bluuebunny/crossref_metadata_2025 huggingface dataset:
Constructing Molecular Classifiers for the Accurate Prognosis of Lung Adenocarcinoma
Authors: Guo Lan , Ma Yan , Ward Rebecca , Castranova Vince , Shi Xianglin , Qian Yong
Published: June 2006

Purpose: Individualized therapy of lung adenocarcinoma depends on the accurate classification of patients into subgroups of poor and good prognosis, which reflects a different probability of disease recurrence and survival following therapy. However, it is currently impossible to reliably identify specific high-risk patients. Here, we propose a computational model system which accurately predicts the clinical outcome of individual patients based on their gene expression profiles.

Experimental Design: Gene signatures were selected using feature selection algorithms random forests, correlation-based feature selection, and gain ratio attribute selection. Prediction models were built using random committee and Bayesian belief networks. The prognostic power of the survival predictors was also evaluated using hierarchical cluster analysis and Kaplan-Meier analysis.

Results: The predictive accuracy of an identified 37-gene survival signature is 0.96 as measured by the area under the time-dependent receiver operating curves. The cluster analysis, using the 37-gene signature, aggregates the patient samples into three groups with distinct prognoses (Kaplan-Meier analysis, P < 0.0005, log-rank test). All patients in cluster 1 were in stage I, with N0 lymph node status (no metastasis) and smaller tumor size (T1 or T2). Additionally, a 12-gene signature correctly predicts the stage of 94.2% of patients.

Conclusions: Our results show that the prediction models based on the expression levels of a small number of marker genes could accurately predict patient outcome for individualized therapy of lung adenocarcinoma. Such an individualized treatment may significantly increase survival due to the optimization of treatment procedures and improve lung cancer survival every year through the 5-year checkpoint.
Tumor-Infiltrating Cytotoxic T Cells but not Regulatory T Cells Predict Outcome in Anal Squamous Cell Carcinoma
Authors: Grabenbauer Gerhard G. , Lahmer Godehard , Distel Luitpold , Niedobitek Gerald
Published: June 2006

Purpose: Tumor-infiltrating lymphocytes (TIL) are a possible prognostic factor in solid tumors. Cytotoxic TILs are generally considered as prognostically favorable, whereas regulatory T cells (Treg) may have adverse effects by virtue of their ability to inhibit effector cells. We have evaluated the effect of T-cell subsets on survival in patients with anal squamous cell carcinoma following radiochemotherapy.

Methods: Biopsy specimens from 38 patients with anal carcinomas were evaluated using tissue microarrays and immunohistochemistry for the presence of tumor-infiltrating immune cells using CD3, CD4, CD8, and CD68 antibodies. Treg were identified using an antibody directed against the transcription factor FoxP3, and granzyme B served as a marker for cytotoxic cells. Intratumoral immune cells were enumerated using a semiautomatic image analysis program. Prognostic effect of TIL subsets was evaluated by the log-rank test comparing no evidence of disease survival for groups with high and low numbers using median values as cutoff.

Results: CD3+ and CD4+ TILs influenced no evidence of disease survival: 3-year rates for patients with low numbers were 89% and 95%, respectively, and 54% (P = 0.02) and 48%, (P = 0.01), respectively, in cases with high numbers. Large numbers of tumor-infiltrating granzyme B+ cytotoxic cells had a significant negative prognostic effect (P = 0.008), whereas no effect was observed for Treg.

Conclusions: TILs were identified as negative prognostic indicators in anal squamous cell carcinomas with granzyme B+ cytotoxic cells showing highest effect on outcome. This is possibly explained by the selection of therapy-resistant tumor cell clones. No prognostic influence of Treg was found. Knowledge of local immune responses is important for the development of immunotherapeutic strategies.
Germ Line Mutations of Mismatch Repair Genes in Hereditary Nonpolyposis Colorectal Cancer Patients with Small Bowel Cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study
Authors: Park Jae-Gahb , Kim Duck-Woo , Hong Chang Won , Nam Byung-Ho , Shin Young-Kyoung , Hong Sung-Hye , Kim Il-Jin , Lim Seok-Byung , Aronson Melyssa , Bisgaard Marie Luise , Brown Gregor J. , Burn John , Chow Elizabeth , Conrad Peggy , Douglas Fiona , Dunlop Malcolm , Ford James , Greenblatt Marc S. , Heikki Jarvinen , Heinimann Karl , Lynch Elly L. , Macrae Finlay , McKinnon Wendy C. , Möeslein Gabriela , Rossi Benedito Mauro , Rozen Paul , Schofield Lyn , Vaccaro Carlos , Vasen Hans , Velthuizen Mary , Viel Alessandra , Wijnen Juul
Published: June 2006

Purpose: The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC).

Experimental Design: A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations.

Results: The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P < 0.001).

Conclusions: In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P < 0.001).
Nuclear Factor-κB Signature of Inflammatory Breast Cancer by cDNA Microarray Validated by Quantitative Real-time Reverse Transcription-PCR, Immunohistochemistry, and Nuclear Factor-κB DNA-Binding
Authors: Van Laere Steven J. , Van der Auwera Ilse , Van den Eynden Gert G. , Elst Hilde J. , Weyler Joost , Harris Adrian L. , van Dam Peter , Van Marck Eric A. , Vermeulen Peter B. , Dirix Luc Y.
Published: June 2006

Purpose: Inflammatory breast cancer (IBC) is the most aggressive form of locally advanced breast cancer with high metastatic potential. In a previous study, we showed that IBC is a different form of breast cancer compared with non-IBC by cDNA microarray analysis. A list of 756 genes with significant expression differences between IBC and non-IBC was identified. In-depth functional analysis revealed the presence of a high number of nuclear factor-κB (NF-κB) target genes with elevated expression in IBC versus non-IBC. This led to the hypothesis that NF-κB contributes to the phenotype of IBC. The aim of the present study was to further investigate the role of NF-κB in IBC.

Experimental Design: Immunohistochemistry and NF-κB DNA-binding experiments were done for all NF-κB subunits (RelA, RelB, cRel, NFkB1, and NFkB2) using IBC and non-IBC specimens. Transcriptionally active NF-κB dimers were identified by means of coexpression analysis. In addition, quantitative real-time reverse transcription-PCR for eight NF-κB target genes, selected upon a significant, 3-fold gene expression difference between IBC and non-IBC by cDNA microarray analysis, was done.

Results: We found a significant overexpression for all of eight selected NF-κB target genes in IBC compared with non-IBC by quantitative real-time reverse transcription-PCR. In addition, we found a statistically elevated number of immunostained nuclei in IBC compared with non-IBC for RelB (P = 0.038) and NFkB1 (P < 0.001). Immunohistochemical data were further validated by NF-κB DNA-binding experiments. Significant correlations between immunohistochemical data and NF-κB DNA binding for RelA, RelB, NFkB1, and NFkB2 were found. Transcriptionally active NF-κB dimers, composed of specific combinations of NF-κB family members, were found in 19 of 44 IBC specimens compared with 2 of 45 non-IBC specimens (P < 0.001). In addition, we found evidence for an estrogen receptor (ER)–mediated inhibition of the NF-κB signaling pathway. NF-κB target genes were significantly elevated in ER− versus ER+ breast tumors. Also, the amount of immunostained nuclei for RelB (P = 0.025) and NFkB1 (P = 0.031) was higher in ER− breast tumors versus ER+ breast tumors.

Conclusions: The NF-κB transcription factor pathway probably contributes to the phenotype of IBC and possibly offers new options for treatment of patients diagnosed with this aggressive form of breast cancer.
Ionizing Radiation Antagonizes Tumor Hypoxia Induced by Antiangiogenic Treatment
Authors: Riesterer Oliver , Honer Michael , Jochum Wolfram , Oehler Christoph , Ametamey Simon , Pruschy Martin
Published: June 2006

Purpose: The combined treatment modality of ionizing radiation with inhibitors of angiogenesis is effective despite the supposition that inhibition of angiogenesis might increase tumor hypoxia and thereby negatively affect radiation sensitivity. To directly assess this still controversial issue, we analyzed treatment-dependent alterations of tumor oxygenation in response to inhibition of angiogenesis alone, ionizing radiation, and combined treatment.

Experimental Design: Serial measurements with high-resolution [18F]fluoromisonidazole positron emission tomography and immunohistochemical detection of the endogenous hypoxia marker glucose transporter-1 were done to determine tumor hypoxia in a murine mammary carcinoma allograft model.

Results: Inhibition of angiogenesis with the clinically relevant vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 reduced microvessel density but had only minimal effects on tumor growth, tumor cell apoptosis, and proliferation. However, PTK787/ZK222584 treatment increased overall and local tumor hypoxia as revealed by extended expression of the hypoxia marker glucose transporter-1 and increased uptake of [18F]fluoromisonidazole. Fractionated irradiation induced a strong growth delay, which was associated with enhanced apoptosis and reduced proliferation of tumor cells but only minor effects on microvessel density and allograft oxygenation. Combined treatment with fractionated irradiation resulted in extended tumor growth delay and tumor cell apoptosis but no increase in tumor hypoxia.

Conclusions: These results show that irradiation antagonizes the increase of hypoxia by vascular endothelial growth factor receptor tyrosine kinase inhibition and abrogates the potential negative effect on tumor hypoxia. Thus, the risk of treatment-induced hypoxia by inhibitors of angiogenesis exists but is kept minimal when combined with a cytotoxic treatment modality.
Effects of 12-O-Tetradecanoylphorbol-13-acetate (TPA) in Combination with Paclitaxel (Taxol) on Prostate Cancer LNCaP Cells Cultured In vitro or Grown as Xenograft Tumors in Immunodeficient Mice
Authors: Zheng Xi , Chang Richard L. , Cui Xiao-Xing , Avila Gina E. , Hebbar Vidya , Garzotto Mark , Shih Weichung Joe , Lin Yong , Lu Shou-En , Rabson Arnold B. , Kong Ah Ng Tony , Conney Allan H.
Published: June 2006

Purpose: To investigate the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with paclitaxel (Taxol) on prostate cancer cells cultured in vitro or grown as tumors in immunodeficient mice.

Experimental Design: Human prostate cancer LNCaP cells in culture were treated with TPA alone or in combination with paclitaxel. NCr immunodeficient mice with well-established LNCaP tumors received i.p. injections with vehicle or with TPA, paclitaxel, or TPA in combination with paclitaxel. The animals either received daily treatment for 5 consecutive days followed by a 2-day intermission, which was repeated for a total of 28 days (experiment 1), or continuous daily treatment for 28 days (experiment 2).

Results: Treatment of LNCaP cells with a combination of TPA and paclitaxel synergistically inhibited the growth and induced apoptosis in cultured LNCaP cells, and this treatment also induced a marked increase in phosphorylated c-Jun-NH2-kinase (JNK). In animal experiments, tumor growth occurred in all mice treated with vehicle. When treated with TPA alone, the percentage of animals with some tumor regression was 33% in experiment 1 and 100% in experiment 2. Treatment of animals with paclitaxel alone caused some tumor regression in 17% and 57% of the animals in experiments 1 and 2, respectively. All animals treated with TPA + paclitaxel in both experiments had some tumor regression.

Conclusions: TPA and paclitaxel in combination had a stronger inhibitory effect on the growth of LNCaP cells in culture or as xenograft tumors in immunodeficient mice than either agent alone. Clinical trials with TPA alone or in combination with paclitaxel in patients with prostate cancer may be warranted.
FAS Death Domain Deletions and Cellular FADD-like Interleukin 1β Converting Enzyme Inhibitory Protein (Long) Overexpression: Alternative Mechanisms for Deregulating the Extrinsic Apoptotic Pathway in Diffuse Large B-Cell Lymphoma Subtypes
Authors: Takahashi Hidenobu , Feuerhake Friedrich , Kutok Jeffery L. , Monti Stefano , Dal Cin Paola , Neuberg Donna , Aster Jon C. , Shipp Margaret A.
Published: June 2006

Purpose: Large B-cell lymphomas (LBCL) arise from normal antigen-exposed B cells at germinal center (GC) or post-GC stages of differentiation. Negative selection of normal low-affinity or self-reactive GC B-cells depends on CD95 (FAS)-mediated apoptosis. FAS mutations that result in deletion of the cytoplasmic death domain destabilize the trimeric receptor and inhibit FAS-mediated apoptosis. This apoptotic pathway is also inhibited when the nuclear factor κB (NFκB) target, cellular FADD-like interleukin 1β converting enzyme inhibitory protein (cFLIP), interacts with the death-inducing signaling complex, assembled around the FAS death domain. Herein, we ask whether FAS death domain mutations and NFκB-mediated overexpression of cFLIP represent alternative mechanisms for deregulating the extrinsic apoptotic pathway in LBCL subtypes defined by gene expression profiling [oxidative phosphorylation, B-cell receptor/proliferation, and host response diffuse LBCLs and primary mediastinal LBCLs].

Experimental Design: The FAS receptor was sequenced, FAS death domain mutations identified, and cFLIP expression assessed in a series of primary LBCLs with gene expression profiling–defined subtype designations and additional genetic analyses [t(14;18) and t(3;v)].

Results: FAS death domain deletions were significantly more common in oxidative phosphorylation tumors, which also have more frequent t(14;18), implicating structural abnormalities of either the extrinsic or intrinsic pathway in this diffuse LBCL subtype. In marked contrast, host response tumors, which have up-regulation of multiple NFκB target genes and increased NFκB activity, express significantly higher levels of cFLIPlong.

Conclusions: These data suggest that the gene expression profiling–defined LBCL subtypes have different mechanisms for deregulating FAS-mediated cell death and, more generally, that these tumor groups differ with respect to their underlying genetic abnormalities.
Phase I/II Trial of an Allogeneic Cellular Immunotherapy in Hormone-Naïve Prostate Cancer
Authors: Simons Jonathan W. , Carducci Michael A. , Mikhak Bahar , Lim Michael , Biedrzycki Barbara , Borellini Flavia , Clift Shirley M. , Hege Kristen M. , Ando Dale G. , Piantadosi Steven , Mulligan Richard , Nelson William G.
Published: June 2006

Purpose: To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer.

Patients and Methods: A single-institution phase I/II trial was done in hormone therapy–naïve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases. Treatments were administered weekly via intradermal injections of 1.2 × 108 GM-CSF gene–transduced, irradiated, cancer cells (6 × 107 LNCaP cells and 6 × 107 PC-3 cells) for 8 weeks.

Results: Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P < 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a+ dendritic cells and CD68+ macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred.

Conclusions: This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.
Which Cyclin E Prevails as Prognostic Marker for Breast Cancer? Results from a Retrospective Study Involving 635 Lymph Node–Negative Breast Cancer Patients
Authors: Sieuwerts Anieta M. , Look Maxime P. , Meijer-van Gelder Marion E. , Timmermans Mieke , Trapman Anita M.A.C. , Garcia Roberto Rodriguez , Arnold Miranda , Goedheer Anneke J.W. , de Weerd Vanja , Portengen Henk , Klijn Jan G.M. , Foekens John A.
Published: June 2006

Purpose: To evaluate the prognostic value of cyclin E with a quantitative method for lymph node–negative primary breast cancer patients.

Patients and Methods: mRNA transcripts of full-length and splice variants of cyclin E1 (CCNE1) and cyclin E2 (CCNE2) were measured by real-time PCR in frozen tumor samples from 635 lymph node–negative breast cancer patients who had not received neoadjuvant or adjuvant systemic therapy.

Results: None of the PCR assays designed for the specific splice variants of the cyclins gave additional prognosis-related information compared with the common assays able to detect all variants. In Cox multivariate analysis, corrected for the traditional prognostic factors, high levels of cyclin E were independently associated with a short distant metastasis-free survival [hazard ratio (HR), 3.40; P < 0.001 for CCNE1 and HR, 1.76; P < 0.001 for CCNE2, respectively]. After dichotomizing the tumors at the median level of 70% tumor cells, the multivariate analysis showed particularly strong results for CCNE1 in the group of 433 patients with stroma-enriched primary tumors (HR, 5.12; P < 0.001). In these tumors, the worst prognosis was found for patients with estrogen receptor–negative tumors expressing high CCNE1 (HR, 9.89; P < 0.001) and for patients with small (T1) tumors expressing high CCNE1 (HR, 8.47; P < 0.001).

Conclusion: Our study shows that both CCNE1 and CCNE2 qualify as independent prognostic markers for lymph node–negative breast cancer patients, and that CCNE1 may provide additional information for specific subgroups of patients.
Markers of Bone Metabolism and Survival in Men with Hormone-Refractory Metastatic Prostate Cancer
Authors: Cook Richard J. , Coleman Robert , Brown Janet , Lipton Allan , Major Pierre , Hei Yong Jiang , Saad Fred , Smith Matthew R.
Published: June 2006

Purpose: To evaluate the relative prognostic value for specific markers of osteoblast and osteoclast activity while controlling for previously reported prognostic variables among men with hormone-refractory metastatic prostate cancer.

Experimental Design: The 643 subjects in this report were participants in multicenter randomized controlled trial of zoledronic acid in men with metastatic prostate cancer. All subjects had bone metastases and disease progression despite medical or surgical castration. Relationships between baseline covariates and overall survival were examined by Cox proportional hazard model. Serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide were assessed as representative specific markers of osteoblast and osteoclast activity, respectively. Other covariates in the model were age, log prostate-specific antigen, hemoglobin, lactate dehydrogenase, albumin, analgesic use, and Eastern Cooperative Oncology Group performance status.

Results: Serum BAP was significantly correlated with urinary N-telopeptide (correlation coefficient = 0.674; 95% confidence interval, 0.628-0.715; P < 0.0001). In univariate analyses, higher levels of serum BAP and urinary N-telopeptide levels were significantly associated with shorter overall survival. After controlling for the other variables, including N-telopeptide, in multivariate models, higher serum BAP levels were consistently associated with shorter survival. In contrast, urinary N-telopeptide levels were not significantly associated with survival in multivariate analyses. Variables retained in the reduced multivariate model were age, log prostate-specific antigen, hemoglobin, lactate dehydrogenase, analgesic use, and BAP.

Conclusions: Serum BAP significantly correlates with urinary N-telopeptide in men with androgen-independent prostate cancer and bone metastases. In multivariate models, higher levels of serum BAP but not urinary N-telopeptide are associated with shorter overall survival.
Activities and Accomplishments of the Cancer and Leukemia Group B Genitourinary Committee
Authors: Small Eric J. , Halabi Susan , Kantoff Phillip , D'Amico Anthony , Stadler Walter , Kelley W. Kevin , Mohler James , Bajorin Dean , Vogelzang Nicholas J.
Published: June 2006

The Cancer and Leukemia Group B Genitourinary (GU) Committee has developed a multidisciplinary approach to treatment of GU cancer and has integrated correlative science research into the major research themes of the GU Committee. In localized prostate cancer, trials have evaluated novel approaches in radiation therapy. For patients with recurrence after local therapy, a trial evaluating local recurrence with salvage prostatectomy and a study of systemic therapy with “peripheral androgen blockade” were undertaken. Major contributions have been made in developing and testing therapeutics for advanced, androgen-independent prostate cancer (ketoconazole, suramin, estramustine/docetaxel, and docetaxel/bevacizumab), and in developing predictive markers and algorithms to assess prognosis in these patients. Contributions in kidney cancer have included the development of novel trial methodology, such as the randomized discontinuation trial design, and the testing of antiangiogenics. In addition to these areas, future work of the committee will include further development of therapy for earlier-stage prostate cancer patients and bladder cancer patients.
The Cancer and Leukemia Group B Pharmacology and Experimental Therapeutics Committee: A Historical Perspective
Authors: Ratain Mark J. , Miller Antonius A. , McLeod Howard L. , Venook Alan P. , Egorin Merrill J. , Schilsky Richard L.
Published: June 2006

The Chemotherapy Committee of Cancer and Leukemia Group B (CALGB) was established in the mid-1970s to assemble a group of experts in cancer chemotherapy and pharmacology who could advise the CALGB disease committees about the optimal use of drugs in the fight against cancer and to provide quality assurance for the chemotherapy section of CALGB protocols. Chaired initially by Edward Henderson and then David Van Echo, the committee was also the repository of studies in diseases for which CALGB did not have a formal committee, such as testis cancer and sarcoma. In 1990, following the appointment of Richard Schilsky as Chair, the name of the committee was changed to the Pharmacology and Experimental Therapeutics (PET) Committee to reflect a more specific focus and scientific agenda (i.e., studies of chemotherapy pharmacology and development of new agents). Three PET Committee reference pharmacology laboratories (led by Merrill Egorin, Tony Miller, and Mark Ratain) were established to measure drug concentrations in biological fluids and to perform pharmacokinetic analyses. In addition, the PET Committee embarked on a number of multi-institution phase I studies. These phase I studies included studies of special populations, including the first prospective study of an anticancer agent (paclitaxel) in patients with hepatic dysfunction. In addition, the Committee studied a number of phase I combinations destined for phase II evaluation in disease-specific committees. Following Dr. Schilsky's election as CALGB Group Chair in 1994, Mark Ratain took over as Chair of the PET Committee and continued to emphasize population pharmacology as the primary theme of the Committee's research agenda. In addition, the PET Committee began to develop novel clinical trial designs, including the first completed randomized discontinuation trial of an antineoplastic agent. Most recently, the PET Committee has launched an ambitious research program in pharmacogenetics, facilitated in large part through the recruitment of Howard McLeod as Vice Chair. This area of research is a collaborative effort with the NIH Pharmacogenetics Research Network and has the potential to definitively address the hypothesis that germ line polymorphisms are a significant determinant of the toxicity and efficacy of anticancer therapy. It is anticipated that the results of the current studies will contribute significantly to the goal of individualizing cancer treatment.
The Cancer and Leukemia Group B Pathology Committee at 50
Authors: Compton Carolyn
Published: June 2006

The Pathology Committee of the Cancer and Leukemia Group B (CALGB) is broadly and deeply integrated into the multidisciplinary clinical and scientific operations of the group. It has five major functions in CALGB. First, it insures the highest possible quality of pathologic data in tissue-based correlative science studies through comprehensive quality control of all tissues collected, banked, and distributed to investigators and of all morphology-based studies done within the CALGB. Within this context, the Pathology Committee has the goal of eliminating, to the greatest degree possible, variation in methodology, interpretation, and reporting of pathologic data that would compromise reproducibility of correlative science results and to assure accuracy, uniformity, and completeness of the pathologic data. Second, the committee provides expert pathologic consultation in the development of clinical trials and correlative science studies that involve pathologic issues and/or materials. Third, it provides high-quality tissue banking and centralized morphology-based technical support services (e.g., histologic sections for immunohistochemistry, tissue microarrays, etc.) for all CALGB investigators. Fourth, it initiates and executes high-quality pathologic research using CALGB and intergroup resources. Lastly, it provides group-wide education on pathology-related issues relevant to trial design, scientific study design, and specimen banking.
Cancer and Leukemia Group B Surgery Committee
Authors: Kohman Leslie J.
Published: June 2006

Surgeons play a vital role in the Cancer and Leukemia Group B by providing patients and specimens for studies of the common solid tumors, and more recently, by serving as investigators who conduct surgically focused research protocols and contribute to the correlative science studies in the Group. Surgical activities encompass thoracic, gastrointestinal, breast, and genitourinary cancers and melanoma. Surgical quality assurance is also an important focus. This article will describe the development and importance of a robust and vigorous surgical component to a strong cooperative group and highlight the many trials conducted by the Cancer and Leukemia Group B surgeons and their contributions to advancement of the care of the patient with solid organ malignancy.
The Cancer and Leukemia Group B Transplant Committee
Authors: Linker Charles , Hurd David
Published: June 2006

The Transplant Committee of the Cancer and Leukemia Group B has a robust portfolio of studies and is poised to make significant contributions to the field. We are working in collaboration with the Cancer and Leukemia Group B Leukemia and Lymphoma Disease Committees and importantly in collaboration with other groups to define the role of both autologous and reduced-intensity allogeneic transplantation in the management of selected hematologic malignancies. Some of our studies have the potential to change the standard of care in areas such as the maintenance therapy for multiple myeloma after autologous transplantation and to generate the data that could lead to acceptance of new approaches to the initial post-remission therapy of older adults with acute myeloid leukemia. The cooperative group setting allows us to advance the transplant field by showing which approaches are successful outside of single institutions and are therefore feasible on a generalized basis.
On the Electric Dipole (hyper)polarizability of Difluorodiacetylene (F-C≡C-C≡C-F)
Authors: Maroulis G.
Published: June 2006

We report static dipole polarizability and hyperpolarizability values difluoroacetylene obtained from finite-field density functional theory and conventional ab initiocalculations with especially designed flexible basis sets of Gaussian-type functions. Our results show that electron correlation has a small effect on the dipole polarizability but a strong one on the hyperpolarizability. The widely used B3LYP method yields molecular properties fairly close to the ab initio ones. The effect of the fluorination on the molecular properties is quite obvious at the self-consistent field level of theory: ᾱ (FCCCCF) < ᾱ (HCCCCF) < ᾱ (HCCCCH) and γ̄ (FCCCCF) < γ̄ (HCCCCF) < γ̄ (HCCCCH).
A Rigorous Method for Synthesis of Offset Shaped Reflector Antennas
Authors: Oliker Vladimir I.
Published: June 2006

In this paper the problem of synthesis of offset shaped single reflector antenna is considered. This problem has to be solved when a reflector antenna system is required to control the field amplitude and/or phase on the far-field or on the output aperture in the near-field. Achieving high efficiency is a very important objective of the design and shaped reflector antennas are used for that purpose.

The equations of the problem are strongly nonlinear partial differential equations which can not be analyzed by standard techniques. Though the problem has been the subject of study by many authors for over 40 years, up until recently, there were no rigorous theoretical results resolving completely the questions of existence and uniqueness. With few exceptions, authors have attacked the problem with heuristic numerical procedures, and, depending on the specific formulation, obtained different results not always in agreement with each other.

In this paper a new method for solving the single reflector problem is presented. The new method allows a complete and mathematically rigorous investigation of this problem. Furthermore, the proposed method lends itself to a numerical implementation and we present here several examples.
Gender, Gender Identity, Ethnicity, and Stereotyping Of Children's Chores:The Israeli Case
Authors: Kulik Liat
Published: June 2006

The present study examines the effect of adults' gender, gender identity, and ethnicity on their stereotyping of children's chores in Israeli society. The sample consists of 238 married and single participants (81 men and 157 women). With respect to children's chores, five main categories are examined: domestic, help with siblings, self-care, outside, and technical. The findings reveal that the impact of geder identity (according to the terms of gender schema theory) on stereotyping of children's chores was less than expected and therefore do not support the research hypotheses. Moreover, the impact of gender was greater than that of gender identity: Women tend to develop less stereotyped attitudes toward children's chores than men do. No effect is found for the participant's country of birth, but mother's country of birth does have an effect.
A Qualitative Study of How Experienced Certified Holistic Nurses Learn to Become Competent Practitioners
Authors: Sharoff Leighsa
Published: June 2006

Purpose: Artistry of holistic nursing requires practitioners to be equipped with the ability to integrate and assimilate knowledge and experience. This integrated wisdom is woven into proficiency and expertise, thus allowing for the transition to an experienced competent health care provider who can meet the complex mélange of practice. This qualitative naturalistic study was designed to explore how 10 experienced certified holistic nurses (HNCs) learned to become competent holistic nurses. Method: In-depth interviews of 10 HNCs, critical incident reports, and a summative focus group. Findings: (a) Disjuncture existed between the structure of traditional nursing and the need of nurses for continued personal and professional growth and development; (b) need for credibility was key to nurses becoming competent holistic nurses; (c) use of informal learning strategies to help them achieve competency; and (d) overcoming challenges emanating from the traditional system as they transitioned to becoming holistic nurses.
Exploring the Effects of Walking the Labyrinth
Authors: Sandor M. Kay , Froman Robin D.
Published: June 2006

Purpose: This pilot study examines the effects of walking a labyrinth. Method: A convenience sample of 25 community members participated in a four-group, repeated measures study to gather information about vital signs and affect before and after labyrinth walks. Because of the small sample size, results were inspected for effect size (ES) differences in pre-to postcomparisons. Mean postwalk scores were also compared to control group scores. Findings: Systolic and diastolic blood pressures showed essentially no ES differences pre to postwalk. The remaining ES comparisons showed .14 ES for pulse differences, .37 ES for respirations, and .22 and .56 ES differences for positive and negative affect measures, respectively. Conclusions: Comparisons of postwalk scores for walkers to nonwalkers showed mixed results in significance of differences. Implications: This pilot study shows the feasibility of the procedures for assessing the effects of labyrinth walking on basic parameters of health.
The relationship between curriculum time for physical education and literacy and numeracy standards in South Australian primary schools
Authors: Dollman Jim , Boshoff Kobie , Dodd Graham
Published: June 2006

There is ongoing debate among educators and in the community about the status of school physical education (PE), particularly in relation to more vocationally-oriented learning areas. Against a backdrop of rising youth obesity, diminishing curriculum time for PE represents a serious public health issue. This study investigated the relation ships between PE curriculum time and literacy and numeracy standards in South Australian primary schools. Schools ( n= 117) were surveyed on average time spent on PE (PEtime), and salient demographic characteristics. Average literacy and numeracy scores from a standardized statewide assessment system (State LaN), were obtained from government records. Regression modelling assessed the relationship between PEtime and State LaN scores, independent of socioeconomic status (SES), percentage of children of non-English-speaking background (NESB), geographic location, staff age structure, and staff PE training. PEtime was unrelated to literacy and numeracy attainment, after control for demographic variables. There was a strong positive relation ship between SES and academic attainment, while a higher proportion of younger staff predicted lower academic attainment. There was no evidence that schools with relatively high PEtime are disadvantaging students in the traditionally academic subjects.
Expected and unexpected cultural heroes
Authors: Eriksen Annelin
Published: June 2006

This article is an attempt to engage with Marshall Sahlins' theory of historical transformation (1985) as well as his latest works on the agency of conjuncture (2004, 2005). It is an attempt to highlight the micro-history of some women and low ranking men on the Melanesian island of Ambrym in Vanuatu, specifically their encounter with the church and the unexpected agency resulting from this encounter. The story of how the different churches in the area got established, the way the chiefs reacted, and the power struggle between chiefs and missionaries is outlined, and placed in comparison with another perspective on the way the church got ‘rooted’ in Ambrym, and how then it travelled and spread. Having outlined the ethnography, the epistemological consequences of different perspectives on culture, change and history are discussed.
Juvenile Police Informants
Authors: Dodge Mary
Published: June 2006

The use of juvenile informants by police is rarely discussed among law enforcement, and published research is virtusally nonexistent. In most cases, ethical issues, legal circumstances, and traditional police secrecy keep any teenager involvement in covert law enforcement operations hidden. This article seeks to shed some light on the use of minors in police investigations through a presentation of known cases and semistructured interviews with law enforcement agents. The qualitative interviews reveal fundamental concerns regarding the precarious nature of the role of juveniles in the investigation process, despite the limitations of the sample size and generalizability of the data. The primary issues addressed in the research include coercion in the recruitment process and the potential for physical and emotional harm of the young informants.
Acetylcholine induces contractile and relaxant effects in canine nasal venous systems
Authors: Wang M. , Lung M. A.
Published: June 2006

Acetylcholine (ACh) induces nasal congestion at low doses but decongestion at high doses. The current study investigated the vascular mechanisms underlying this biphasic nasal airway response in dogs.

Collecting and outflow veins from anterior and posterior nasal venous systems and the septal mucosa (containing sinusoidal venous plexuses) were isolated. Thein vitroisometric tension of the vascular segments was monitored to reflect vascular reactivity. Immunohistochemical localisation of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase and endothelial nitric oxide synthase (eNOS) was performed.

ACh did not affect the venous plexuses but contracted the anterior collecting vein and the outflow veins of both systems in a concentration-dependent manner; the responses were unaffected by nitro-L-arginine-methyl-ester (L-NAME). ACh relaxed posterior collecting veins at low concentrations but contracted them at higher concentrations;L-NAME enhanced the contractions but inhibited the relaxations, with the inhibition reversed byL-arginine. NADPH-diaphorase and eNOS were located predominantly in the posterior collecting veins.

The fact that acetylcholine at low concentrations relaxes posterior collecting veins but contracts other collecting and outflow veins implies that the agonistin vivomay induce nasal congestion by increasing posterior blood volume. At higher concentrations, acetylcholine contracts posterior collecting veins as well, implying diminished blood volume in both venous systems, and consequently nasal decongestion. The induced contraction in posterior collecting veins is nitric oxide-independent, while the induced relaxation is nitric oxide-dependent.
Vaginal microbicides: detecting toxicities in vivothat paradoxically increase pathogen transmission
Authors: Cone Richard A , Hoen Timothy , Wong XiXi , Abusuwwa Raed , Anderson Deborah J , Moench Thomas R
Published: June 2006

Background

Microbicides must protect against STD pathogens without causing unacceptable toxic effects. Microbicides based on nonoxynol-9 (N9) and other detergents disrupt sperm, HSV and HIV membranes, and these agents are effective contraceptives. But paradoxically N9 fails to protect women against HIV and other STD pathogens, most likely because it causes toxic effects that increase susceptibility. The mouse HSV-2 vaginal transmission model reported here: (a) Directly tests for toxic effects that increase susceptibility to HSV-2, (b) Determines in vivo whether a microbicide can protect against HSV-2 transmission without causing toxicities that increase susceptibility, and (c) Identifies those toxic effects that best correlate with the increased HSV susceptibility.

Methods

Susceptibility was evaluated in progestin-treated mice by delivering a low-dose viral inoculum (0.1 ID50) at various times after delivering the candidate microbicide to detect whether the candidate increased the fraction of mice infected. Ten agents were tested – five detergents: nonionic (N9), cationic (benzalkonium chloride, BZK), anionic (sodium dodecylsulfate, SDS), the pair of detergents in C31G (C14AO and C16B); one surface active agent (chlorhexidine); two non-detergents (BufferGel®, and sulfonated polystyrene, SPS); and HEC placebo gel (hydroxyethylcellulose). Toxic effects were evaluated by histology, uptake of a 'dead cell' dye, colposcopy, enumeration of vaginal macrophages, and measurement of inflammatory cytokines.

Results

A single dose of N9 protected against HSV-2 for a few minutes but then rapidly increased susceptibility, which reached maximum at 12 hours. When applied at the minimal concentration needed for brief partial protection, all five detergents caused a subsequent increase in susceptibility at 12 hours of ~20–30-fold. Surprisingly, colposcopy failed to detect visible signs of the N9 toxic effect that increased susceptibility at 12 hours. Toxic effects that occurred contemporaneously with increased susceptibility were rapid exfoliation and re-growth of epithelial cell layers, entry of macrophages into the vaginal lumen, and release of one or more inflammatory cytokines (Il-1β, KC, MIP 1α, RANTES). The non-detergent microbicides and HEC placebo caused no significant increase in susceptibility or toxic effects.

Conclusion

This mouse HSV-2 model provides a sensitive method to detect microbicide-induced toxicities that increase susceptibility to infection. In this model, there was no concentration at which detergents provided protection without significantly increasing susceptibility.
EPHB2 germline variants in patients with colorectal cancer or hyperplastic polyposis
Authors: Kokko Antti , Laiho Päivi , Lehtonen Rainer , Korja Sanna , Carvajal-Carmona Luis G , Järvinen Heikki , Mecklin Jukka-Pekka , Eng Charis , Schleutker Johanna , Tomlinson Ian PM , Vahteristo Pia , Aaltonen Lauri A
Published: June 2006

Background

Ephrin receptor B2 (EPHB2) has recently been proposed as a novel tumor suppressor gene in colorectal cancer (CRC). Inactivation of the gene has been shown to correlate with progression of colorectal tumorigenesis, and somatic mutations have been reported in both colorectal and prostate tumors.

Methods

Here we have analyzed the EPHB2 gene for germline alterations in 101 individuals either with 1) CRC and a personal or family history of prostate cancer (PC), or 2) intestinal hyperplastic polyposis (HPP), a condition associated with malignant degeneration such as serrated adenoma and CRC.

Results

Four previously unknown missense alterations were observed, which may be associated with the disease phenotype. Two of the changes, I361V and R568W, were identified in Finnish CRC patients, but not in over 300 Finnish familial CRC or PC patients or more than 200 population-matched healthy controls. The third change, D861N, was observed in a UK HPP patient, but not in additional 40 UK HPP patients or in 200 UK healthy controls. The fourth change R80H, originally identified in a Finnish CRC patient, was also found in 1/106 familial CRC patients and in 9/281 healthy controls and is likely to be a neutral polymorphism.

Conclusion

We detected novel germline EPHB2 alterations in patients with colorectal tumors. The results suggest a limited role for these EPHB2 variants in colon tumor predisposition. Further studies including functional analyses are needed to confirm this.
Prognostic value of p27Kip1expression in Basaloid Squamous Cell Carcinoma of the larynx
Authors: Salerno Grazia , Di Vizio Dolores , Staibano Stefania , Mottola Giampiero , Quaremba Giuseppe , Mascolo Massimo , Galli Vieri , De Rosa Gaetano , Insabato Luigi
Published: June 2006

Background

Very few reports have investigated the role of cell cycle regulators as biomarkers in Basaloid Squamous Cell Carcinoma (BSCC) of the larynx, a definite morphologic, uncommon, very aggressive variant of squamous cell carcinoma. Lower expression of Ki67/Mib-1, a proliferation marker highly expressed in the majority of tumours, and p53, a tumour suppressor protein that can induce an arrest of the G1-S transition, was related to a better prognosis in laryngeal BSCC. In the head and neck, p27kip1, a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors, has emerged as an independent prognostic factor, able to identify low-expressing tumours with unfavourable course. Up to date the role of this protein was never studied in BSCC. Aim of our study was to investigate the potential prognostic value of p27kip1 levels and their correlation with Ki67/Mib-1 and p53 expression in BSCC of the larynx.

Methods

The retrospective study group consisted of 15 male and 1 female patients, affected by laryngeal BSCC, ranging in age from 44 to 69 years (mean 58). The tumour originated from the supraglottis in thirtheen cases and from the glottis in the remaining three. Ten patients had metastatic cervical lymph nodes at presentation and were classified as N+. Post surgical stage was IV in four patients, III in nine, II in two cases and I in the remaining one. Follow-up ranged from a minimum of 5 months up to 9 years. Paraffin-embedded tissue sections of each laryngeal tumour were analyzed for p27kip, Ki67/Mib-1 and p53 expression by immunohistochemistry.

Results

The immunohistochemical study showed p27kip1 expression in 40% of the patients with no evidence of disease (NED) and in none (0%) of the patients dead of disease (DOD), whilst p53 was expressed in 60% of patients in NED status and in 90% of patients in DOD status. Ki67/Mib-1 was positive in 80% of NED patients and in 100% of DOD patients. At multivariate analysis, performed by means of Discriminant analysis, low levels of p27kip1 expression significantly correlated with poor prognosis (P < 0.05).

Conclusion

p27kip1 protein has been shown to be a significant independent prognostic factor in laryngeal SCC. In our series of laryngeal BSCC the resulting data seem to confirm the clinical prognostic relevance of p27kip1 low expression, which directly correlated with biological aggressiveness and consequent shortened survival.