bluuebunny/crossref_metadata_2025 huggingface dataset:
Common and specific genomic sequences of avian and human extraintestinal pathogenic Escherichia coli as determined by genomic subtractive hybridization
Authors: Kariyawasam Subhashinie , Scaccianoce Jennifer A , Nolan Lisa K
Published: August 2007

Background

Suppression subtractive hybridization (SSH) strategy was used with extraintestinal pathogenic Escherichia coli (EXPEC) that cause avian colibacillosis (avian pathogenic E. coli or APEC) and human urinary tract infections (uropathogenic E. coli or UPEC) to determine if they possessed genes that were host and/or niche specific. Both APEC and UPEC isolates were used as tester and driver strains in 4 different SSHs in order to obtain APEC- and UPEC-specific subtraction fragments (SFs).

Results

These procedures yielded a total of 136 tester-specific SFs of which 85 were APEC-derived and 51 were UPEC-derived. Most of the APEC-derived SFs were associated with plasmids; whereas, the majority of UPEC-derived sequences matched to the bacterial chromosome. We further determined the distribution of these tester-derived sequences in a collection of UPEC and APEC isolates using polymerase chain reaction techniques. Plasmid-borne, APEC-derived sequences (tsh, cva B, tra R, tra C and sop B) were predominantly present in APEC, as compared to UPEC. Of the UPEC-derived SFs, those encoding hemolysin D and F1C major and minor fimbrial subunits were present only in UPEC. However, two UPEC-derived SFs that showed strong similarity to the uropathgenic-specific protein gene (usp) occurred in APEC, demonstrating that usp is not specific to UPEC.

Conclusion

This study provides evidence of the genetic variability of ExPEC as well as genomic similarities between UPEC and APEC; it did not identify any single marker that would dictate host and/or niche specificity in APEC or UPEC. However, further studies on the genes that encode putative or hypothetical proteins might offer important insight into the pathogenesis of disease, as caused by these two ExPEC.
Meningitis registry of hospitalized cases in children: epidemiological patterns of acute bacterial meningitis throughout a 32-year period
Authors: Theodoridou Maria N , Vasilopoulou Vasiliki A , Atsali Erato E , Pangalis Anastasia M , Mostrou Glyceria J , Syriopoulou Vassiliki P , Hadjichristodoulou Christos S
Published: August 2007

Background

Bacterial meningitis remains a source of substantial morbidity and mortality in childhood. During the last decades gradual changes have been observed in the epidemiology of bacterial meningitis, related to the introduction of new polysaccharide and conjugate vaccines. The study presents an overview of the epidemiological patterns of acute bacterial meningitis in a tertiary children 's hospital during a 32-year period, using information from a disease registry. Moreover, it discusses the contribution of communicable disease registries in the study of acute infectious diseases.

Methods

In the early 1970s a Meningitis Registry (MR) was created for patients admitted with meningitis in Aghia Sofia Children's Hospital in Athens. The MR includes demographic, clinical and laboratory data as well as treatment, complications and outcome of the patients. In 2000 a database was created and the collected data were entered, analyzed and presented in three chronological periods: A (1974–1984), B (1985–1994) and C (1995–2005).

Results

Of the 2,477 cases of bacterial meningitis registered in total, 1,146 cases (46.3%) were classified as "probable" and 1,331 (53.7%) as "confirmed" bacterial meningitis. The estimated mean annual Incidence Rate (IR) was 16.9/100,000 for bacterial meningitis, 8.9/100,000 for Neisseria meningitidis, 1.3/100,000 for Streptococcus pneumoniae, 2.5/100,000 for Haemophilus influenzae type b (Hib) before vaccination and 0.4/100,000 for Hib after vaccination. Neisseria meningitis constituted the leading cause of childhood bacterial meningitis for all periods and in all age groups. Hib was the second most common cause of bacterial meningitis before the introduction of Hib conjugate vaccine, in periods A and B. The incidence of bacterial meningitis due to Streptococcus pneumoniae was stable. The long-term epidemiological pattern of Neisseria meningitidis appears in cycles of approximately 10 years, confirmed by a significant rise of IR in period C. The Case Fatality Rate (CFR) from all causes was 3.8%, while higher CFR were estimated for Streptococcus pneumoniae (7.5%, RR=2.1, 95% CI 1.2–3.7) and Neisseria meningitidis (4.8%, RR=1.7, 95% CI 1.1–2.5) compared to other pathogens. Moreover, overall CFR varied significantly among the three time periods (p = 0.0015), and was estimated to be higher in period C.

Conclusion

By using the MR we were able to delineate long-term changes in the epidemiology of bacterial meningitis. Thus the MR proved to be a useful tool in the study and the prevention of communicable diseases in correlation with prevention strategies, such as vaccinations.
The prevalance, epidemiology and risk factors for onychomycosis in hemodialysis patients
Authors: Kuvandik Güven , Çetin Meryem , Genctoy Gultekin , Horoz Mehmet , Duru Mehmet , Akcali Cenk , Satar Salim , Kiykim Ahmet A , Kaya Hasan
Published: August 2007

Background

Onychomycosis has a high prevalance among immunocompromised patients such as diabetics and hemodialysis patients. In the present study, we aimed to investigate the prevalence of onychomycosis among hemodialysis patients with and without diabetes mellitus, and to find out the factors likely to be associated with the development of onychomycosis among hemodialysis patients.

Methods

One hundred and nine hemodialysis patients were enrolled. Fifty-seven of hemodialysis patients had the diagnosis of diabetes mellitus. Nail scrapings were obtained from 76 patients who had dystrophic nail changes. Samples were examined with 20% potassium hydroxide solution and all of the samples were inoculated on Saboraud's dextrose agar, potateus dextrose agar and mycobiotic agar. Diagnosis of onychomycosis was based on the presence of both positive clinical signs and positive potassium hydroxide test.

Results

Onychomycosis was diagnosed in 26.6% of hemodialysis patients. Diabetes mellitus was present in 68.9% of patients with onychomycosis. Toenail scraping cultures were reported to be positive in 19.7% of patients with dystrophic nail changes. Logistic regression analysis revealed that the presence of diabetes mellitus and the mean duration of hemodialysis were the significant predictors associated with the development of onychomycosis.

Conclusion

The prevalence of dystrophic nail changes and onychomycosis is increased among hemodialysis patients. The dialysis duration and the presence of diabetes mellitus are the independent risk factors associated with the development of onychomycosis in uraemic patients.
Attitudes, understanding, and concerns regarding medical research amongst Egyptians: A qualitative pilot study
Authors: Khalil Susan S , Silverman Henry J , Raafat May , El-Kamary Samer , El-Setouhy Maged
Published: August 2007

Background

Medical research must involve the participation of human subjects. Knowledge of patients' perspectives and concerns with their involvement in research would enhance recruitment efforts, improve the informed consent process, and enhance the overall trust between patients and investigators. Several studies have examined the views of patients from Western countries. There is limited empirical research involving the perspectives of individuals from developing countries. The purpose of this study is to examine the attitudes of Egyptian individuals toward medical research. Such information would help clarify the type and extent of concerns regarding research participation of individuals from cultural, economic, and political backgrounds that differ from those in developed countries.

Methods

We conducted semi-structured interviews with 15 Egyptian individuals recruited from the outpatient settings (public and private) at Ain Shams University in Cairo, Egypt. Interviews were taped, transcribed, and translated. Thematic analysis followed.

Results

All individuals valued the importance of medical research; however most would not participate in research that involved more than minimal risk. Individuals were comfortable with studies involving surveys and blood sampling, but many viewed drug trials as being too risky. All participants valued the concept of informed consent, as they thought that their permission to be in a research study was paramount. Many participants had discomfort with or difficulty in the understanding several research concepts: randomization, double-blind, and clinical equipoise. Trust in the physicians performing research was important in deciding to participate in clinical research. The small sample size and the selection bias associated with obtaining information from only those who agreed to participate in a research study represent limitations in this study.

Conclusion

Overall, individuals in our sample recognize the value of medical research and have a great deal of trust regarding medical research and their participation in research. There were, however, concerns with the level of research risks associated with several types of medical research. Many also demonstrated confusion with certain research methodologies. We recommend 1) enhanced educational efforts regarding general research concepts to enhance the validity of informed consent and 2) further survey studies in other areas of Egypt to determine the generalizability of our results.
PKCepsilon and an increase in intracellular calcium concentration are necessary for PGF2alpha to inhibit LH-stimulated progesterone secretion in cultured bovine steroidogenic luteal cells
Authors: Goravanahally Madhusudan P , Sen Aritro , Inskeep Emmet K , Flores Jorge A
Published: August 2007

The hypotheses that PKCepsilon is necessary for: 1) PGF2alpha to inhibit LH-stimulated progesterone (P4) secretion, and 2) for the expression of key prostaglandin synthesizing/metabolizing enzymes were tested in bovine luteal cells in which PKCepsilon expression had been ablated using a validated siRNA protocol. Steroidogenic cells from Day -6 bovine corpus luteum (CL) were isolated and transfected to reduce PKCepsilon expression after 48, 72 and 96 h. A third tested hypothesis was that an increase in intracellular calcium concentration ([Ca(2+)]i) is the cellular mechanism through which PGF2alpha inhibits luteal progesterone. The hypothesis was tested with two pharmacological agents. In the first test, the dose-dependent effects on raising the [Ca(2+)]i with the ionophore, A23187, on basal and LH-stimulated P4 secretion in cells collected from early (Day -4) and mid-cycle (Day -10) bovine CL was examined. In the second test, the ability of PGF2alpha to inhibit LH-stimulated P4 secretion in Day-10 luteal cells was examined under conditions in which an elevation in [Ca(2+)]i had been buffered by means of the intracellular calcium chelator, Bapta-AM.

PKCepsilon expression was reduced 65 and 75% by 72 and 96 h after transfection, respectively. In cells in which PKCepsilon expression was ablated by 75%, the inhibitory effect of PGF2alpha on LH-stimulated P4 secretion was only 29% lower than in the LH-stimulated group. In contrast, it was reduced by 75% in the group where PKCepsilon expression had not been reduced (P < 0.05). Real time PCR analysis indicated that there were no differences in the expression of cyclooxygenase-2 (COX-2), aldoketoreductase 1B5 (AKR1B5), prostaglandin E synthase (PGES), hydroxyprostaglandin-15 dehydrogenase (PGDH) and PGE2 -9-reductase as a function of PKCepsilon down-regulation. Finally, LH stimulated secretion of P4 at each luteal stage (Day -4 and -10), and PGF2alpha inhibited this only in Day -10 cells (P < 0.05). When A23187 was used at concentrations greater than 0.1 μmol, the induced elevation in [Ca(2+)]i inhibited the effect of LH on secretion of P4 in Day -4 and -10 cells (P < 0.05, Fig. 5). The inhibitory effect of PGF2alpha on LH-stimulated P4 in Day -10 cells was reduced if an increase in [Ca(2+)]i was prevented with Bapta-AM. These results support the hypothesis that differential expression of PKCepsilon and an elevation of [Ca(2+)]i are important for acquisition of luteolytic response to PGF2alpha.
Application of Atomic Dielectric Resonance Spectroscopy for the screening of blood samples from patients with clinical variant and sporadic CJD
Authors: Fagge Timothy J , Barclay G Robin , Stove G Colin , Stove Gordon , Robinson Michael J , Head Mark W , Ironside James W , Turner Marc L
Published: August 2007

Background

Sub-clinical variant Creutzfeldt-Jakob disease (vCJD) infection and reports of vCJD transmission through blood transfusion emphasise the need for blood screening assays to ensure the safety of blood and transplanted tissues. Most assays aim to detect abnormal prion protein (PrPSc), although achieving required sensitivity is a challenge.

Methods

We have used innovative Atomic Dielectric Resonance Spectroscopy (ADRS), which determines dielectric properties of materials which are established by reflectivity and penetration of radio/micro waves, to analyse blood samples from patients and controls to identify characteristic ADR signatures unique to blood from vCJD and to sCJD patients. Initial sets of blood samples from vCJD, sCJD, non-CJD neurological diseases and normal healthy adults (blood donors) were screened as training samples to determine group-specific ADR characteristics, and provided a basis for classification of blinded sets of samples.

Results

Blood sample groups from vCJD, sCJD, non-CJD neurological diseases and normal healthy adults (blood donors) screened by ADRS were classified with 100% specificity and sensitivity, discriminating these by a co-variance expert analysis system.

Conclusion

ADRS appears capable of recognising and discriminating serum samples from vCJD, sCJD, non-CJD neurological diseases, and normal healthy adults, and might be developed to provide a system for primary screening or confirmatory assay complementary to other screening systems.
Targeting APOBEC3A to the viral nucleoprotein complex confers antiviral activity
Authors: Goila-Gaur Ritu , Khan Mohammad A , Miyagi Eri , Kao Sandra , Strebel Klaus
Published: August 2007

Background

APOBEC3 (A3) proteins constitute a family of cytidine deaminases that provide intracellular resistance to retrovirus replication and to transposition of endogenous retroelements. A3A has significant homology to the C-terminus of A3G but has only a single cytidine deaminase active site (CDA), unlike A3G, which has a second N-terminal CDA previously found to be important for Vif sensitivity and virus encapsidation. A3A is packaged into HIV-1 virions but, unlike A3G, does not have antiviral properties. Here, we investigated the reason for the lack of A3A antiviral activity.

Results

Sequence alignment of A3G and A3A revealed significant homology of A3A to the C-terminal region of A3G. However, while A3G co-purified with detergent-resistant viral nucleoprotein complexes (NPC), virus-associated A3A was highly detergent-sensitive leading us to speculate that the ability to assemble into NPC may be a property conveyed by the A3G N-terminus. To test this model, we constructed an A3G-3A chimeric protein, in which the N-terminal half of A3G was fused to A3A. Interestingly, the A3G-3A chimera was packaged into HIV-1 particles and, unlike A3A, associated with the viral NPC. Furthermore, the A3G-3A chimera displayed strong antiviral activity against HIV-1 and was sensitive to inhibition by HIV-1 Vif.

Conclusion

Our results suggest that the A3G N-terminal domain carries determinants important for targeting the protein to viral NPCs. Transfer of this domain to A3A results in A3A targeting to viral NPCs and confers antiviral activity.
Human immunodeficiency virus type 1 specific cytotoxic T lymphocyte responses in Chinese infected with HIV-1 B'/C Recombinant (CRF07_BC)
Authors: Chen Jianping , Hong Kunxue , Jia Mingming , Liu Hongwei , Zhang Yuanzhi , Liu Sha , Zhang Xiaoqing , Zhao Hongjing , Peng Hong , Ma Pengfei , Xing Hui , Ruan Yuhua , Williams Katie L , Yu Xu G , Altfeld Marcus , Walker Bruce D , Shao Yiming
Published: August 2007

Background

The characterization of HIV-1-specific T cell responses in people infected with locally circulating HIV-1 strain will facilitate the development of HIV-1 vaccine. Sixty intravenous drug users infected with HIV-1 circulating recombinant form 07_BC (CRF07_BC), which has been spreading rapidly in western China from north to south, were recruited from Xinjiang, China to assess the HIV-1-specific T cell responses at single peptide level with overlapping peptides (OLP) covering the whole concensus clades B and C proteome.

Results

The median of the total magnitude and total number of OLPs recognized by CTL responses were 10925 SFC/million PBMC and 25 OLPs, respectively, when tested by clade C peptides, which was significantly higher than when tested by clade B peptides. The immunodominant regions, which cover 14% (58/413) of the HIV-1 proteome, are widely distributed throughout the HIV-1 proteome except in Tat, Vpu and Pol-PR, with Gag, Pol-RT, Pol-Int and Nef being most frequently targeted. The subdominant epitopes are mostly located in p24, Nef, integrase, Vpr and Vif. Of the responses directed to clade C OLPs, 61.75% (972/1574) can be observed when tested with corresponding clade B OLPs. However, Pol-PR and Vpu tend to be targeted in the clade B sequence rather than the clade C sequence, which is in line with the recombinant pattern of CRF07_BC. Stronger and broader CTL responses in subjects with CD4 cell counts ranging from 200 to 400/mm3 were observed when compared to those with less than 200/mm3 or more than 400/mm3, though there have been no significant correlations identified between the accumulative CTL responses or overall breadth and CD4 cell count or plasma viral load.

Conclusion

This is the first study conducted to comprehensively address T cell responses in Chinese subjects infected with HIV-1 CRF07_BC in which subtle differences in cross-reactivity were observed, though similar patterns of overall immune responses were demonstrated with clade B infected populations. The immunodominant regions identified in this population can facilitate future HIV-1 vaccine development in China.
Synchronously diagnosed lymph nodal collision tumor of malignant melanoma and chonic lymphocytic leukemia/small lymphocytic lymphoma: case report
Authors: El Demellawy Dina , Ross Catherine , Sur Monalisa , Alowami Salem
Published: August 2007

Synchronous composite tumors have been described but are uncommon. Moreover, simultaneous occurrence of synchronous tumors in the same tissue or organ is even less common. We report a case of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma and malignant melanoma (MM) occurring synchronously in the same lymph node. Several cases of an association between cutaneous malignancies and lymphoproliferative disorders have been reported. Some of which included CLL and MM, occurring in the same patient often CLL after MM. The risk of having CLL after MM has been reported to be increased. Various genetic and environmental etiologies have been postulated, but have as yet not been proven. To our knowledge this is the first time that synchronous occurrence of these two malignant processes in the same tissue is described. In this case it is important that the melanoma was recognized in the excised lymph node, as this finding had much more critical treatment and long term survival consequences.
Verifying 4D gated radiotherapy using time-integrated electronic portal imaging: a phantom and clinical study
Authors: van Sörnsen de Koste John R , Cuijpers Johan P , de Geest Frank GM , Lagerwaard Frank J , Slotman Ben J , Senan Suresh
Published: August 2007

Background

Respiration-gated radiotherapy (RGRT) can decrease treatment toxicity by allowing for smaller treatment volumes for mobile tumors. RGRT is commonly performed using external surrogates of tumor motion. We describe the use of time-integrated electronic portal imaging (TI-EPI) to verify the position of internal structures during RGRT delivery

Methods

TI-EPI portals were generated by continuously collecting exit dose data (aSi500 EPID, Portal vision, Varian Medical Systems) when a respiratory motion phantom was irradiated during expiration, inspiration and free breathing phases. RGRT was delivered using the Varian RPM system, and grey value profile plots over a fixed trajectory were used to study object positions. Time-related positional information was derived by subtracting grey values from TI-EPI portals sharing the pixel matrix. TI-EPI portals were also collected in 2 patients undergoing RPM-triggered RGRT for a lung and hepatic tumor (with fiducial markers), and corresponding planning 4-dimensional CT (4DCT) scans were analyzed for motion amplitude.

Results

Integral grey values of phantom TI-EPI portals correlated well with mean object position in all respiratory phases. Cranio-caudal motion of internal structures ranged from 17.5–20.0 mm on planning 4DCT scans. TI-EPI of bronchial images reproduced with a mean value of 5.3 mm (1 SD 3.0 mm) located cranial to planned position. Mean hepatic fiducial markers reproduced with 3.2 mm (SD 2.2 mm) caudal to planned position. After bony alignment to exclude set-up errors, mean displacement in the two structures was 2.8 mm and 1.4 mm, respectively, and corresponding reproducibility in anatomy improved to 1.6 mm (1 SD).

Conclusion

TI-EPI appears to be a promising method for verifying delivery of RGRT. The RPM system was a good indirect surrogate of internal anatomy, but use of TI-EPI allowed for a direct link between anatomy and breathing patterns.
Analysis of the spectral hole in velocity versus depth resolution for reflection traveltimes with limited aperture
Authors: Bube Kenneth P. , Langan Robert T. , Nemeth Tamas
Published: August 2007

It is difficult to resolve the ambiguity between velocity and reflector depth using reflection traveltimes when the aperture is small, as is common for deep reflectors. For velocity perturbations that are independent of the vertical variable, there is an even stronger velocity-versus-depth ambiguity at a horizontal wavelength of 2.5 times the reflector depth. We give a theoretical explanation of why this spectral hole occurs. When the maximum offset is small, there are velocity and reflector depth perturbations that cause almost cancelling traveltime perturbations; the net traveltime perturbations are second order in offset, making resolution between velocity and depth difficult at all wavelengths. But for the particular wavelength [Formula: see text] ≈ 2.565 times the reflector depth, an extra term in the Taylor expansion for traveltime near zero offset vanishes; the net traveltime perturbations are fourth order in offset. Thus velocity-versus-depth resolution degrades much sooner at this wavelength as the maximum offset gets small. We show in addition that this behavior extends to velocity perturbations that can depend on the vertical variable, and spectral holes in velocity-versus-depth resolution can appear at any horizontal wavelength. Velocity perturbations with very simple vertical variation are sufficient to create these spectral holes. This behavior is not limited to extremely small apertures; the effect of this spectral hole can be felt when the maximum angle of incidence is as large as 25°.
Intellectual Property
Authors: Walker David A.
Published: August 2007

The Intellectual Property department in each issue of Geophysics provides U.S. patent abstracts, published patent abstracts of U.S. patent applications, and published abstracts filed under the Patent Cooperation Treaty (PCT).
Phase I/II Trial of Temsirolimus Combined With Interferon Alfa for Advanced Renal Cell Carcinoma
Authors: Motzer Robert J. , Hudes Gary R. , Curti Brendan D. , McDermott David F. , Escudier Bernard J. , Negrier Sylvie , Duclos Brigitte , Moore Laurence , O'Toole Timothy , Boni Joseph P. , Dutcher Janice P.
Published: August 2007

Purpose

Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC.

Patients and Methods

Patients were enrolled onto a multicenter, ascending-dose study of temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information.

Results

Seventy-one patients were entered to receive one of six dose levels. The recommended dose was temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia for all patients and those who received the recommended dose. Among patients who received the recommended dose (n = 39), 8% achieved partial response and 36% had stable disease for at least 24 weeks. Median progression-free survival for all patients in the study was 9.1 months.

Conclusion

The combination of temsirolimus and IFN has an acceptable safety profile and displays antitumor activity in patients with advanced RCC. Temsirolimus 15 mg plus IFN 6 MU is the recommended dose for evaluation in a randomized phase III study.
Prevalence, Clinical Pattern, and Outcome of CNS Involvement in Childhood and Adolescent Non-Hodgkin's Lymphoma Differ by Non-Hodgkin's Lymphoma Subtype: A Berlin-Frankfurt-Münster Group Report
Authors: Salzburg Janina , Burkhardt Birgit , Zimmermann Martin , Wachowski Olga , Woessmann Wilhelm , Oschlies Ilske , Klapper Wolfram , Wacker Hans-Heinrich , Ludwig Wolf-Dieter , Niggli Felix , Mann Georg , Gadner Helmut , Riehm Hansjoerg , Schrappe Martin , Reiter Alfred
Published: August 2007

Purpose

We analyzed the prevalence, clinical pattern, and prognostic impact of CNS involvement in a large cohort of children and adolescents diagnosed with non-Hodgkin's lymphoma (NHL), with special attention to differences according to NHL subtype.

Patients and Methods

From October 1986 to December 2002, 2,381 patients (median age, 9.37 years; range, 0.2 to 23.8 years; female-to-male ratio, 1:2.7) from Germany, Austria, and Switzerland were registered. A total of 2,086 patients were eligible for the consecutive multicenter protocols NHL–Berlin-Frankfurt-Münster [BFM] -86, NHL-BFM-90, and NHL-BFM-95, and could be evaluated for outcome.

Results

CNS involvement was diagnosed in 141 (5.9%) of 2,381 patients and was associated with an advanced stage of NHL. The percentage of CNS-positive patients was 8.8% for Burkitt's lymphoma/Burkitt's leukemia (BL/B-ALL), 5.4% for precursor B–lymphoblastic lymphoma (pB-LBL), 3.3% for anaplastic large-cell lymphoma, 3.2% for T-cell–LBL, 2.6% for diffuse large B-cell lymphoma, and 0% for primary mediastinal large B-cell NHL (P < .001). Most CNS-positive patients with pB-LBL, T-LBL, or BL/B-ALL had meningeal disease. The probability of event-free survival (pEFS; ± SE) at 5 years was 85% ± 1% for the 2,086 protocol patients (median follow-up, 6.5 years; range, 0.3 to 17.7 years). For the 112 CNS-positive patients, pEFS was 64% ± 5%, compared with 86% ± 1% for the 1,927 CNS-negative patients (P < .001). Although CNS disease had no impact on pEFS for advanced-stage T-LBL patients, CNS-positive patients with BL/B-ALL had a worse average outcome than CNS-negative patients with stage IV BL/B-ALL (60% ± 5% v 81% ± 3%; P < .001). In multivariate analysis, CNS disease was the strongest predictor for relapse in BL/B-ALL patients with advanced-stage disease.

Conclusion

Six percent of childhood/adolescent NHL patients were CNS positive. However, the prevalence, pattern, and prognostic impact of CNS involvement differed among NHL subtypes.
Multicenter, Randomized, Phase II Trial of CI-1033, an Irreversible Pan-ERBB Inhibitor, for Previously Treated Advanced Non–Small-Cell Lung Cancer
Authors: Jänne Pasi A. , von Pawel Joachim , Cohen Roger B. , Crino Lucio , Butts Charles A. , Olson Steven S. , Eiseman Irene A. , Chiappori Alberto A. , Yeap Beow Y. , Lenehan Peter F. , Dasse Kathy , Sheeran Meredith , Bonomi Philip D.
Published: August 2007

Purpose

To evaluate the efficacy of the pan-ERBB inhibitor, CI-1033, in platinum-refractory or recurrent advanced-stage non–small-cell lung cancer (NSCLC).

Patients and Methods

This open-label, randomized phase II trial evaluated CI-1033 in patients with advanced-stage NSCLC who experienced treatment failure after or were refractory to platinum-based chemotherapy. Three oral CI-1033 doses were evaluated in 21-day dosing cycles: 50 mg daily for 21 consecutive days, 150 mg daily for 21 consecutive days, and 450 mg daily for 14 consecutive days followed by 7 days of no treatment. The primary efficacy end point was the 1-year survival rate.

Results

One hundred sixty-six patients were randomly assigned to treatment. Baseline patient demographics were well balanced. The most common drug-related adverse events were rash and diarrhea. The 450-mg arm (14 days on/7 days off) was closed early due to an excessive rate of adverse events. The 1-year survival rates were 29%, 26%, and 29%, respectively, in the three arms. The response rates were 2%, 2%, and 4%, and stable disease was confirmed in 16%, 23%, and 18% of patients, respectively, in the three study arms. Exploratory analyses demonstrated a prolonged survival in patients who developed a rash and in those with baseline tumor ERBB-2 expression.

Conclusion

CI-1033 had modest activity in unselected NSCLC patients but did not meet its primary end point. Future studies should focus on identifying methods of patient selection.
Prostate-Specific Antigen and Pain Surrogacy Analysis in Metastatic Hormone-Refractory Prostate Cancer
Authors: Armstrong Andrew J. , Garrett-Mayer Elizabeth , Ou Yang Yi-Chun , Carducci Michael A. , Tannock Ian , de Wit Ronald , Eisenberger Mario
Published: August 2007

Purpose

It is currently unclear if early prostate-specific antigen (PSA) or pain improvements are adequate surrogates for overall survival in men with metastatic hormone-refractory prostate cancer (HRPC). Here we examined various degrees of PSA decline and pain response as surrogates for the survival benefit observed in the TAX327 trial.

Patients and Methods

In the TAX327 trial, 1,006 men with HRPC were randomly assigned to receive docetaxel in two schedules, or mitoxantrone, each with prednisone: 989 men provided data on 3-month PSA decline. Surrogacy was examined for post-treatment changes in PSA and pain response using Cox proportional hazards models to calculate the proportion of treatment effect (PTE) explained by each potential surrogate.

Results

A ≥ 30% PSA decline within 3 months of treatment initiation provides the highest degree of surrogacy, with a PTE of 0.66 (95% CI, 0.23 to 1.0), and was associated with a hazard ratio (HR) of 0.50 (95% CI, 0.43 to 0.58) for overall survival after adjusting for treatment effect. Introduction of a ≥ 30% PSA decline is predictive of survival regardless of treatment arm. Other changes in PSA or PSA kinetics, PSA normalization, and pain responses were highly prognostic but weaker surrogates for survival.

Conclusion

In the TAX327 trial, a PSA decline of ≥ 30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival, confirming data from the Southwest Oncology Group 9916 trial. However, given the wide CIs around the estimate of this moderate surrogate effect, overall survival should remain the preferred end point for phase III trials of cytotoxic agents in HRPC.
Nuclear Factor-kB Tumor Expression Predicts Response and Survival in Irinotecan-Refractory Metastatic Colorectal Cancer Treated With Cetuximab-Irinotecan Therapy
Authors: Scartozzi Mario , Bearzi Italo , Pierantoni Chiara , Mandolesi Alessandra , Loupakis Fotios , Zaniboni Alberto , Catalano Vincenzo , Quadri Antonello , Zorzi Fausto , Berardi Rossana , Biscotti Tommasina , Labianca Roberto , Falcone Alfredo , Cascinu Stefano
Published: August 2007

Purpose

NF-kB expression has been shown to be responsible for resistance to antineoplastic agents and it also plays a part in the activation of the epidermal growth factor receptor downstream signaling pathway in colorectal tumors. The aim of our analysis was to investigate a correlation between NF-kB expression, response rate, time to progression, and survival in advanced colorectal cancer patients receiving cetuximab and irinotecan.

Patients and Methods

We analyzed retrospectively the immunoreactivity for NF-kB in irinotecan-refractory patients receiving cetuximab and irinotecan.

Results

Seventy-six patients were analyzed. Cetuximab and irinotecan were administered as second-line chemotherapy in 19 patients and after ≥ two lines of chemotherapy in the remaining 57 patients. We observed a partial response (PR) in 16 patients for an overall response rate of 24%. Thirty-two patients (48%) experienced progressive disease; median time to progression (TTP) was 3.6 months and median overall survival was 10.3 months. NF-kB was positive in 46 patients (60%). All main clinical characteristics were well balanced between NF-kB–positive and NF-kB–negative patients. The response rate was 10% (four PRs) versus 48% (12 PRs; P = .0007) in NF-kB–positive and NF-kB–negative tumors, respectively. Median TTP in NF-kB–positive patients was 3 v 6.4 months in the remaining patients (P = .021). Median overall survival was 9.5 v 15.8 months for NF-kB–positive and NF-kB–negative patients, respectively (P = .036)

Conclusion

The difference in median TTP, overall survival, and response rate seem to confirm that NF-kB may play a crucial role in predicting the efficacy of cetuximab and irinotecan in advanced colorectal tumors.
Epidermal Growth Factor Receptor Mutation Status and Adjuvant Chemotherapy With Uracil-Tegafur for Adenocarcinoma of the Lung
Authors: Suehisa Hiroshi , Toyooka Shinichi , Hotta Katsuyuki , Uchida Akiko , Soh Junichi , Fujiwara Yoshiro , Matsuo Keitaro , Ouchida Mamoru , Takata Minoru , Kiura Katsuyuki , Date Hiroshi
Published: August 2007

Purpose

Adjuvant chemotherapy with uracil-tegafur has been demonstrated to prolong survival among patients with resected lung adenocarcinomas. Epidermal growth factor receptor (EGFR) mutations have been reported to be present in lung adenocarcinomas. The present study evaluated whether the EGFR status could be used as a biologic predictor of the outcome of adjuvant chemotherapy with uracil-tegafur.

Patients and Methods

The EGFR mutational status of 187 patients with resected lung adenocarcinomas was determined using a polymerase chain reaction–based assay for EGFR exons 19 and 21; the results were then correlated with the effect of adjuvant uracil-tegafur chemotherapy on survival. The antiproliferative effect of fluorouracil (FU) on adenocarcinoma cell lines with EGFR wild-type or mutant type status was examined by measuring the inhibitory concentrations at 50% (IC50s).

Results

Among the 187 patients, 68 received uracil-tegafur as adjuvant chemotherapy, and 119 were not treated with any chemotherapeutic agents. EGFR mutations were present in 79 patients (43%). Overall, the adjuvant chemotherapy with uracil-tegafur significantly prolonged survival compared with the control group (hazard ratio = 0.38; P = .005). The survival benefit of adjuvant chemotherapy with uracil-tegafur was also examined after stratifying the patients according to EGFR mutation status. Adjuvant chemotherapy significantly prolonged survival among patients with EGFR wild-type tumors (hazard ratio = 0.34; P = .013) but not among patients with EGFR mutant tumors. In an in vitro experiment, the IC50s of EGFR mutant cells to FU were higher than those of wild-type cells, indicating that EGFR wild-type cells are more sensitive to FU than mutant cells.

Conclusion

EGFR status influenced the effect of adjuvant chemotherapy with uracil-tegafur. Adjuvant chemotherapy could be customized based on EGFR status.
Pleural Effusion in Patients With Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure
Authors: Quintás-Cardama Alfonso , Kantarjian Hagop , O'Brien Susan , Borthakur Gautham , Bruzzi John , Munden Reginald , Cortes Jorge
Published: August 2007

Purpose

We investigated the risk factors and management of pleural effusion associated with dasatinib therapy for chronic myelogenous leukemia (CML) after failure of imatinib.

Patients and Methods

We analyzed 138 patients with CML treated with dasatinib from November 2003 to January 2006 in one phase I (n = 50) and four phase II (n = 88) studies for the development of pleural effusion.

Results

Pleural effusion occurred in 48 patients (35%; grade 3/4 in 23 [17%]), including 29% of those treated in chronic phase (CP), 50% in accelerated phase (AP), and 33% in blast phase (BP). By multivariate analysis, history of cardiac disease, hypertension, and use of a twice-daily schedule (v once daily) were identified as factors associated with development of pleural effusions. Effusions were exudative in 78% of the assessable cases. In some patients, effusions were associated with reversible increments of right ventricular systolic pressure. Management included transient dasatinib interruption in 83%, diuretics in 71%, pulse steroids in 27%, and thoracentesis in 19% of patients.

Conclusion

Pleural effusions occur during dasatinib therapy, particularly among patients in AP or BP. A twice-daily schedule may result in a higher incidence of pleural effusion. Close monitoring and timely intervention may allow patients to continue therapy and achieve the desired clinical benefit.
Sequential and combinatorial inputs from Nodal, Delta2/Notch and FGF/MEK/ERK signalling pathways establish a grid-like organisation of distinct cell identities in the ascidian neural plate
Authors: Hudson Clare , Lotito Sonia , Yasuo Hitoyoshi
Published: August 2007

The ascidian neural plate has a grid-like organisation, with six rows and eight columns of aligned cells, generated by a series of stereotypical cell divisions. We have defined unique molecular signatures for each of the eight cells in the posterior-most two rows of the neural plate - rows I and II. Using a combination of morpholino gene knockdown, dominant-negative forms and pharmacological inhibitors, we tested the role of three signalling pathways in defining these distinct cell identities. Nodal signalling at the 64-cell stage was found to be required to define two different neural plate domains - medial and lateral - with Nodal inducing lateral and repressing medial identities. Delta2, an early Nodal target, was found to then subdivide each of the lateral and medial domains to generate four columns. Finally, a separate signalling system along the anteroposterior axis, involving restricted ERK1/2 activation,was found to promote row I fates and repress row II fates. Our results reveal how the sequential integration of three signalling pathways - Nodal,Delta2/Notch and FGF/MEK/ERK - defines eight different sub-domains that characterise the ascidian caudal neural plate. Most remarkably, the distinct fates of the eight neural precursors are each determined by a unique combination of inputs from these three signalling pathways.
The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation
Authors: Shang Enyuan , Nickerson Helen D. , Wen Duancheng , Wang Xiangyuan , Wolgemuth Debra J.
Published: August 2007

Brdt is a testis-specific member of the distinctive BET sub-family of bromodomain motif-containing proteins, a motif that binds acetylated lysines and is implicated in chromatin remodeling. Its expression is restricted to the germ line, specifically to pachytene and diplotene spermatocytes and early spermatids. Targeted mutagenesis was used to generate mice carrying a mutant allele of Brdt, BrdtΔBD1, which lacks only the first of the two bromodomains that uniquely characterize BET proteins. Homozygous BrdtΔBD1/ΔBD1mice were viable but males were sterile, producing fewer and morphologically abnormal sperm. Aberrant morphogenesis was first detected in step 9 elongating spermatids, and those elongated spermatids that were formed lacked the distinctive foci of heterochromatin at the peri-nuclear envelope. Quantitative reverse transcription (RT)-PCR showed threefold increased levels of histone H1t (Hist1h1t) in BrdtΔBD1/ΔBD1testes and chromatin immunoprecipitation revealed that Brdt protein, but not BrdtΔBD1 protein, was associated with the promoter of H1t. Intracytoplasmic sperm injection suggested that the DNA in the BrdtΔBD1 mutant sperm could support early embryonic development and yield functional embryonic stem cells. This is the first demonstration that deletion of just one of the two bromodomains in members of the BET sub-family of bromodomain-containing proteins has profound effects on in vivo differentiation.
The testis-specific proteasome subunit Prosα6T of D. melanogaster is required for individualization and nuclear maturation during spermatogenesis
Authors: Zhong Lei , Belote John M.
Published: August 2007

Most regulated proteolysis in eukaryotes is carried out by the 26S proteasome. This large, multisubunit complex comprises a catalytic core particle (20S proteasome) and a regulatory particle (19S regulator) capping each end. In Drosophila, about a third of the 32 proteasome subunits are found to have testis-specific isoforms, encoded by paralogous genes. Here,we characterize in detail the spermatogenic expression of the core particle subunit Prosα6 (Pros35) and its testis-specific isoform Prosα6T. Using GFP-tagged transgenes, it is shown that whereas the Prosα6 subunit is expressed in early stages of spermatogenesis, gradually fading away following meiosis, the testis-specific Prosα6T becomes prominent in spermatid nuclei and cytoplasm after meiosis, and persists in mature sperm. In addition, these subunits are found in numerous `speckles' near individualization complexes, similar to the previously described expression pattern of the caspase Dronc (Nedd2-like caspase), suggesting a link to the apoptosis pathway. We also studied the phenotypes of a loss-of-function mutant of Prosα6T generated by targeted homologous recombination. Homozygous males are sterile and show spermatogenic defects in sperm individualization and nuclear maturation, consistent with the expression pattern of Prosα6T. The results demonstrate a functional role of testis-specific proteasomes during Drosophila spermatogenesis.
A regulatory network involving Foxn4, Mash1 and delta-like 4/Notch1 generates V2a and V2b spinal interneurons from a common progenitor pool
Authors: Del Barrio Marta G. , Taveira-Marques Raquel , Muroyama Yuko , Yuk Dong-In , Li Shengguo , Wines-Samuelson Mary , Shen Jie , Smith Hazel K. , Xiang Mengqing , Rowitch David , Richardson William D.
Published: August 2007

In the developing central nervous system, cellular diversity depends in part on organising signals that establish regionally restricted progenitor domains, each of which produces distinct types of differentiated neurons. However, the mechanisms of neuronal subtype specification within each progenitor domain remain poorly understood. The p2 progenitor domain in the ventral spinal cord gives rise to two interneuron (IN) subtypes, V2a and V2b,which integrate into local neuronal networks that control motor activity and locomotion. Foxn4, a forkhead transcription factor, is expressed in the common progenitors of V2a and V2b INs and is required directly for V2b but not for V2a development. We show here in experiments conducted using mouse and chick that Foxn4 induces expression of delta-like 4 (Dll4) and Mash1 (Ascl1). Dll4 then signals through Notch1 to subdivide the p2 progenitor pool. Foxn4, Mash1 and activated Notch1 trigger the genetic cascade leading to V2b INs, whereas the complementary set of progenitors, without active Notch1, generates V2a INs. Thus, Foxn4 plays a dual role in V2 IN development: (1) by initiating Notch-Delta signalling, it introduces the asymmetry required for development of V2a and V2b INs from their common progenitors; (2) it simultaneously activates the V2b genetic programme.
Effect of Sample Aliquot Size on the Limit of Detection and Reproducibility of Clinical Assays
Authors: Chen Guorong , Kobayashi Lori , Nazarenko Irina
Published: August 2007

Background: Nucleic acid amplification technologies significantly improved the limit of detection (LOD) for diagnostic assays. The ability of these assays to amplify fewer than 10 target copies of DNA or RNA imposes new requirements on the preparation of clinical samples. We report a statistical method to determine how large of an aliquot is necessary to reproducibly provide a detectable number of cells.

Methods: We determined the success probability (p) based on aliquot size and sample volume. The binomial distribution, based on p and the concentration of cells in sample, was used to calculate the probability of getting no target objects in an aliquot and to determine the minimum number of objects per aliquot necessary to generate a reproducible clinical assay.

Results: The described method was applied to find a minimum aliquot volume required for a set LOD, false-negative rate (FNR), and %CV. For example, to keep FNR <0.01% for 0.5%, 1% and 2% aliquots (minimum 2000, 1000, and 500 cells per sample) are required. Comparison between experimental and predicted FNR demonstrated good correlation for the small volume aliquots and/or low concentration of target. When 4 μL of 200 copies/mL of plasmid is amplified, predicted and experimental FNRs are 47.2% and 44.9%.

Conclusion: This probability model is a useful tool to predict the impact of aliquot volume on the LOD and reproducibility of clinical assays. Even for samples for which pathogens are homogeneously distributed, it is theoretically impossible to collect a single pathogen consistently if the concentration of pathogen is below a certain limit.
A Novel Equation to Estimate Glomerular Filtration Rate Using Beta-Trace Protein
Authors: White Christine A , Akbari Ayub , Doucette Steve , Fergusson Dean , Hussain Naser , Dinh Laurent , Filler Guido , Lepage Nathalie , Knoll Greg A
Published: August 2007

Background: Beta-trace protein (BTP) is a low molecular weight glycoprotein that is a more sensitive marker of glomerular filtration rate (GFR) than serum creatinine. The utility of BTP has been limited by the lack of an equation to translate BTP into an estimate of GFR. The objectives of this study were to develop a BTP-based GFR estimation equation.

Methods: We measured BTP and GFR by 99mtechnetium-diethylenetriaminepentaacetic acid in 163 stable adult renal transplant recipients. Stepwise multiple regression models were created to predict GFR corrected for body surface area. The following variables were considered for entry into the model: BTP, urea, sex, albumin, creatinine, age, and race.

Results: BTP alone accounted for 75.6% of variability in GFR. The model that included all the predictor variables had the largest coefficient of determination (R2) at 0.821. The model with only BTP, urea, and sex had only a slightly lower R2 of 0.81 and yielded the following equation: GFR mL · min−1 · (1.73 m2)−1 = 112.1 × BTP−0.662 × Urea−0.280 × (0.88 if female). A 2nd equation (R2 = 0.79) using creatinine instead of urea was also developed: GFR mL · min−1 · (1.73 m2)−1 = 1.678 × BTP−0.758 × creatinine−0.204 × (0.871 if female).

Conclusions: We have shown that BTP can be used in a simple equation to estimate GFR. Further study is needed in other populations to determine accuracy and clinical utility of this equation.