little distinction made at present between levels of service provision. There is a pressing need to determine which populations do not enjoy access to specialized palliative care services in particular.

Methods

Catchments around existing specialized palliative care services in the Canadian province of British Columbia were calculated based on real road travel time. Census block face population counts were linked to postal codes associated with road segments in order to determine the percentage of the total population more than one hour road travel time from specialized palliative care.

Results

Whilst 81% of the province's population resides within one hour from at least one specialized palliative care service, spatial access varies greatly by regional health authority. Based on the definition of specialized palliative care adopted for the study, the Northern Health Authority has, for instance, just two such service locations, and well over half of its population do not have reasonable spatial access to such care.

Conclusion

Strategic location analysis methods must be developed and used to accurately locate future palliative services in order to provide spatial access to the greatest number of people, and to ensure that limited health resources are allocated wisely. Improved spatial access has the potential to reduce travel-times for patients, for palliative care workers making home visits, and for travelling practitioners. These methods are particularly useful for health service planners – and provide a means to rationalize their decision-making. Moreover, they are extendable to a number of health service allocation problems.
The relationship between bioelectrical impedance phase angle and subjective global assessment in advanced colorectal cancer
Authors: Gupta Digant , Lis Christopher G , Dahlk Sadie L , King Jessica , Vashi Pankaj G , Grutsch James F , Lammersfeld Carolyn A
Published: July 2008

Background

Bioelectrical Impedance (BIA) derived phase angle is increasingly being used as an objective indicator of nutritional status in advanced cancer. Subjective Global Assessment (SGA) is a subjective method of nutritional status. The objective of this study was to investigate the association between BIA derived phase angle and SGA in advanced colorectal cancer.

Methods

We evaluated a case series of 73 stages III and IV colorectal cancer patients. Patients were classified as either well-nourished or malnourished using the SGA. BIA was conducted on all patients and phase angle was calculated. The correlation between phase angle and SGA was studied using Spearman correlation coefficient. Receiver Operating Characteristic curves were estimated using the non-parametric method to determine the optimal cut-off levels of phase angle.

Results

Well-nourished patients had a statistically significantly higher (p = 0.005) median phase angle score (6.12) as compared to those who were malnourished (5.18). The Spearman rank correlation coefficient between phase angle and SGA was found to be 0.33 (p = 0.004), suggesting better nutritional status with higher phase angle scores.

A phase angle cut-off of 5.2 was 51.7% sensitive and 79.5% specific whereas a cut-off of 6.0 was 82.8% sensitive and 54.5% specific in detecting malnutrition. Interestingly, a phase angle cut-off of 5.9 demonstrated high diagnostic accuracy in males who had failed primary treatment for advanced colorectal cancer.

Conclusion

Our study suggests that bioimpedance phase angle is a potential nutritional indicator in advanced colorectal cancer. Further research is needed to elucidate the optimal cut-off levels of phase angle that can be incorporated into the oncology clinic for better nutritional evaluation and management.
Pollutant effects on genotoxic parameters and tumor-associated protein levels in adults: a cross sectional study
Authors: De Coster Sam , Koppen Gudrun , Bracke Marc , Schroijen Carmen , Den Hond Elly , Nelen Vera , Van de Mieroop Els , Bruckers Liesbeth , Bilau Maaike , Baeyens Willy , Schoeters Greet , van Larebeke Nik
Published: July 2008

Background

This study intended to investigate whether residence in areas polluted by heavy industry, waste incineration, a high density of traffic and housing or intensive use of pesticides, could contribute to the high incidence of cancer observed in Flanders.

Methods

Subjects were 1583 residents aged 50–65 from 9 areas with different types of pollution. Cadmium, lead, p,p'-DDE, hexachlorobenzene, PCBs and dioxin-like activity (Calux test) were measured in blood, and cadmium, t,t'-muconic acid and 1-hydroxypyrene in urine. Effect biomarkers were prostate specific antigen, carcinoembryonic antigen and p53 protein serum levels, number of micronuclei per 1000 binucleated peripheral blood cells, DNA damage (comet assay) in peripheral blood cells and 8-hydroxy-deoxyguanosine in urine. Confounding factors were taken into account.

Results

Overall significant differences between areas were found for carcinoembryonic antigen, micronuclei, 8-hydroxy-deoxyguanosine and DNA damage. Compared to a rural area with mainly fruit production, effect biomarkers were often significantly elevated around waste incinerators, in the cities of Antwerp and Ghent, in industrial areas and also in other rural areas. Within an industrial area DNA strand break levels were almost three times higher close to industrial installations than 5 kilometres upwind of the main industrial installations (p < 0.0001). Positive exposure-effect relationships were found for carcinoembryonic antigen (urinary cadmium, t,t'-muconic acid, 1-hydroxypyrene and blood lead), micronuclei (PCB118), DNA damage (PCB118) and 8-hydroxy-deoxyguanosine (t,t'-muconic acid, 1-hydroxypyrene). Also, we found significant associations between values of PSA above the p90 and higher values of urinary cadmium, between values of p53 above the p90 and higher serum levels of p,p'-DDE, hexachlorobenzene and marker PCBs (PCB 138, 153 and 180) and between serum levels of p,p'-DDE above the p90 and higher serum values of carcinoembryonic antigen. Significant associations were also found between effect biomarkers and occupational or lifestyle parameters.

Conclusion

Levels of internal exposure, and residence near waste incinerators, in cities, or close to important industries, but not in areas with intensive use of pesticides, showed positive correlations with biomarkers associated with carcinogenesis and thus probably contribute to risk of cancer. In some rural areas, the levels of these biomarkers were not lower than in the rest of Flanders.
EpiScanGIS: an online geographic surveillance system for meningococcal disease
Authors: Reinhardt Markus , Elias Johannes , Albert Jürgen , Frosch Matthias , Harmsen Dag , Vogel Ulrich
Published: July 2008

Background

Surveillance of infectious diseases increasingly relies on Geographic Information Systems (GIS). The integration of pathogen fine typing data in dynamic systems and visualization of spatio-temporal clusters are a technical challenge for system development.

Results

An online geographic information system (EpiScanGIS) based on open source components has been launched in Germany in May 2006 for real time provision of meningococcal typing data in conjunction with demographic information (age, incidence, population density). Spatio-temporal clusters of disease detected by computer assisted cluster analysis (SaTScan™) are visualized on maps. EpiScanGIS enables dynamic generation of animated maps. The system is based on open source components; its architecture is open for other infectious agents and geographic regions. EpiScanGIS is available at http://www.episcangis.org, and currently has 80 registered users, mostly from the public health service in Germany. At present more than 2,900 cases of invasive meningococcal disease are stored in the database (data as of June 3, 2008).

Conclusion

EpiScanGIS exemplifies GIS applications and early-warning systems in laboratory surveillance of infectious diseases.
Smac/DIABLO enhances the therapeutic potential of chemotherapeutic drugs and irradiation, and sensitizes TRAIL-resistant breast cancer cells
Authors: Fandy Tamer E , Shankar Sharmila , Srivastava Rakesh K
Published: July 2008

Background

Drug resistance is a major concern in cancer therapy. Here, we investigate the clinical potential of the second mitochondria-derived activator of caspase (Smac/DIABLO) in enhancing the apoptosis-inducing potential of commonly used anticancer drugs (paclitaxel, doxorubicin, etoposide, tamoxifen), irradiation and TRAIL in breast carcinoma.

Methods

Breast cancer cells were overexpressed with Smac/DIABLO gene (full-length or Δ55 Smac/DIABLO) or treated with Smac/DIABLO peptide to enhance the apoptosis-inducing potential of chemotherapeutic drugs and irradiation, and sensitize TRAIL-resistant cells. Cell viability and apoptosis were measured by XTT assay and DAPI staining, respectively. Protein-protein interaction was determined by immunoprecipitation followed by the Western blot analysis.

Results

Overexpression of Smac/DIABLO gene (full-length or Δ55 Smac/DIABLO) or treatment with Smac/DIABLO peptide enhances apoptosis induced by paclitaxel, doxorubicin, etoposide, tamoxifen, and irradiation in breast cancer cells. Overexpression of Smac/DIABLO resulted in an increased interaction of Smac/DIABLO with IAPs, which correlated with an increase in caspase-3 activity and apoptosis. Furthermore, Smac/DIABLO sensitized TRAIL-resistant breast cancer cell lines to undergo apoptosis through caspase-3 activation. These data suggest that apoptotic events down-stream of mitochondria were intact in TRAIL-resistant cells since ectopic expression of Smac/DIABLO or pretreatment of cells with Smac/DIABLO peptide completely restored TRAIL sensitivity.

Conclusion

The ability of Smac/DIABLO agonists to enhance the apoptosis-inducing potential of chemotherapeutic drugs and irradiation, and sensitize TRAIL-resistant tumor cells suggests that Smac/DIABLO may induce fundamental alterations in cell signaling pathways. Thus, Smac/DIABLO agonists can be used as promising new candidates for cancer treatment by potentiating cytotoxic therapies.
Granulocyte-colony stimulating factor producing rectal cancer
Authors: Takahashi Hiroki , Yasuda Akira , Ochi Nubuo , Sakamoto Masaki , Takayama Satoru , Wakasugi Takehiro , Funahashi Hitoshi , Sawai Hirozumi , Satoh Mikinori , Akamo Yoshimi , Takeyama Hiromitsu
Published: July 2008

Background

Granulocyte-colony stimulating factor (G-CSF)-producing cancer has been reported to occur in various organs, especially the lung. However, G-CSF-producing colorectal cancer (CRC) has never been reported in the English literature.

Case presentation

A 57-year-old man was admitted for the surgical removal of a rectal cancer. Some hepatic tumors in the liver were revealed concurrently, and their appearance suggested multiple liver metastases. Low anterior resection was performed. with the help of histopathological examination and immunohistochemical studies, we diagnosed this case to be an undifferentiated carcinoma of the rectum. After the operation, the white blood cell (WBC) count increased gradually to 81,000 cells/μL. Modified-FOLFOX6 therapy was initiated to treat the liver metastases, but there was no effect, and peritoneal dissemination had also occurred. The serum level of G-CSF was elevated to 840 pg/mL (normal range, <18.1 pg/mL). Furthermore, immunohistochemistry with a specific monoclonal antibody against G-CSF was positive; therefore, we diagnosed this tumor as a G-CSF-producing cancer. The patient died from rapid growth of the liver metastases and peritoneal dissemination 2 months after surgery.

Conclusion

This is the first case of G-CSF-producing rectal cancer, and its prognosis was very poor.
The role of upstream sequences in selecting the reading frame on tmRNA
Authors: Miller Mickey R , Healey David W , Robison Stephen G , Dewey Jonathan D , Buskirk Allen R
Published: July 2008

Background

tmRNA acts first as a tRNA and then as an mRNA to rescue stalled ribosomes in eubacteria. Two unanswered questions about tmRNA function remain: how does tmRNA, lacking an anticodon, bypass the decoding machinery and enter the ribosome? Secondly, how does the ribosome choose the proper codon to resume translation on tmRNA? According to the -1 triplet hypothesis, the answer to both questions lies in the unique properties of the three nucleotides upstream of the first tmRNA codon. These nucleotides assume an A-form conformation that mimics the codon-anticodon interaction, leading to recognition by the decoding center and choice of the reading frame. The -1 triplet hypothesis is important because it is the most credible model in which direct binding and recognition by the ribosome sets the reading frame on tmRNA.

Results

Conformational analysis predicts that 18 triplets cannot form the correct structure to function as the -1 triplet of tmRNA. We tested the tmRNA activity of all possible -1 triplet mutants using a genetic assay in Escherichia coli. While many mutants displayed reduced activity, our findings do not match the predictions of this model. Additional mutagenesis identified sequences further upstream that are required for tmRNA function. An immunoblot assay for translation of the tmRNA tag revealed that certain mutations in U85, A86, and the -1 triplet sequence result in improper selection of the first codon and translation in the wrong frame (-1 or +1) in vivo.

Conclusion

Our findings disprove the -1 triplet hypothesis. The -1 triplet is not required for accommodation of tmRNA into the ribosome, although it plays a minor role in frame selection. Our results strongly disfavor direct ribosomal recognition of the upstream sequence, instead supporting a model in which the binding of a separate ligand to A86 is primarily responsible for frame selection.
Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury
Authors: Lloyd Eric , Somera-Molina Kathleen , Van Eldik Linda J , Watterson D Martin , Wainwright Mark S
Published: July 2008

Background

Traumatic brain injury (TBI) with its associated morbidity is a major area of unmet medical need that lacks effective therapies. TBI initiates a neuroinflammatory cascade characterized by activation of astrocytes and microglia, and increased production of immune mediators including proinflammatory cytokines and chemokines. This inflammatory response contributes both to the acute pathologic processes following TBI including cerebral edema, in addition to longer-term neuronal damage and cognitive impairment. However, activated glia also play a neuroprotective and reparative role in recovery from injury. Thus, potential therapeutic strategies targeting the neuroinflammatory cascade must use careful dosing considerations, such as amount of drug and timing of administration post injury, in order not to interfere with the reparative contribution of activated glia.

Methods

We tested the hypothesis that attenuation of the acute increase in proinflammatory cytokines and chemokines following TBI would decrease neurologic injury and improve functional neurologic outcome. We used the small molecule experimental therapeutic, Minozac (Mzc), to suppress TBI-induced up-regulation of glial activation and proinflammatory cytokines back towards basal levels. Mzc was administered in a clinically relevant time window post-injury in a murine closed-skull, cortical impact model of TBI. Mzc effects on the acute increase in brain cytokine and chemokine levels were measured as well as the effect on neuronal injury and neurobehavioral function.

Results

Administration of Mzc (5 mg/kg) at 3 h and 9 h post-TBI attenuates the acute increase in proinflammatory cytokine and chemokine levels, reduces astrocyte activation, and the longer term neurologic injury, and neurobehavioral deficits measured by Y maze performance over a 28-day recovery period. Mzc-treated animals also have no significant increase in brain water content (edema), a major cause of the neurologic morbidity associated with TBI.

Conclusion

These results support the hypothesis that proinflammatory cytokines contribute to a glial activation cycle that produces neuronal dysfunction or injury following TBI. The improvement in long-term functional neurologic outcome following suppression of cytokine upregulation in a clinically relevant therapeutic window indicates that selective targeting of neuroinflammation may lead to novel therapies for the major neurologic morbidities resulting from head injury, and indicates the potential of Mzc as a future therapeutic for TBI.
Analysis of draft Australian rehabilitation service standards: comparison with international standards
Authors: Graham Susan K , Cameron Ian D , Dickson Hugh G
Published: July 2008

Background

Following her review of health systems and structures Dwyer [1] suggested that there is a need to evaluate models of care for individuals with chronic diseases. Rehabilitation services aim to optimise the activity and participation of individuals with restrictions due to both acute and chronic conditions. Assessing and optimising the standard of these services is one method of assuring the quality of service delivered to these individuals. Knowledge of baseline standards allows evaluation of the impact of health care reforms in this area of need. The aim of this article is to compare the currently available rehabilitation service standards in Australia with those used in the USA and the UK.

Results

The mixed method qualitative analysis performed on the three sets of standards demonstrated repeatability and convergence via the use of triangulation. Australian Faculty of Rehabilitation Medicine (AFRM) standards were found to be consistent and concise, to provide definitions, and to cover the majority of clinically relevant issues to an extent similar to the other rehabilitation service standards. Inclusion of standards for business practices, the rehabilitation process for the person served, and outpatient and community-based rehabilitation services should be considered by the AFRM.

Conclusion

The AFRM standards are an appropriate way of assessing rehabilitation services in Australia. As suggested by other workers [2, 3] there should be ongoing review and field testing of the standards to maximise the relevance and utilisation of the standards.
Tracheobronchopathia osteochondroplastica: A rare cause of chronic cough with haemoptysis
Authors: Willms Hinrich , Wiechmann Volker , Sack Ulrich , Gillissen Adrian
Published: July 2008

A case of tracheobronchopathia osteochondroplastic (TPO) was diagnosed in a 69-year old male with prolonged cough. TPO is a rare condition of unknown cause and only sporadic cases have been reported. The condition is benign, characterized by submucosal nodules growing from the submucosal layer of the airways, protruding into the bronchial lumen. The bronchscopic view together with bronchial cartilage with abnormal distributed mineralization of the histologic examination of theses nodules leads to the correct diagnosis. Mild cases are treated symptomatically, whereas we tried an inhaled corticosteroid. Prominent protrusions in the trachea or the bronchi must be removed. In most cases the disease is stable over years but progressive forms have been reported. TPO may cause chronic refractory cough, which eventually is the only prominent symptom of this disease.
A rapid and robust method for simultaneously measuring changes in the phytohormones ABA, JA and SA in plants following biotic and abiotic stress
Authors: Forcat Silvia , Bennett Mark H , Mansfield John W , Grant Murray R
Published: July 2008

We describe an efficient method for the rapid quantitative determination of the abundance of three acidic plant hormones from a single crude extract directly by LC/MS/MS. The method exploits the sensitivity of MS and uses multiple reaction monitoring and isotopically labelled samples to quantify the phytohormones abscisic acid, jasmonic acid and salicylic acid in Arabidopsis leaf tissue.
A study of candidate genes for day blindness in the standard wire haired dachshund
Authors: Wiik Anne Caroline , Ropstad Ernst-Otto , Bjerkås Ellen , Lingaas Frode
Published: July 2008

Background

A genetic study was performed to identify candidate genes associated with day blindness in the standard wire haired dachshund. Based on a literature review of diseases in dogs and human with phenotypes similar to day blindness, ten genes were selected and evaluated as potential candidate genes associated with day blindness in the breed.

Results

Three of the genes, CNGB3, CNGA3 and GNAT2, involved in cone degeneration and seven genes and loci, ABCA4, RDH5, CORD8, CORD9, RPGRIP1, GUCY2D and CRX, reported to be involved in cone-rod dystrophies were studied. Polymorphic markers at each of the candidate loci were studied in a family with 36 informative offspring. The study revealed a high frequency of recombinations between the candidate marker alleles and the disease.

Conclusion

Since all of the markers were at the exact position of the candidate loci, and several recombinations were detected for each of the loci, all ten genes were excluded as causal for this canine, early onset cone-rod dystrophy. The described markers may, however, be useful to screen other canine resource families segregating eye diseases for association to the ten genes.
Flow: Statistics, visualization and informatics for flow cytometry
Authors: Frelinger Jacob , Kepler Thomas B , Chan Cliburn
Published: July 2008

Flow is an open source software application for clinical and experimental researchers to perform exploratory data analysis, clustering and annotation of flow cytometric data. Flow is an extensible system that offers the ease of use commonly found in commercial flow cytometry software packages and the statistical power of academic packages like the R BioConductor project.
Assignment of isochores for all completely sequenced vertebrate genomes using a consensus
Authors: Schmidt Thorsten , Frishman Dmitrij
Published: July 2008

We show that although the currently available isochore mapping methods agree on the isochore classification of about two-thirds of the human DNA, they produce significantly different results with regard to the location of isochore boundaries and isochore length distribution. We present a new consensus isochore assignment method based on majority voting and provide IsoBase, a comprehensive on-line database of isochore maps for all completely sequenced vertebrate genomes.
C-reactive protein (CRP) induces chemokine secretion via CD11b/ICAM-1 interaction in human adherent monocytes
Authors: Montecucco Fabrizio , Steffens Sabine , Burger Fabienne , Pelli Graziano , Monaco Claudia , Mach François
Published: July 2008

Several studies support C-reactive protein (CRP) as a systemic cardiovascular risk factor. The recent detection of CRP in arterial intima suggests a dual activity in atherosclerosis as a circulating and tissue mediator on vascular and immune cells. In the present paper, we focused on the inflammatory effects of CRP on human monocytes, which were isolated by Ficoll-Percoll gradients and cultured in adherence to polystyrene, endothelial cell monolayer, or in suspension. Chemokine levels, adhesion molecule, and chemokine receptor expression were detected by ELISA, flow cytometry, and real-time RT-PCR. Migration assays were performed in a Boyden chamber. Stimulation with CRP induced release of CCL2, CCL3, and CCL4 in adherent monocytes through the binding to CD32a, CD32b, and CD64, whereas no effect was observed in suspension culture. This was associated with CRP-induced up-regulation of adhesion molecules membrane-activated complex 1 (Mac-1) and ICAM-1 on adherent monocytes. Blockade of Mac-1/ICAM-1 interaction inhibited the CRP-induced chemokine secretion. In addition, CRP reduced mRNA and surface expression of corresponding chemokine receptors CCR1, CCR2, and CCR5 in adherent monocytes. This effect was a result of chemokine secretion, as coincubation with neutralizing anti-CCL2, anti-CCL3, and anti-CCL4 antibodies reversed the effect of CRP. Accordingly, a reduced migration of CRP-treated monocytes to CCL2 and CCL3 was observed. In conclusion, our data suggest an in vitro model to study CRP activities in adherent and suspension human monocytes. CRP-mediated induction of adhesion molecules and a decrease of chemokine receptors on adherent monocytes might contribute to the retention of monocytes within atherosclerotic lesions and recruitment of other circulating cells.
Randomized Controlled Clinical Effectiveness Trial of Cognitive Behavior Therapy Compared With Treatment As Usual for Persistent Insomnia in Patients With Cancer
Authors: Espie Colin A. , Fleming Leanne , Cassidy James , Samuel Leslie , Taylor Lynne M. , White Craig A. , Douglas Neil J. , Engleman Heather M. , Kelly Heidi-Louise , Paul James
Published: July 2008

Purpose

Persistent insomnia is a common complaint in cancer survivors, but is seldom satisfactorily addressed. The adaptation to cancer care of a validated, cost-effective intervention may offer a practicable solution. The aim of this study was to investigate the clinical effectiveness of protocol-driven cognitive behavior therapy (CBT) for insomnia, delivered by oncology nurses.

Patients and Methods

Randomized, controlled, pragmatic, two-center trial of CBT versus treatment as usual (TAU) in 150 patients (103 females; mean age, 61 years.) who had completed active therapy for breast, prostate, colorectal, or gynecological cancer. The study conformed to CONSORT guidelines. Primary outcomes were sleep diary measures at baseline, post-treatment, and 6-month follow-up. Actigraphic sleep, health-related quality of life (QOL), psychopathology, and fatigue were secondary measures. CBT comprised five, small group sessions across consecutive weeks, after a manualized protocol. TAU represented normal clinical practice; the appropriate control for a clinical effectiveness study.

Results

CBT was associated with mean reductions in wakefulness of 55 minutes per night compared with no change in TAU. These outcomes were sustained 6 months after treatment. Standardized relative effect sizes were large for complaints of difficulty initiating sleep, waking from sleep during the night, and for sleep efficiency (percentage of time in bed spent asleep). CBT was associated with moderate to large effect sizes for five of seven QOL outcomes, including significant reduction in daytime fatigue. There was no significant interaction effect between any of these outcomes and baseline demographic, clinical, or sleep characteristics.

Conclusion

CBT for insomnia may be both clinically effective and feasible to deliver in real world practice.
Mutation of the Wilms’ Tumor 1 Gene Is a Poor Prognostic Factor Associated With Chemotherapy Resistance in Normal Karyotype Acute Myeloid Leukemia: The United Kingdom Medical Research Council Adult Leukaemia Working Party
Authors: Virappane Priya , Gale Rosemary , Hills Robert , Kakkas Ioannis , Summers Karin , Stevens Jane , Allen Christopher , Green Claire , Quentmeier Hilmar , Drexler Hans , Burnett Alan , Linch David , Bonnet Dominique , Lister T. Andrew , Fitzgibbon Jude
Published: July 2008

Purpose

To determine the clinical relevance of Wilms’ tumor 1 (WT1) gene mutations in acute myeloid leukemia (AML) with normal karyotype (NK).

Patients and Methods

Exons 7 and 9 of WT1 were screened in samples from 470 young adult NK AMLs using a combination of direct sequencing and high-resolution capillary electrophoresis.

Results

Overall, 51 mutations were detected in 47 cases (10%): 46 frameshift mutations with insertion/deletion of one to 28 base pairs in exon 7 (n = 45) or exon 9 (n = 1), with a median mutant level of 45% (range, 8% to 86%), and five substitutions in exon 9: D396N (n = 3), H397Y (n = 1) and H397Q (n = 1). Patients with WT1 mutations had an inferior response to induction chemotherapy compared with wild-type cases (complete remission rate, 79% v 90%, odds ratio [OR] = 3.02; 95% CI, 1.17 to 7.82; P = .02), a higher rate of resistant disease (15% v 4%; OR = 9.33; 95% CI, 2.38 to 36.6; P = .001), an increased cumulative incidence of relapse (67% v 43%, hazard ratio [HR] = 3.02; 95% CI, 1.69 to 5.38; P = .0008), with a reduction in both relapse-free survival (22% v 44%; HR = 2.16; 95% CI, 1.32 to 3.55; P = .005) and overall survival (26% v 47%; HR = 1.91; 95% CI, 1.23 to 2.95; P = .007) at 5 years. In multivariate analysis, which included FLT3 internal tandem duplication and NPM1 mutation status, the presence of a WT1 mutation remained an independent adverse prognostic factor.

Conclusion

WT1 mutations are a negative prognostic indicator in NK AML and may be suitable for the development of targeted therapy.
A Synthetic Lethal Therapeutic Approach: Poly(ADP) Ribose Polymerase Inhibitors for the Treatment of Cancers Deficient in DNA Double-Strand Break Repair
Authors: Ashworth Alan
Published: July 2008

Cancer cells frequently harbor defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis but also provides a weakness in the tumor that can be exploited therapeutically. Tumors with compromised ability to repair double-strand DNA breaks by homologous recombination, including those with defects in BRCA1 and BRCA2, are highly sensitive to blockade of the repair of DNA single-strand breaks via the inhibition of the enzyme poly(ADP) ribose polymerase. This provides the basis for a novel synthetic lethal approach to cancer therapy.
AIDS-Related Malignancies: State of the Art and Therapeutic Challenges
Authors: Spano Jean-Philippe , Costagliola Dominique , Katlama Christine , Mounier Nicolas , Oksenhendler Eric , Khayat David
Published: July 2008

Despite the impact of combination antiretroviral therapy (cART) on HIV-related mortality, malignancy remains an important cause of death in the current era. Although the advent of cART has resulted in reductions in the incidence of Kaposi's sarcoma and non-Hodgkin's lymphoma, non–AIDS-defining malignancies present an increased risk for HIV-infected patients, characterized by some common clinical features, generally with a more aggressive behavior and a more advanced disease at diagnosis, which is responsible for poorer patient outcomes. Specific therapeutic recommendations are lacking for these new nonopportunistic malignancies, such as Hodgkin's lymphoma, anal cancer, lung cancer, hepatocarcinoma, and many others. Antiretroviral agents have a propensity for causing drug interactions as a result of their ability to either inhibit or induce the cytochrome P450 (CYP) enzyme system. Because many antineoplastic drugs are also metabolized by the CYP system, coadministration with cART could result in either drug accumulation with increased toxicity, or decreased efficacy of one or both classes of drugs. Further research delineating the combined safety and pharmacokinetics of antiretrovirals and antineoplastic therapy is necessary. Special considerations of these AIDS-related and non–AIDS-related malignancies and their clinical and therapeutic aspects constitute the subject of this review.
Low-Dose Interleukin-2 Immunotherapy Does Not Improve Outcome of Patients Age 60 Years and Older With Acute Myeloid Leukemia in First Complete Remission: Cancer and Leukemia Group B Study 9720
Authors: Baer Maria R. , George Stephen L. , Caligiuri Michael A. , Sanford Ben L. , Bothun Sandra M. , Mrózek Krzysztof , Kolitz Jonathan E. , Powell Bayard L. , Moore Joseph O. , Stone Richard M. , Anastasi John , Bloomfield Clara D. , Larson Richard A.
Published: July 2008

Purpose

Cancer and Leukemia Group B (CALGB) 9720 evaluated subcutaneous low-dose recombinant interleukin-2 (rIL-2) maintenance immunotherapy as a strategy for prolonging remission in older patients with acute myeloid leukemia (AML).

Patients and Methods

AML patients age 60 years and older in first complete remission after induction and consolidation chemotherapy were randomly assigned to no further therapy or a 90-day regimen of 14-day cycles of low-dose rIL-2, aimed at expanding natural killer (NK) cells, followed by 3-day higher doses aimed at activating cytotoxicity of expanded NK cells to lyse residual AML cells. All randomly assigned patients were included in an intention-to-treat analysis.

Results

A total of 163 (64%) of 254 patients who completed induction and consolidation chemotherapy on CALGB 9720 were randomly assigned to rIL-2 (n = 81) or no further therapy (n = 82); the most common reasons for lack of random assignment were patient refusal and relapse. Fifteen patients randomly assigned to rIL-2 never initiated it because of refusal, intercurrent medical problems, or relapse, and 24 patients initiated rIL-2 but stopped early because of toxicity or relapse. Grade 4 toxicities during rIL-2 therapy included thrombocytopenia (65%) and neutropenia (64%), and grade 3 toxicities included anemia (33%), infection (24%) and malaise/fatigue (14%). Forty-two patients (52%) randomly assigned to rIL-2 completed the full 90-day course. Patients in both arms had similar distributions of both disease-free (combined median = 6.1 months; P = .47) and overall survival (combined median = 14.7 months; P = .61) after random assignment. Moreover, the 42 patients who completed all planned therapy did not show prolongation of disease-free or overall survival.

Conclusion

Low-dose rIL-2 maintenance immunotherapy is not a successful strategy in older AML patients.
Monte Carlo methods for sensitivity analysis of Poisson-driven stochastic systems, and applications
Authors: Bordenave Charles , Torrisi Giovanni Luca
Published: July 2008

We extend a result due to Zazanis (1992) on the analyticity of the expectation of suitable functionals of homogeneous Poisson processes with respect to the intensity of the process. As our main result, we provide Monte Carlo estimators for the derivatives. We apply our results to stochastic models which are of interest in stochastic geometry and insurance.
Optimal selection policies for a sequence of candidate drugs
Authors: Charalambous C. , Gittins J. C.
Published: July 2008

Pharmaceutical companies have to face huge risks and enormous costs of production before they can produce a drug. Efficient allocation of resources is essential to help in maximizing profits. Yu and Gittins (2007) described a model and associated software for determining efficient allocations for a preclinical research project. This is the starting point for this paper. We provide explicit optimal policies for the selection of successive candidate drugs for two restricted versions of the Yu and Gittins (2007) model. To some extent these policies are likely to be applicable to the unrestricted model.
Large deviation estimates of the crossing probability for pinned Gaussian processes
Authors: Caramellino Lucia , Pacchiarotti Barbara
Published: July 2008

The paper deals with the asymptotic behavior of the bridge of a Gaussian process conditioned to stay innfixed points atnfixed past instants. In particular, functional large deviation results are stated for small time. Several examples are considered: integrated or not fractional Brownian motions andm-fold integrated Brownian motion. As an application, the asymptotic behavior of the exit probability is studied and used for the practical purpose of the numerical computation, via Monte Carlo methods, of the hitting probability up to a given time of the unpinned process.
A characterization of the first hitting time of double integral processes to curved boundaries
Authors: Touboul Jonathan , Faugeras Olivier
Published: July 2008

The problem of finding the probability distribution of the first hitting time of a double integral process (DIP) such as the integrated Wiener process (IWP) has been an important and difficult endeavor in stochastic calculus. It has applications in many fields of physics (first exit time of a particle in a noisy force field) or in biology and neuroscience (spike time distribution of an integrate-and-fire neuron with exponentially decaying synaptic current). The only results available are an approximation of the stationary mean crossing time and the distribution of the first hitting time of the IWP to a constant boundary. We generalize these results and find an analytical formula for the first hitting time of the IWP to a continuous piecewise-cubic boundary. We use this formula to approximate the law of the first hitting time of a general DIP to a smooth curved boundary, and we provide an estimation of the convergence of this method. The accuracy of the approximation is computed in the general case for the IWP and the effective calculation of the crossing probability can be carried out through a Monte Carlo method.
Steady-state analysis of a multiserver queue in the Halfin-Whitt regime
Authors: Gamarnik David , Momčilović Petar
Published: July 2008

We consider a multiserver queue in the Halfin-Whitt regime: as the number of serversngrows without a bound, the utilization approaches 1 from below at the rateAssuming that the service time distribution is lattice valued with a finite support, we characterize the limiting scaled stationary queue length distribution in terms of the stationary distribution of an explicitly constructed Markov chain. Furthermore, we obtain an explicit expression for the critical exponent for the moment generating function of a limiting stationary queue length. This exponent has a compact representation in terms of three parameters: the amount of spare capacity and the coefficients of variation of interarrival and service times. Interestingly, it matches an analogous exponent corresponding to a single-server queue in the conventional heavy-traffic regime.
Multivariate risk processes with interacting intensities
Authors: Bäuerle Nicole , Grübel Rudolf
Published: July 2008

The classical models in risk theory consider a single type of claim. In the insurance business, however, several business lines with separate claim arrival processes appear naturally, and the individual claim processes may not be independent. We introduce a new class of models for such situations, where the underlying counting process is a multivariate continuous-time Markov chain of pure-birth type and the dependency of the components arises from the fact that the birth rate for a specific claim type may depend on the number of claims in the other component processes. Under certain conditions, we obtain a fluid limit, i.e. a functional law of large numbers for these processes. We also investigate the consequences of such results for questions of interest in insurance applications. Several specific subclasses of the general model are discussed in detail and the Cramér asymptotics of the ruin probabilities are derived in particular cases.
Queues with Delays in Two-State Strategies and Lévy Input
Authors: Bekker R. , Boxma O. J. , Kella O.
Published: July 2008

We consider a reflected Lévy process without negative jumps, starting at the origin. When the reflected process first upcrosses level K, a timer is activated. After D time units, the timer expires and the Lévy exponent of the Lévy process is changed. As soon as the process hits zero again, the Lévy exponent reverses to the original function. If the process has reached the origin before the timer expires then the Lévy exponent does not change. Using martingale techniques, we analyze the steady-state distribution of the resulting process, reflected at the origin. We pay special attention to the cases of deterministic and exponential timers, and to the following three special Lévy processes: (i) a compound Poisson process plus negative drift (corresponding to an M/G/1 queue), (ii) Brownian motion, and (iii) a Lévy process that is a subordinator until the timer expires.
Weak Convergence Limits for Sojourn Times in Cyclic Queues Under Heavy Traffic Conditions
Authors: Daduna Hans , Malchin Christian , Szekli Ryszard
Published: July 2008

We consider sequences of closed cycles of exponential single-server nodes with a single bottleneck. We study the cycle time and the successive sojourn times of a customer when the population sizes go to infinity. Starting from old results on the mean cycle times under heavy traffic conditions, we prove a central limit theorem for the cycle time distribution. This result is then utilised to prove a weak convergence characteristic of the vector of a customer's successive sojourn times during a cycle for a sequence of networks with population sizes going to infinity. The limiting picture is a composition of a central limit theorem for the bottleneck node and an exponential limit for the unscaled sequences of sojourn times for the nonbottleneck nodes.
Diffusion Approximation of State-Dependent G-Networks Under Heavy Traffic
Authors: Leite Saul C. , Fragoso Marcelo D.
Published: July 2008

This paper is concerned with the characterization of weak-sense limits of state-dependent G-networks under heavy traffic. It is shown that, for a certain class of networks (which includes a two-layer feedforward network and two queues in tandem), it is possible to approximate the number of customers in the queue by a reflected stochastic differential equation. The benefits of such an approach are that it describes the transient evolution of these queues and allows the introduction of controls, inter alia. We illustrate the application of the results with numerical experiments.
A Lévy Insurance Risk Process with Tax
Authors: Albrecher Hansjörg , Renaud Jean-François , Zhou Xiaowen
Published: July 2008

Using fluctuation theory, we solve the two-sided exit problem and identify the ruin probability for a general spectrally negative Lévy risk process with tax payments of a loss-carry-forward type. We study arbitrary moments of the discounted total amount of tax payments and determine the surplus level to start taxation which maximises the expected discounted aggregate income for the tax authority in this model. The results considerably generalise those for the Cramér-Lundberg risk model with tax.
Equilibrium Selection in Evolutionary Games with Imperfect Monitoring
Authors: Chen Hsiao-Chi , Chow Yunshyong
Published: July 2008

In this paper we analyze players' long-run behavior in evolutionary coordination games with imperfect monitoring in a large population. Players can observe signals corresponding to other players' unseen actions and use the proposed simple or maximum likelihood estimation algorithm to extract information from the signals. In the simple learning process we find conditions for the risk-dominant and the non-risk-dominant equilibria to emerge alone in the long run. Furthermore, we find that the two equilibria can coexist in the long run. In contrast, the coexistence of the two equilibria is the only limit distribution under the maximum likelihood estimation learning algorithm. We also analyze the long-run equilibria of other 2x2 symmetric games under imperfect monitoring.
A Poisson Approximation for an Occupancy Problem with Collisions
Authors: Nakata Toshio
Published: July 2008

We study collision probabilities concerning the simple balls-and-bins problem developed by Wendl (2003). In this article we give the factorial moment of the number of collisions. Moreover, we obtain a Poisson approximation for the number of collisions using the Chen-Stein method.
Bounding the Size and Probability of Epidemics on Networks
Authors: Miller Joel C.
Published: July 2008

We consider an infectious disease spreading along the edges of a network which may have significant clustering. The individuals in the population have heterogeneous infectiousness and/or susceptibility. We define theout-transmissibilityof a node to be the marginal probability that it would infect a randomly chosen neighbor given its infectiousness and the distribution of susceptibility. For a given distribution of out-transmissibility, we find the conditions which give the upper (or lower) bounds on the size and probability of an epidemic, under weak assumptions on the transmission properties, but very general assumptions on the network. We find similar bounds for a given distribution of in-transmissibility (the marginal probability of being infected by a neighbor). We also find conditions giving global upper bounds on the size and probability. The distributions leading to these bounds are network independent. In the special case of networks with high girth (locally tree-like), we are able to prove stronger results. In general, the probability and size of epidemics are maximal when the population is homogeneous and minimal when the variance of in- or out-transmissibility is maximal.
Convergence of At-The-Money Implied Volatilities to the Spot Volatility
Authors: Durrleman Valdo
Published: July 2008

We study the convergence of at-the-money implied volatilities to the spot volatility in a general model with a Brownian component and a jump component of finite variation. This result is a consequence of the robustness of the Black-Scholes formula and of the central limit theorem for martingales.
A Variable Step Size Riemannian Sum for an Itô Integral
Authors: Rapoo E.
Published: July 2008

We investigate the problem of using a Riemannian sum with random subintervals to approximate the iterated Itô integral ∫wdw - or, equivalently, solving the corresponding stochastic differential equation by Euler's method with variable step sizes. In the past this task has been used as a counterexample to illustrate that variable step sizes must be used with extreme caution in stochastic numerical analysis. This article establishes a class of variable step size schemes which do work.
Relating Time and Customer Averages for Queues Using ‘forward’ Coupling from the Past
Authors: Peköz Erol A. , Ross Sheldon M.
Published: July 2008

We give a new method for simulating the time average steady-state distribution of a continuous-time queueing system, by extending a ‘read-once’ or ‘forward’ version of the coupling from the past (CFTP) algorithm developed for discrete-time Markov chains. We then use this to give a new proof of the ‘Poisson arrivals see time averages’ (PASTA) property, and a new proof for why renewal arrivals see either stochastically smaller or larger congestion than the time average if interarrival times are respectively new better than used in expectation (NBUE) or new worse than used in expectation (NWUE).
A Note on Conditioning and Stochastic Domination for Order Statistics
Authors: Dubhashi Devdatt , Häggström Olle
Published: July 2008

For an order statistic (X1:n,…,Xn:n) of a collection of independent but not necessarily identically distributed random variables, and anyi∈ {1,…,n}, the conditional distribution of (Xi+1:n,…,Xn:n) givenXi:n>sis shown to be stochastically increasing ins. This answers a question by Hu and Xie (2006).
Two Remarks on Blackwell's Theorem
Authors: Lehrer Ehud , Shmaya Eran
Published: July 2008

In a decision problem with uncertainty a decision maker receives partial information about the actual state via an information structure. After receiving a signal, he is allowed to withdraw and gets zero profit. We say that one structure is better than another when a withdrawal option exists if it may never happen that one structure guarantees a positive profit while the other structure guarantees only zero profit. This order between information structures is characterized in terms that are different from those used by Blackwell's comparison of experiments. We also treat the case of a malevolent nature that chooses a state in an adverse manner. It turns out that Blackwell's classical characterization also holds in this case.