bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring compartment-specific substrate cleavage by cathepsins B, K, L, and S at physiological pH and redox conditions
Authors: Jordans Silvia , Jenko-Kokalj Saša , Kühl Nicole M , Tedelind Sofia , Sendt Wolfgang , Brömme Dieter , Turk Dušan , Brix Klaudia
Published: September 2009

Background

Cysteine cathepsins are known to primarily cleave their substrates at reducing and acidic conditions within endo-lysosomes. Nevertheless, they have also been linked to extracellular proteolysis, that is, in oxidizing and neutral environments. Although the impact of reducing or oxidizing conditions on proteolytic activity is a key to understand physiological protease functions, redox conditions have only rarely been considered in routine enzyme activity assays. Therefore we developed an assay to test for proteolytic processing of a natural substrate by cysteine cathepsins which accounts for redox potentials and pH values corresponding to the conditions in the extracellular space in comparison to those within endo-lysosomes of mammalian cells.

Results

The proteolytic potencies of cysteine cathepsins B, K, L and S towards thyroglobulin were analyzed under conditions simulating oxidizing versus reducing environments with neutral to acidic pH values. Thyroglobulin, the precursor molecule of thyroid hormones, was chosen as substrate, because it represents a natural target of cysteine cathepsins. Thyroglobulin processing involves thyroid hormone liberation which, under physiological circumstances, starts in the extracellular follicle lumen before being continued within endo-lysosomes. Our study shows that all cathepsins tested were capable of processing thyroglobulin at neutral and oxidizing conditions, although these are reportedly non-favorable for cysteine proteases. All analyzed cathepsins generated distinct fragments of thyroglobulin at extracellular versus endo-lysosomal conditions as demonstrated by SDS-PAGE followed by immunoblotting or N-terminal sequencing. Moreover, the thyroid hormone thyroxine was liberated by the action of cathepsin S at extracellular conditions, while cathepsins B, K and L worked most efficiently in this respect at endo-lysosomal conditions.

Conclusion

The results revealed distinct cleavage patterns at all conditions analyzed, indicating compartment-specific processing of thyroglobulin by cysteine cathepsins. In particular, proteolytic activity of cathepsin S towards the substrate thyroglobulin can now be understood as instrumental for extracellular thyroid hormone liberation. Our study emphasizes that the proteolytic functions of cysteine cathepsins in the thyroid are not restricted to endo-lysosomes but include pivotal roles in extracellular substrate utilization. We conclude that understanding of the interplay and fine adjustment of protease networks in vivo is better approachable by simulating physiological conditions in protease activity assays.
From sequence to dynamics: the effects of transcription factor and polymerase concentration changes on activated and repressed promoters
Authors: González Pérez Abel , Espinosa Angarica Vladimir , Collado-Vides Julio , Vasconcelos Ana Tereza Ribeiro
Published: September 2009

Background

The fine tuning of two features of the bacterial regulatory machinery have been known to contribute to the diversity of gene expression within the same regulon: the sequence of Transcription Factor (TF) binding sites, and their location with respect to promoters. While variations of binding sequences modulate the strength of the interaction between the TF and its binding sites, the distance between binding sites and promoters alter the interaction between the TF and the RNA polymerase (RNAP).

Results

In this paper we estimated the dissociation constants (K

d
) of several E. coli TFs in their interaction with variants of their binding sequences from the scores resulting from aligning them to Positional Weight Matrices. A correlation coefficient of 0.78 was obtained when pooling together sites for different TFs. The theoretically estimated K

d
values were then used, together with the dissociation constants of the RNAP-promoter interaction to analyze activated and repressed promoters. The strength of repressor sites -- i.e., the strength of the interaction between TFs and their binding sites -- is slightly higher than that of activated sites. We explored how different factors such as the variation of binding sequences, the occurrence of more than one binding site, or different RNAP concentrations may influence the promoters' response to the variations of TF concentrations. We found that the occurrence of several regulatory sites bound by the same TF close to a promoter -- if they are bound by the TF in an independent manner -- changes the effect of TF concentrations on promoter occupancy, with respect to individual sites. We also found that the occupancy of a promoter will never be more than half if the RNAP concentration-to-K

p
ratio is 1 and the promoter is subject to repression; or less than half if the promoter is subject to activation. If the ratio falls to 0.1, the upper limit of occupancy probability for repressed drops below 10%; a descent of the limits occurs also for activated promoters.

Conclusion

The number of regulatory sites may thus act as a versatility-producing device, in addition to serving as a source of robustness of the transcription machinery. Furthermore, our results show that the effects of TF concentration fluctuations on promoter occupancy are constrained by RNAP concentrations.
Characterization of WRKYco-regulatory networks in rice and Arabidopsis
Authors: Berri Stefano , Abbruscato Pamela , Faivre-Rampant Odile , Brasileiro Ana CM , Fumasoni Irene , Satoh Kouji , Kikuchi Shoshi , Mizzi Luca , Morandini Piero , Pè Mario Enrico , Piffanelli Pietro
Published: September 2009

Background

The WRKY transcription factor gene family has a very ancient origin and has undergone extensive duplications in the plant kingdom. Several studies have pointed out their involvement in a range of biological processes, revealing that a large number ofWRKYgenes are transcriptionally regulated under conditions of biotic and/or abiotic stress. To investigate the existence ofWRKYco-regulatory networks in plants, a whole gene familyWRKYs expression study was carried out in rice (Oryza sativa). This analysis was extended toArabidopsis thalianataking advantage of an extensive repository of gene expression data.

Results

The presented results suggested that 24 members of the riceWRKYgene family (22% of the total) were differentially-regulated in response to at least one of the stress conditions tested. We defined the existence of nine OsWRKYgene clusters comprising both phylogenetically related and unrelated genes that were significantly co-expressed, suggesting that specific sets ofWRKYgenes might act in co-regulatory networks. This hypothesis was tested by Pearson Correlation Coefficient analysis of the ArabidopsisWRKYgene family in a large set of Affymetrix microarray experiments.AtWRKYswere found to belong to two main co-regulatory networks (COR-A, COR-B) and two smaller ones (COR-C and COR-D), all including genes belonging to distinct phylogenetic groups. The COR-A network contained severalAtWRKYgenes known to be involved mostly in response to pathogens, whose physical and/or genetic interaction was experimentally proven. We also showed that specific co-regulatory networks were conserved between the two model species by identifying Arabidopsis orthologs of the co-expressedOsWRKYgenes.

Conclusion

In this work we identified sets of co-expressedWRKYgenes in both rice and Arabidopsis that are functionally likely to cooperate in the same signal transduction pathways. We propose that, making use of data from co-regulatory networks, it is possible to highlight novel clusters of plant genes contributing to the same biological processes or signal transduction pathways. Our approach will contribute to unveil gene cooperation pathways not yet identified by classical genetic analyses. This information will open new routes contributing to the dissection of WRKY signal transduction pathways in plants.
Inversion 2La is associated with enhanced desiccation resistance in Anopheles gambiae
Authors: Gray Emilie M , Rocca Kyle AC , Costantini Carlo , Besansky Nora J
Published: September 2009

Background

Anopheles gambiae, the principal vector of malignant malaria in Africa, occupies a wide range of habitats. Environmental flexibility may be conferred by a number of chromosomal inversions non-randomly associated with aridity, including 2La. The purpose of this study was to determine the physiological mechanisms associated with the 2La inversion that may result in the preferential survival of its carriers in hygrically-stressful environments.

Methods

Two homokaryotypic populations of A. gambiae (inverted 2La and standard 2L+a) were created from a parental laboratory colony polymorphic for 2La and standard for all other known inversions. Desiccation resistance, water, energy and dry mass of adult females of both populations were compared at several ages and following acclimation to a more arid environment.

Results

Females carrying 2La were significantly more resistant to desiccation than 2L+a females at emergence and four days post-emergence, for different reasons. Teneral 2La females had lower rates of water loss than their 2L+a counterparts, while at four days, 2La females had higher initial water content. No differences in desiccation resistance were found at eight days, with or without acclimation. However, acclimation resulted in both populations significantly reducing their rates of water loss and increasing their desiccation resistance. Acclimation had contrasting effects on the body characteristics of the two populations: 2La females boosted their glycogen stores and decreased lipids, whereas 2La females did the contrary.

Conclusion

Variation in rates of water loss and response to acclimation are associated with alternative arrangements of the 2La inversion. Understanding the mechanisms underlying these traits will help explain how inversion polymorphisms permit exploitation of a heterogeneous environment by this disease vector.
Genes encoding novel secreted and transmembrane proteins are temporally and spatially regulated during Drosophila melanogasterembryogenesis
Authors: Zúñiga Alejandro , Hödar Christian , Hanna Patricia , Ibáñez Freddy , Moreno Pablo , Pulgar Rodrigo , Pastenes Luis , González Mauricio , Cambiazo Verónica
Published: September 2009

Background

Morphogenetic events that shape the Drosophila melanogaster embryo are tightly controlled by a genetic program in which specific sets of genes are up-regulated. We used a suppressive subtractive hybridization procedure to identify a group of developmentally regulated genes during early stages of D. melanogaster embryogenesis. We studied the spatiotemporal activity of these genes in five different intervals covering 12 stages of embryogenesis.

Results

Microarrays were constructed to confirm induction of expression and to determine the temporal profile of isolated subtracted cDNAs during embryo development. We identified a set of 118 genes whose expression levels increased significantly in at least one developmental interval compared with a reference interval. Of these genes, 53% had a phenotype and/or molecular function reported in the literature, whereas 47% were essentially uncharacterized. Clustering analysis revealed demarcated transcript groups with maximum gene activity at distinct developmental intervals. In situ hybridization assays were carried out on 23 uncharacterized genes, 15 of which proved to have spatiotemporally restricted expression patterns. Among these 15 uncharacterized genes, 13 were found to encode putative secreted and transmembrane proteins. For three of them we validated our protein sequence predictions by expressing their cDNAs in Drosophila S2R+ cells and analyzed the subcellular distribution of recombinant proteins. We then focused on the functional characterization of the gene CG6234. Inhibition of CG6234 by RNA interference resulted in morphological defects in embryos, suggesting the involvement of this gene in germ band retraction.

Conclusion

Our data have yielded a list of developmentally regulated D. melanogaster genes and their expression profiles during embryogenesis and provide new information on the spatiotemporal expression patterns of several uncharacterized genes. In particular, we recovered a substantial number of unknown genes encoding putative secreted and transmembrane proteins, suggesting new components of signaling pathways that might be incorporated within the existing regulatory networks controlling D. melanogaster embryogenesis. These genes are also good candidates for additional targeted functional analyses similar to those we conducted for CG6234.

See related minireview by Vichas and Zallen: http://www.jbiol.com/content/8/8/76
Effect of nutritional recovery with soybean flour diet on body composition, energy balance and serum leptin concentration in adult rats
Authors: Cheim Loanda Maria G , Oliveira Elisângela A , Arantes Vanessa C , Veloso Roberto V , Reis Marise Auxiliadora B , Gomes-da-Silva Maria Helena G , Carneiro Everardo M , Boschero Antonio C , Latorraca Márcia Q
Published: September 2009

Background

Malnutrition in early life is associated with obesity in adulthood and soybean products may have a beneficial effect on its prevention and treatment. This study evaluated body composition, serum leptin and energy balance in adult rats subjected to protein restriction during the intrauterine stage and lactation and recovering on a soybean flour diet.

Methods

Five groups of the Wistar strain of albino rats were used: CC, offspring born to and suckled by mothers fed a control diet and fed the same diet after weaning; CS, offspring born to and suckled by mothers fed a control diet and fed a soybean diet with 17% protein after weaning; LL, offspring of mothers fed a low protein diet and fed the same diet after weaning; LC, offspring of mothers fed a low protein diet, but fed a control diet after weaning; LS, offspring of mothers fed a low protein diet, but fed a soybean diet with 17% protein after weaning. Food intake, body, perirenal and retroperitoneal adipose tissue were measured in grams. Leptin was quantified using the Enzyme Linked Immuno Sorbent Assay (ELISA) and insulin by radioimmunoassay (RIA). Carcass composition was determined by chemical methods and energy expenditure was calculated by the difference between energy intake and carcass energy gain. Data were tested by analysis of variance (ANOVA).

Results

The LC and LS groups had higher energetic intake concerning body weight, lower energy expenditure, proportion of fat carcass and fat pads than CC and CS groups. The LS group showed reduced body weight gain and lower energy efficiency, which was reflected in less energy gain as protein and the proportion of carcass protein, and lower energy gain as lipid than in the LC groups, although both groups had eaten the same amount of diet and showed equal energy expenditure. Serum leptin did not differ among groups and was unrelated to food or energy intake and energy expenditure. Serum insulin was higher in the LS than in the LC group.

Conclusion

Protein restriction during intrauterine life and lactation periods did not provoke obesity in adulthood. Nutritional recovery with soybean diet decreased the body weight at the expense of lower energy efficiency with repercussion on lean mass.
An overview of cardiovascular risk factor burden in sub-Saharan African countries: a socio-cultural perspective
Authors: BeLue Rhonda , Okoror Titilayo A , Iwelunmor Juliet , Taylor Kelly D , Degboe Arnold N , Agyemang Charles , Ogedegbe Gbenga
Published: September 2009

Background

Sub-Saharan African (SSA) countries are currently experiencing one of the most rapid epidemiological transitions characterized by increasing urbanization and changing lifestyle factors. This has resulted in an increase in the incidence of non-communicable diseases, especially cardiovascular disease (CVD). This double burden of communicable and chronic non-communicable diseases has long-term public health impact as it undermines healthcare systems.

Purpose

The purpose of this paper is to explore the socio-cultural context of CVD risk prevention and treatment in sub-Saharan Africa. We discuss risk factors specific to the SSA context, including poverty, urbanization, developing healthcare systems, traditional healing, lifestyle and socio-cultural factors.

Methodology

We conducted a search on African Journals On-Line, Medline, PubMed, and PsycINFO databases using combinations of the key country/geographic terms, disease and risk factor specific terms such as "diabetes and Congo" and "hypertension and Nigeria". Research articles on clinical trials were excluded from this overview. Contrarily, articles that reported prevalence and incidence data on CVD risk and/or articles that report on CVD risk-related beliefs and behaviors were included. Both qualitative and quantitative articles were included.

Results

The epidemic of CVD in SSA is driven by multiple factors working collectively. Lifestyle factors such as diet, exercise and smoking contribute to the increasing rates of CVD in SSA. Some lifestyle factors are considered gendered in that some are salient for women and others for men. For instance, obesity is a predominant risk factor for women compared to men, but smoking still remains mostly a risk factor for men. Additionally, structural and system level issues such as lack of infrastructure for healthcare, urbanization, poverty and lack of government programs also drive this epidemic and hampers proper prevention, surveillance and treatment efforts.

Conclusion

Using an African-centered cultural framework, the PEN3 model, we explore future directions and efforts to address the epidemic of CVD risk in SSA.
Modeling system states in liver cells: Survival, apoptosis and their modifications in response to viral infection
Authors: Philippi Nicole , Walter Dorothee , Schlatter Rebekka , Ferreira Karine , Ederer Michael , Sawodny Oliver , Timmer Jens , Borner Christoph , Dandekar Thomas
Published: September 2009

Background

The decision pro- or contra apoptosis is complex, involves a number of different inputs, and is central for the homeostasis of an individual cell as well as for the maintenance and regeneration of the complete organism.

Results

This study centers on Fas ligand (FasL)-mediated apoptosis, and a complex and internally strongly linked network is assembled around the central FasL-mediated apoptosis cascade. Different bioinformatical techniques are employed and different crosstalk possibilities including the integrin pathway are considered. This network is translated into a Boolean network (74 nodes, 108 edges). System stability is dynamically sampled and investigated using the software SQUAD. Testing a number of alternative crosstalk possibilities and networks we find that there are four stable system states, two states comprising cell survival and two states describing apoptosis by the intrinsic and the extrinsic pathways, respectively. The model is validated by comparing it to experimental data from kinetics of cytochrome c release and caspase activation in wildtype and Bid knockout cells grown on different substrates. Pathophysiological modifications such as input from cytomegalovirus proteins M36 and M45 again produces output behavior that well agrees with experimental data.

Conclusion

A network model for apoptosis and crosstalk in hepatocytes shows four different system states and reproduces a number of different conditions around apoptosis including effects of different growth substrates and viral infections. It produces semi-quantitative predictions on the activity of individual nodes, agreeing with experimental data. The model (SBML format) and all data are available for further predictions and development.
Multicenter Randomized Phase II Study of Weekly or Twice-Weekly Bortezomib Plus Rituximab in Patients With Relapsed or Refractory Follicular or Marginal-Zone B-Cell Lymphoma
Authors: de Vos Sven , Goy André , Dakhil Shaker R. , Saleh Mansoor N. , McLaughlin Peter , Belt Robert , Flowers Christopher R. , Knapp Mark , Hart Lowell , Patel-Donnelly Dipti , Glenn Martha , Gregory Stephanie A. , Holladay Charles , Zhang Tracy , Boral Anthony L.
Published: September 2009

Purpose

To determine overall response rate (ORR), time to progression (TTP), and duration of response (DOR) with twice-weekly/weekly bortezomib plus rituximab, and evaluate safety/tolerability, in patients with relapsed or refractory CD20+ follicular lymphoma (FL) or marginal-zone lymphoma.

Patients and Methods

Patients were randomly assigned (minimization method) to bortezomib 1.3 mg/m2 twice weekly (days 1, 4, 8, and 11; 21-day cycle, five cycles; arm A) or bortezomib 1.6 mg/m2 weekly (days 1, 8, 15, and 22; 35-day cycle, three cycles; arm B) plus rituximab 375 mg/m2 weekly for 4 weeks (both arms). Response/progression was determined by International Workshop Response Criteria using oncologist/radiologist-adjudicated data from independent radiology review and investigator assessment.

Results

Eighty-one patients (arm A, n = 41; arm B, n = 40) were enrolled. Dose-intensity was higher in arm A; mean total bortezomib received was similar between arms (18.5 and 17.1 mg/m2). In arm A, ORR was 49% (14% complete response [CR]/CR unconfirmed [CRu]), median TTP was 7.0 months, and median DOR was not reached. In arm B, ORR was 43% (10% CR/CRu), and median TTP/DOR were 10.0/9.3 months. The weekly combination regimen seemed better tolerated. Grade 3 or worse adverse events seemed more common in arm A (54%) versus arm B (35%), including thrombocytopenia (10% v 0%) and peripheral neuropathy (10% v 5%), but diarrhea seemed less frequent (7% v 15%). No grade 4 toxicities were reported in arm B.

Conclusion

Both bortezomib plus rituximab regimens seem feasible in relapsed or refractory indolent lymphomas. The more convenient weekly combination regimen is being compared with single-agent rituximab in an ongoing phase III study in relapsed FL.
Pegylated Liposomal Doxorubicin Plus Docetaxel Significantly Improves Time to Progression Without Additive Cardiotoxicity Compared With Docetaxel Monotherapy in Patients With Advanced Breast Cancer Previously Treated With Neoadjuvant-Adjuvant Anthracycline Therapy: Results From a Randomized Phase III Study
Authors: Sparano Joseph A. , Makhson Anatoly N. , Semiglazov Vladimir F. , Tjulandin Sergei A. , Balashova Olga I. , Bondarenko Igor N. , Bogdanova Natalia V. , Manikhas George M. , Oliynychenko Gennadiy P. , Chatikhine Valery A. , Zhuang Sen H. , Xiu Liang , Yuan Zhilong , Rackoff Wayne R.
Published: September 2009

Purpose

To determine whether the combination of pegylated liposomal doxorubicin (PLD) and docetaxel significantly prolongs time to disease progression compared with docetaxel alone without an increase in cardiac toxicity in women with advanced breast cancer who had experienced relapse at least 1 year after prior adjuvant or neoadjuvant anthracycline therapy.

Patients and Methods

This international, phase III study randomly assigned 751 patients to receive either docetaxel 75 mg/m2 (n = 373) or PLD 30 mg/m2 followed by docetaxel 60 mg/m2 every 21 days (n = 378) and continued until disease progression or prohibitive toxicity. The primary end point was time to progression (TTP). Secondary end points were overall survival (OS), objective response rate (ORR), cardiac toxicity, and safety.

Results

Treatment with PLD-docetaxel significantly improved median TTP from 7.0 to 9.8 months (hazard ratio [HR] = 0.65; 95% CI, 0.55 to 0.77; P = .000001) and the ORR from 26% to 35% (P = .0085). OS was similar between the two groups (HR = 1.02; 95% CI, 0.86 to 1.22). The incidence of grade 3 or 4 adverse events were similar (78% v 72%), although a higher incidence of hand-foot syndrome (24% v 0%) and mucositis/stomatitis (12% v 1%) were observed in the PLD-docetaxel combination. Protocol-defined left ventricular ejection fraction decreases and congestive heart failure were reported in 5% and 1% in both treatment arms, respectively.

Conclusion

The PLD-docetaxel combination was more effective than docetaxel alone in women with metastatic breast cancer who had experienced relapse at least 1 year after prior adjuvant anthracycline therapy without an increase in cardiac toxicity, although mucocutaneous toxicity was more common.
Prognostic Significance of Copy-Number Alterations in Multiple Myeloma
Authors: Avet-Loiseau Hervé , Li Cheng , Magrangeas Florence , Gouraud Wilfried , Charbonnel Catherine , Harousseau Jean-Luc , Attal Michel , Marit Gerald , Mathiot Claire , Facon Thierry , Moreau Philippe , Anderson Kenneth C. , Campion Loïc , Munshi Nikhil C. , Minvielle Stéphane
Published: September 2009

Purpose

Chromosomal aberrations are a hallmark of multiple myeloma but their global prognostic impact is largely unknown.

Patients and Methods

We performed a genome-wide analysis of malignant plasma cells from 192 newly diagnosed patients with myeloma using high-density, single-nucleotide polymorphism (SNP) arrays to identify genetic lesions associated with prognosis.

Results

Our analyses revealed deletions and amplifications in 98% of patients. Amplifications in 1q and deletions in 1p, 12p, 14q, 16q, and 22q were the most frequent lesions associated with adverse prognosis, whereas recurrent amplifications of chromosomes 5, 9, 11, 15, and 19 conferred a favorable prognosis. Multivariate analysis retained three independent lesions: amp(1q23.3), amp(5q31.3), and del(12p13.31). When adjusted to the established prognostic variables (ie, t(4;14), del(17p), and serum β2-microglobulin [Sβ2M]), del(12p13.31) remained the most powerful independent adverse marker (P < .0001; hazard ratio [HR], 3.17) followed by Sβ2M (P < .0001; HR, 2.78) and the favorable marker amp(5q31.3) (P = .0005; HR, 0.37). Patients with amp(5q31.3) alone and low Sβ2M had an excellent prognosis (5-year overall survival, 87%); conversely, patients with del(12p13.31) alone or amp(5q31.3) and del(12p13.31) and high Sβ2M had a very poor outcome (5-year overall survival, 20%). This prognostic model was validated in an independent validation cohort of 273 patients with myeloma.

Conclusion

These findings demonstrate the power and accessibility of molecular karyotyping to predict outcome in myeloma. In addition, integration of expression of genes residing in the lesions of interest revealed putative features of the disease driving short survival.
Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium
Authors: Trippett Tanya M. , Herzog Cynthia , Whitlock James A. , Wolff Johannes , Kuttesch John , Bagatell Rochelle , Hunger Stephen P. , Boklan Jessica , Smith Amy A. , Arceci Robert J. , Katzenstein Howard M. , Harbison Christopher , Zhou Xiaofei , Lu Haolan , Langer Christiane , Weber Martin , Gore Lia
Published: September 2009

Purpose

To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors.

Patients and Methods

This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m2) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m2/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected.

Results

Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m2 weekly plus irinotecan 16 mg/m2/d (pediatric) or 20 mg/m2/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%).

Conclusion

The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.
IKZF1(Ikaros) Deletions inBCR-ABL1–Positive Acute Lymphoblastic Leukemia Are Associated With Short Disease-Free Survival and High Rate of Cumulative Incidence of Relapse: A GIMEMA AL WP Report
Authors: Martinelli Giovanni , Iacobucci Ilaria , Storlazzi Clelia Tiziana , Vignetti Marco , Paoloni Francesca , Cilloni Daniela , Soverini Simona , Vitale Antonella , Chiaretti Sabina , Cimino Giuseppe , Papayannidis Cristina , Paolini Stefania , Elia Loredana , Fazi Paola , Meloni Giovanna , Amadori Sergio , Saglio Giuseppe , Pane Fabrizio , Baccarani Michele , Foà Robin
Published: September 2009

Purpose

The causes of the aggressive nature of BCR-ABL1–positive adult acute lymphoblastic leukemia (ALL) are unknown. To identify, at the submicroscopic level, oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed an investigation of genomic copy number alterations using single nucleotide polymorphism array, genomic polymerase chain reaction, and sequencing of candidate genes.

Patients and Methods

Eighty-three patients with de novo adult Philadelphia chromosome (Ph) –positive ALL were enrolled onto institutional (n = 17) or Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Working Party delle Leucemia Acute (n = 66) clinical trials. Treatments included tyrosine kinase inhibitor (TKI) alone, conventional chemotherapy, or a combination of TKI and chemotherapy.

Results

A 7p12 deletion of IKZF1 (Ikaros) was identified in 52 (63%) of 83 patients. The pattern of deletion varied among different patients, but the two most common deletion types were loss of exons 4 to 7 in 31 (37%) of 83 patients and loss of exons 2 to 7 in 17 (20%) of 83 patients. Disease-free survival (DFS) was shorter in patients with IKZF1 deletion versus patients with IKZF1 wild type (10 v 32 months, respectively; P = .02). Furthermore, a significantly shorter cumulative incidence of relapse was recorded in patients with IKZF1 deletion versus patients with IKZF1 wild type (10.1 v 56.1 months, respectively; P = .001). Multivariate analysis confirmed the negative prognostic impact of IKZF1 deletion on DFS (P = .04).

Conclusion

We conclude that IKZF1 deletions are likely to be a genomic alteration that significantly affects the prognosis of Ph-positive ALL in adults.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor Danusertib in Patients With Advanced or Metastatic Solid Tumors
Authors: Steeghs Neeltje , Eskens Ferry A.L.M. , Gelderblom Hans , Verweij Jaap , Nortier Johan W.R. , Ouwerkerk Jan , van Noort Conny , Mariani Mariangela , Spinelli Riccardo , Carpinelli Patrizia , Laffranchi Bernard , de Jonge Maja J.A.
Published: September 2009

Purpose

Danusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of danusertib with additional pharmacokinetic, biomarker, and efficacy assessments.

Patients and Methods

Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m2 in the 6-hour IVS, and from 250 mg/m2 in the 3-hour IVS, were studied.

Results

Fifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m2 for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m2 or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients.

Conclusion

Dose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m2 infused over 6 hours on days 1, 8, and 15 every 28 days.
Phase II Study of Yttrium-90–Ibritumomab Tiuxetan in Patients With Relapsed or Refractory Mantle Cell Lymphoma
Authors: Wang Michael , Oki Yasuhiro , Pro Barbara , Romaguera Jorge Enrique , Rodriguez Maria Alma , Samaniego Felipe , McLaughlin Peter , Hagemeister Frederick , Neelapu Sattva , Copeland Amanda , Samuels Barry I. , Loyer Evelyne M. , Ji Yuan , Younes Anas
Published: September 2009

Purpose

This phase II trial evaluated the safety and efficacy of yttrium-90 (90Y)–ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma (MCL).

Patients and Methods

Patients with relapsed or refractory MCL were eligible for the study if they had adequate major organ function and performance status. Those with CNS disease, pleural effusion, circulating lymphoma cells ≥ 5,000/μL, or history of stem-cell transplant were ineligible. Patients with a platelet count ≥ 150,000/μL received a dose of 0.4 mCi/kg of 90Y–ibritumomab tiuxetan, whereas those with a platelet count less than 150,000/μL received a dose of 0.3 mCi/kg.

Results

Thirty-four patients with a median age of 68 years (range, 52 to 79 years) received the therapeutic dose. The patients had received a median of three prior treatment regimens (range, one to six treatment regimens), including those that contained rituximab (n = 32) and bortezomib (n = 7). Of the 32 patients with measurable disease, 10 (31%) achieved complete or partial remission. After a median follow-up of 22 months (range, 2 to 72+ months), an intent-to-treat analysis revealed a median event-free survival (EFS) duration of 6 months and an overall survival duration of 21 months. The median EFS for those who achieved partial or complete remission was 28 months, while it was 3 months for those whose disease did not respond (P < .0001); it was 9 months for patients whose tumor measured less than 5 cm in the largest diameter before treatment and 3 months for those whose tumor measured ≥ 5 cm (P = .015).

Conclusion

The single-agent activity of 90Y–ibritumomab tiuxetan and its favorable safety profile warrant its further development for the treatment of MCL.
Randomized Double-Blind Placebo-Controlled Trial of Thalidomide in Combination With Gemcitabine and Carboplatin in Advanced Non–Small-Cell Lung Cancer
Authors: Lee Siow Ming , Rudd Robin , Woll Penella J. , Ottensmeier Christian , Gilligan David , Price Allan , Spiro Stephen , Gower Nicole , Jitlal Mark , Hackshaw Allan
Published: September 2009

Purpose

Cancers rely on angiogenesis for their growth and dissemination. We hypothesized that thalidomide, an oral antiangiogenic agent, when combined with chemotherapy, and as maintenance treatment, would improve survival in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL).

Results

The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001).

Conclusion

In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histology.
New Lesions Detected by Single Nucleotide Polymorphism Array–Based Chromosomal Analysis Have Important Clinical Impact in Acute Myeloid Leukemia
Authors: Tiu Ramon V. , Gondek Lukasz P. , O'Keefe Christine L. , Huh Jungwon , Sekeres Mikkael A. , Elson Paul , McDevitt Michael A. , Wang Xiao Fei , Levis Mark J. , Karp Judith E. , Advani Anjali S. , Maciejewski Jaroslaw P.
Published: September 2009

Purpose

Cytogenetics is the primary outcome predictor in acute myeloid leukemia (AML). Metaphase cytogenetics (MC) detects an abnormal karyotype in only half of patients with AML, however. Single nucleotide polymorphism arrays (SNP-A) can detect acquired somatic uniparental disomy (UPD) and other cryptic defects, even in samples deemed normal by MC. We hypothesized that SNP-A will improve detection of chromosomal defects in AML and that this would enhance the prognostic value of MC.

Patients and Methods

We performed 250K and 6.0 SNP-A analyses on 140 patients with primary (p) and secondary (s) AML and correlated the results with clinical outcomes and Flt-3/nucleophosmin (NPM-1) status.

Results

SNP-A is more sensitive than MC in detecting unbalanced lesions (pAML, 65% v 39%, P = .002; and sAML, 78% v 51%, P = .003). Acquired somatic UPD, not detectable by MC, was common in our AML cohort (29% in pAML and 35% in sAML). Patients with SNP-A lesions including acquired somatic UPD exhibited worse overall survival (OS) and event-free survival (EFS) in pAML with normal MC and in pAML/sAML with abnormal MC. SNP-A improved the predictive value of Flt-3 internal tandem duplication/NPM-1 status, with inferior survival seen in patients with additional SNP-A defects. Multivariate analyses confirmed the independent predictive value of SNP-A defects for OS (hazard ratio [HR] = 2.52; 95% CI, 1.29 to 5.22; P = .006) and EFS (HR = 1.72; 95% CI, 1.12 to 3.48; P = .04).

Conclusion

SNP-A analysis allows enhanced detection of chromosomal abnormalities and provides important prognostic impact in AML.
Serum 25-Hydroxyvitamin D3 Levels Are Associated With Breslow Thickness at Presentation and Survival From Melanoma
Authors: Newton-Bishop Julia A. , Beswick Samantha , Randerson-Moor Juliette , Chang Yu-Mei , Affleck Paul , Elliott Faye , Chan May , Leake Susan , Karpavicius Birute , Haynes Sue , Kukalizch Kairen , Whitaker Linda , Jackson Sharon , Gerry Edwina , Nolan Clarissa , Bertram Chandra , Marsden Jerry , Elder David E. , Barrett Jennifer H. , Bishop D. Timothy
Published: September 2009

Purpose

A cohort study was carried out to test the hypothesis that higher vitamin D levels reduce the risk of relapse from melanoma.

Methods

A pilot retrospective study of 271 patients with melanoma suggested that vitamin D may protect against recurrence of melanoma. We tested these findings in a survival analysis in a cohort of 872 patients recruited to the Leeds Melanoma Cohort (median follow-up, 4.7 years).

Results

In the retrospective study, self-reports of taking vitamin D supplements were nonsignificantly correlated with a reduced risk of melanoma relapse (odds ratio = 0.6; 95% CI, 0.4 to 1.1; P = .09). Nonrelapsers had higher mean 25-hydroxyvitamin D3 levels than relapsers (49 v 46 nmol/L; P = .3; not statistically significant). In the cohort (prospective) study, higher 25-hydroxyvitamin D3 levels were associated with lower Breslow thickness at diagnosis (P = .002) and were independently protective of relapse and death: the hazard ratio for relapse-free survival (RFS) was 0.79 (95% CI, 0.64 to 0.96; P = .01) for a 20 nmol/L increase in serum level. There was evidence of interaction between the vitamin D receptor (VDR) BsmI genotype and serum 25-hydroxyvitamin D3 levels on RFS.

Conclusion

Results from the retrospective study were consistent with a role for vitamin D in melanoma outcome. The cohort study tests this hypothesis, providing evidence that higher 25-hydroxyvitamin D3 levels, at diagnosis, are associated with both thinner tumors and better survival from melanoma, independent of Breslow thickness. Patients with melanoma, and those at high risk of melanoma, should seek to ensure vitamin D sufficiency. Additional studies are needed to establish optimal serum levels for patients with melanoma.
Vincristine, Actinomycin, and Cyclophosphamide Compared With Vincristine, Actinomycin, and Cyclophosphamide Alternating With Vincristine, Topotecan, and Cyclophosphamide for Intermediate-Risk Rhabdomyosarcoma: Children's Oncology Group Study D9803
Authors: Arndt Carola A.S. , Stoner Julie A. , Hawkins Douglas S. , Rodeberg David A. , Hayes-Jordan Andrea A. , Paidas Charles N. , Parham David M. , Teot Lisa A. , Wharam Moody D. , Breneman John C. , Donaldson Sarah S. , Anderson James R. , Meyer William H.
Published: September 2009

Purpose

The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC).

Patients and Methods

Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided α level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC.

Results

A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups.

Conclusion

For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.
Primary Testicular Diffuse Large B-Cell Lymphoma: A Population-Based Study on the Incidence, Natural History, and Survival Comparison With Primary Nodal Counterpart Before and After the Introduction of Rituximab
Authors: Gundrum Jacob D. , Mathiason Michelle A. , Moore Derek B. , Go Ronald S.
Published: September 2009

Purpose

We performed a population-based study of primary testicular diffuse large B-cell lymphoma (DLBCL) in the United States to determine its incidence and survival trends, prognostic factors, and clinical outcome compared with males with nodal DLBCL.

Patients and Methods

The Surveillance, Epidemiology, and End Results database was reviewed to identify patients diagnosed between 1980 and 2005. To study the potential impact of the introduction of rituximab on survival, we used the year 2000 as cutoff point.

Results

We identified 769 patients with testicular DLBCL. The median age at diagnosis was 68.0 years. The incidence of DLBCL increased over time, with the highest rate among whites (twice that of blacks). The median overall survival (OS) for the whole group was 4.6 years, whereas the disease-specific survival (DSS) rates at 3, 5, and 15 years were 71.5%, 62.4%, and 43.0%, respectively. Independent predictors of worse DSS were older age, diagnosis before 1986, advanced stage, left testicular involvement, and not having surgery and radiation. The use of radiation did not change significantly over time. When testicular and nodal DLBCL patients were analyzed together, testicular primary was an independent predictor of better OS and DSS. Unlike nodal DLBCL, DSS did not improve in the patients with testicular DLBCL diagnosed after the year 2000.

Conclusion

The incidence of testicular DLBCL is increasing. Compared with nodal DLBCL, testicular DLBCL patients have a better overall prognosis but are at higher risk of late disease-related deaths. The introduction of rituximab in clinical practice does not seem to improve their early outcome.
A Recursive Algorithm for Finding All Nondominated Extreme Points in the Outcome Set of a Multiobjective Integer Programme
Authors: Przybylski Anthony , Gandibleux Xavier , Ehrgott Matthias
Published: September 2009

In this paper, we present two versions of an algorithm for the computation of all nondominated extreme points in the outcome set of a multiobjective integer programme. We define adjacency of these points based on weight space decomposition. Thus, our algorithms generalise the well-known dichotomic scheme to compute the set of nondominated extreme points in the outcome set of a biobjective programme. Both algorithms are illustrated with and numerically tested on instances of the assignment and knapsack problems with three objectives.
Novel Computer-Controlled Saturation of Dynamic Centrifuge Models Using High Viscosity Fluids
Authors: Stringer M. E. , Madabhushi S. P. G.
Published: September 2009

The practice of saturating centrifuge models with a highly viscous pore fluid is widely used. As the fluid saturates the model, care must be taken to ensure that the hydraulic gradients are not too high to cause excessive disturbance to the model. A new computer-controlled saturation system (CAM-Sat) has been developed and implemented at the University of Cambridge to aid the saturation of soil models with a high viscosity pore fluid. Models are saturated under vacuum and pore fluid enters through ports in the model’s base. The system controls the ingress of pore fluid into the model by monitoring the fluid mass flux and then altering the pressure drop between a reservoir of pore fluid and the model. The system was found to be stable across a wide range of fluid viscosities and sand types. A further test showed that the system was able to respond to changes in mass flux demanded by the researcher.