Brief Butyltin Exposure Induces Irreversible Inhibition of the Cytotoxic Function on Human Natural Killer Cells, in Vitro

Environmental Research. Jan, 2002  |  Pubmed ID: 11896664

Despite mounting evidence on butyltin (BT) contamination and related immunotoxic effects on wildlife, very little is known about BT-associated immunotoxic effects on humans, particularly the effects on human natural killer (NK) lymphocyte function. Our earlier studies demonstrated that in vitro exposure to environmentally relevant concentrations of BTs negatively affect human NK cells and that there are measurable levels of BTs in human blood. In this study we examined whether the inhibition of NK cell cytotoxic function induced by a brief exposure (1 h) to BTs is reversible when the cells are allowed to recover in BT-free media for up to 6 days. Standard methods were used in chemical preparation, blood sampling, NK cell isolation, and 51-Chromium release assay. The results revealed that exposure to 300 nM TBT for 1 h caused an approximately 65- decrease in NK cytotoxic function, whether the lymphocytes were given as long as a 6-day recovery period or no recovery period. There was no recovery (nor any further loss) of NK cytotoxic function following removal of the compound. Exposure to 5 microM DBT for 1 h showed a 41% decrease in cytotoxic function with 0-h recovery and an 83% decrease after a 24-h recovery period. Thus, not only is there no significant recovery of NK cytotoxic function when the lymphocytes are allowed to incubate in BT-free medium for up to 6 days but there is additional loss of cytotoxic function. The results indicated that short-term exposure to BTs causes persistent negative effects on NK cell ability to kill cancer cells.

Interleukins 2 and 12 Produce Recovery of Cytotoxic Function in Tributyltin-exposed Human Natural Killer Cells

Environmental Research. Mar, 2002  |  Pubmed ID: 12051798

Cytotoxic function of human natural killer (NK) cells is modulated by a variety of cytokines. Interleukins (IL) 2 and 12 are both potent stimulators of NK cell cytotoxic function. Tributyltin (TBT) is used in a variety of consumer products and industrial applications. TBT is found in dairy products, meat, and fish. We and others have shown that there are measurable levels of TBT in human blood. Butyltins appear to increase the risk of cancer and viral infections in exposed individuals. We have demonstrated that the ability of NK cells to kill tumor cells is greatly diminished after a l-h exposure to TBT and that this inhibition persists even after removal of the compound. In the current study we examine the effects of the NK-stimulatory ILs, IL2 and IL12, on the ability of NK cells to recover from the persistent inhibitory effects of a 1-h TBT treatment. Highly purified NK cells (> 95% CD16(+)) or a lymphocyte preparation containing both T lymphocytes and NK cells were treated with 300 nM TBT and then allowed to recover for 24 h, 48 h, 4 days, and 6 days in TBT-free media containing no interleukin, 1000 U/mL IL2, 20 ng/mL IL l2, or a combination of IL2 plus IL12. Tumor killing function was then tested using a radioactive chromium release assay. As seen in our previous studies there is no recovery of NK cell cytotoxic function even after a 6-day recovery period when no interleukin is present in the medium. However, there is significant recovery of NK cytotoxic function when IL2, IL12, or the combination of IL2 plus IL12 is present in the medium during the recovery period.

Factorial Design Considerations

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Aug, 2002  |  Pubmed ID: 12177102

Factorial designs may be proposed to test extra questions within a clinical trial. A common approach to sample size and analysis for factorial trials assumes no statistical interactions and does not adjust for multiple testing. This investigation considered the trade-off between potential gains from testing more questions with fewer patients versus how often a factorial trial might arrive at an incorrect conclusion.

Dose-dense Anthracycline-based Chemotherapy for Node-positive Breast Cancer

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Sep, 2002  |  Pubmed ID: 12202664

Theoretical considerations and clinical experience suggest that dose-dense chemotherapy may be superior to other approaches using the same drugs. We studied a dose-dense combination of doxorubicin and cyclophosphamide, with or without fluorouracil, as adjuvant therapy.

Adjuvant Chemotherapy with Cyclophosphamide, Methotrexate, and 5-fluorouracil, Vincristine, and Prednisone Compared with Single-agent L-phenylalanine Mustard for Patients with Operable Breast Carcinoma and Positive Axillary Lymph Nodes: 20-year Results of a Southwest Oncology Group Study

Cancer. Jan, 2003  |  Pubmed ID: 12491501

Adjuvant combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil plus vincristine and prednisone (CMFVP) was compared with single-agent L-phenylalanine mustard (L-PAM) for the treatment of patients with axillary lymph node positive primary breast carcinoma over 20-years of follow-up.

Statistics in Clinical Trials

Current Oncology Reports. Jan, 2004  |  Pubmed ID: 14664759

Statistical developments over the past several years are described in this review. Efforts in phase I studies have focused on efficient estimation of maximum tolerated dose. Issues investigated for phase II trials include incorporation of multiple endpoints and randomization. For phase III trials, methods to reduce time or use the sample size more efficiently have been investigated. However, design innovations come with costs, including possible increased risk of incorrect conclusions. Other recent challenging statistical developments in clinical trials relate to use of complementary outcomes such as quality of life and to associated biologic questions, including the emergence of the field of genomics.

Do Estimates of Long-term Survival Tell Us Whether Patients Diagnosed with Breast Cancer Before Age 50 Years Are Ever Cured?

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Feb, 2004  |  Pubmed ID: 14691128

Exploratory Evidence on the Market for Effective Depression Care in Pittsburgh

Psychiatric Services (Washington, D.C.). Apr, 2004  |  Pubmed ID: 15067150

Despite the existence of effective and relatively cost-effective depression treatments, many depressed patients do not receive appropriate care. The authors assessed opportunities for increasing the rate of effective depression treatment by investigating the market for such treatment in the Pittsburgh area.

A Southwest Oncology Group Randomized Phase II Study of Doxorubicin and Paclitaxel As Frontline Chemotherapy for Women with Metastatic Breast Cancer

Breast Cancer Research and Treatment. May, 2004  |  Pubmed ID: 15111772

To evaluate whether the high complete response (CR) rates for the combination of doxorubicin and paclitaxel in metastatic breast cancer observed in two European studies could be replicated in a multi-institutional cooperative group trial.

Tributyltin Exposure Causes Decreased Granzyme B and Perforin Levels in Human Natural Killer Cells

Toxicology. Aug, 2004  |  Pubmed ID: 15212818

Natural Killer (NK) cells are a subset of lymphocytes that are capable of killing tumor cells, virally infected cells and antibody coated cells. Tributyltin (TBT) is a toxic chemical used for various industrial purposes such as: slime control in paper mills, disinfection of circulating industrial cooling waters, anti-fouling agents in shower curtains and the preservation of wood. TBT can be found in edible items such as dairy products and fish. This study investigates the mechanism by which TBT exposure decreases the immune function of human NK cells, in vitro. Cytotoxic function, the expression of the cytotoxic proteins (granzyme B and perforin), and cAMP response element binding protein (CREB) phosphorylation were examined. NK cells exposed to 300 nM TBT for 1 h showed no significant decrease in cytotoxic function, levels of granzyme B and perforin, or phosphorylation of CREB. However, mRNA levels for the cytotoxic proteins were significantly decreased. A 24 h exposure to 200 nM TBT caused significant decreases in cytotoxic function, levels of granzyme B and perforin, and levels of granzyme B and perforin mRNA. When NK cells were exposed to 300 nM TBT for 1h followed by a 24 h period in TBT-free media, again there were significant decreases in NK cell cytotoxic function, levels of granzyme B and perforin and their mRNA. A 1h exposure to 300 nM TBT followed by a 48 h period in TBT-free media showed similar changes in cytotoxic function and levels of granzyme B and perforin as seen after 24 h in TBT-free media. Additionally, both of these exposures showed significant decreases in phosphorylation of CREB. These results indicate that TBT exposures can disrupt the transcription of granzyme B and perforin and that this disruption cannot be entirely accounted for by a decrease in phosphorylated CREB (phosphoCREB) levels.

HER-2 Amplification, HER-1 Expression, and Tamoxifen Response in Estrogen Receptor-positive Metastatic Breast Cancer: a Southwest Oncology Group Study

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Sep, 2004  |  Pubmed ID: 15355892

Preclinical data indicate that expression of the ErbB family of receptors, such as HER-2 and HER-1 (EGFR) may be involved in endocrine resistance. Evidence of resistance from clinical studies has been inconsistent. The present study examined whether HER-2 gene amplification or HER-1 expression predicted response to tamoxifen.

An Ethnographic Study of Collaborative Clinical Trial Protocol Writing

Studies in Health Technology and Informatics. 2004  |  Pubmed ID: 15361057

Clinical trial protocol documents play an important role in clinical research. However, clinical protocol writing remains a complex and relatively un-studied process. Protocols are often written by teams of people, yet little prior research has captured the problems or analyzed the collaboration support needs of protocol writers. Here we present the results of an initial ethnographic study into the clinical trial protocol writing processes at a representative cooperative clinical trial group funded by National Cancer Institute (NCI). We analyzed the collaborative nature of the writing process, identified common problems, derived information and communication support needs of collaborative clinical protocol writers, and provided recommendations to streamline the process. We believe that this paper contributes useful implications for the design of future collaborative clinical protocol writing tools.

Sequencing of Tamoxifen and Radiotherapy After Breast-conserving Surgery in Early-stage Breast Cancer

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Jan, 2005  |  Pubmed ID: 15545669

Tamoxifen (TAM) is thought to exert a cytostatic effect on hormone-sensitive breast cancer cells. Some preclinical studies show reduced radiosensitivity in irradiated malignant mammary epithelial cells when pretreated with TAM; other studies refute these results. Recent randomized clinical trials suggest an antagonistic effect of TAM on cytotoxic therapy, with improved disease-free survival (DFS) with sequential versus concurrent TAM. An exploratory analysis was undertaken to evaluate the optimal sequencing of TAM and radiotherapy (RT) after breast-conserving surgery.

Randomized, Controlled Trial of Cyclophosphamide, Methotrexate, and Fluorouracil Versus Cyclophosphamide, Doxorubicin, and Fluorouracil with and Without Tamoxifen for High-risk, Node-negative Breast Cancer: Treatment Results of Intergroup Protocol INT-0102

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Nov, 2005  |  Pubmed ID: 16293862

We evaluated the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) versus cyclophosphamide, doxorubicin, and fluorouracil (CAF) in node-negative breast cancer patients with and without tamoxifen (TAM), overall and by hormone receptor (HR) status.

Sequenced Compared with Simultaneous Anthracycline and Cyclophosphamide in High-risk Stage I and II Breast Cancer: Final Analysis from INT-0137 (S9313)

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Feb, 2007  |  Pubmed ID: 17308269

We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A --> C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC).

Clinical Activity and Immune Modulation in Cancer Patients Treated with CP-870,893, a Novel CD40 Agonist Monoclonal Antibody

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2007  |  Pubmed ID: 17327609

The cell-surface molecule CD40 activates antigen-presenting cells and enhances immune responses. CD40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective CD40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study.

An Analysis of Reporting of Sexually Transmissible Infections in Indigenous Australians in Mainstream Australian Newspapers

Sexual Health. Mar, 2007  |  Pubmed ID: 17382031

To investigate the nature of, and trends in, Australian print media coverage of sexually transmissible infections (STI) in indigenous Australians.

Intensive Dose-dense Compared with High-dose Adjuvant Chemotherapy for High-risk Operable Breast Cancer: Southwest Oncology Group/Intergroup Study 9623

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. May, 2007  |  Pubmed ID: 17404368

Southwest Oncology Group (SWOG)/Intergroup study 9623 was undertaken to compare treatment with an anthracycline-based adjuvant chemotherapy regimen followed by high-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell support (AHPCS) with a modern dose-dense dose-escalated (nonstandard) regimen including both an anthracycline and a taxane.

Phase III Randomized Placebo-controlled Trial of Two Doses of Megestrol Acetate As Treatment for Menopausal Symptoms in Women with Breast Cancer: Southwest Oncology Group Study 9626

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Apr, 2008  |  Pubmed ID: 18375894

Prior progestin studies treating hot flashes in women have been short duration and single dose. This study tests the progestin megestrol acetate (MA) at two doses versus placebo over 6 months.

DNA Damage Induced by Chronic Inflammation Contributes to Colon Carcinogenesis in Mice

The Journal of Clinical Investigation. Jul, 2008  |  Pubmed ID: 18521188

Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis.

Aag-initiated Base Excision Repair Drives Alkylation-induced Retinal Degeneration in Mice

Proceedings of the National Academy of Sciences of the United States of America. Jan, 2009  |  Pubmed ID: 19139400

Vision loss affects >3 million Americans and many more people worldwide. Although predisposing genes have been identified their link to known environmental factors is unclear. In wild-type animals DNA alkylating agents induce photoreceptor apoptosis and severe retinal degeneration. Alkylation-induced retinal degeneration is totally suppressed in the absence of the DNA repair protein alkyladenine DNA glycosylase (Aag) in both differentiating and postmitotic retinas. Moreover, transgenic expression of Aag activity restores the alkylation sensitivity of photoreceptors in Aag null animals. Aag heterozygotes display an intermediate level of retinal degeneration, demonstrating haploinsufficiency and underscoring that Aag expression confers a dominant retinal degeneration phenotype.

Phase II Study of the Anti-insulin-like Growth Factor Type 1 Receptor Antibody CP-751,871 in Combination with Paclitaxel and Carboplatin in Previously Untreated, Locally Advanced, or Metastatic Non-small-cell Lung Cancer

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. May, 2009  |  Pubmed ID: 19380445

We conducted a phase II study of combination of the anti-insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non-small-cell lung cancer (NSCLC).

Adjuvant Chemotherapy and Timing of Tamoxifen in Postmenopausal Patients with Endocrine-responsive, Node-positive Breast Cancer: a Phase 3, Open-label, Randomised Controlled Trial

Lancet. Dec, 2009  |  Pubmed ID: 20004966

Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy.

A Card Before You Leave: Participation and Mental Health in Northern Ireland

Health and Human Rights. 2009  |  Pubmed ID: 20845851

Due to a recent and dramatic rise in suicide and self-harm rates, mental health services have received a high level of attention in the politics of Northern Ireland, resulting in the implementation of numerous policies and the publication of many public reviews on the subject. Critically, these policies have also emphasized and required the participation of mental health service users in decision making about service design, implementation, and monitoring. This paper analyzes the experience of a group of mental health service users in north and west Belfast, the Public Initiative for the Prevention of Suicide-Greater Shankill Bereaved Families Rights Group supported by the Particpation and the Practice of Rights Project, as they campaigned for policy change using a human rights-based approach. It considers, first, the group's use of a participatory, "bottom-up" approach to set human rights indicators and benchmarks defined by group members themselves as an example of meaningful participation from an affected group. The paper then looks specifically at one of the group's issues--follow-up care--and reveals how the group was able to bring about policy change on this issue across Northern Ireland. Finally, it discusses how the group's experience in this campaign has revealed problems with the way that the government currently engages with mental health service users in Northern Ireland. The article closes by identifying key next steps to be taken as the focus of the campaign shifts to ensuring that active, free, and meaningful participation takes place in accordance with international human rights standards.

Network Analysis of Associations Between Serum Interferon-α Activity, Autoantibodies, and Clinical Features in Systemic Lupus Erythematosus

Arthritis and Rheumatism. Apr, 2011  |  Pubmed ID: 21162028

Interferon-α (IFNα) is a primary pathogenic factor in systemic lupus erythematosus (SLE), and high IFNα levels may be associated with particular clinical manifestations. The prevalence of individual clinical and serologic features differs significantly by ancestry. This study was undertaken to detect associations between clinical and serologic disease manifestations and serum IFNα activity in a large diverse SLE cohort, using multivariate and network analyses.

Toward Enabling Winter Occupations: Testing a Winter Coat Designed for Older Adults

Canadian Journal of Occupational Therapy. Revue Canadienne D'ergothérapie. Feb, 2011  |  Pubmed ID: 21395199

Previous research indicates that older adults have difficulties using winter clothing, which contributes to their risk of isolation during winter. Research has also shown that a winter coat that requires less flexibility, strength, and dexterity would help support this population.

Semiquantitative Assessment of Subchondral Bone Marrow Edema-like Lesions and Subchondral Cysts of the Knee at 3T MRI: a Comparison Between Intermediate-weighted Fat-suppressed Spin Echo and Dual Echo Steady State Sequences

BMC Musculoskeletal Disorders. 2011  |  Pubmed ID: 21906292

Choice of appropriate MR pulse sequence is important for any research studies using imaging-derived data. The aim of this study was to compare semiquantitative assessment of subchondral bone marrow edema-like lesions and subchondral cysts using intermediate-weighted (IW) fat-suppressed (fs) spin echo and Dual Echo Steady State (DESS) sequences on 3 T MRI.

Preliminary Efficacy of the Anti-insulin-like Growth Factor Type 1 Receptor Antibody Figitumumab in Patients with Refractory Ewing Sarcoma

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Dec, 2011  |  Pubmed ID: 22025154

Patients with Ewing sarcoma (ES) with metastases and those who relapse fare poorly and receive therapies that carry significant toxicity. This phase 1/2 study was conducted to evaluate the efficacy of figitumumab in advanced ES.

Risk Factors for MRI-detected Patello-femoral and Tibio-femoral Cartilage Loss During a 6-month Period: The JOG Study

Arthritis and Rheumatism. Dec, 2011  |  Pubmed ID: 22213129

PURPOSE: Aim was to assess several baseline risk factors that may predict patello-femoral and tibio-femoral cartilage loss during a 6 month period. METHODS AND MATERIALS: For 177 subjects with chronic knee pain, 3T MRI of both knees was performed at baseline and follow-up. Knees were semiquantitatively assessed evaluating cartilage morphology, subchondral bone marrow lesions (BMLs), meniscal morphology/extrusion, synovitis and effusion. Age, gender and body mass index (BMI), BMLs, meniscal damage/extrusion, synovitis, effusion and prevalent cartilage damage in the same subregion were evaluated as possible risk factors for cartilage loss. Logistic regression models were applied to predict cartilage loss. Models were adjusted for age, gender, treatment, and BMI. RESULTS: 79 (1.6%) subregions showed incident or worsening cartilage damage at follow-up. None of the demographic risk factors were predictive of future cartilage loss. Predictors for patello-femoral cartilage loss were effusion (adjusted odds ratio [aOR] 3.5, 95% confidence interval [CI] 1.3-9.4) and prevalent cartilage damage in the same subregion (aOR 4.3, 95% CI 1.3-14.1). Risk factors for tibio-femoral cartilage loss were baseline meniscal extrusion (aOR 3.6, 95% CI 1.3-10.1), prevalent bone marrow lesions (BMLs) (aOR 4.7, 95% CI 1.1-19.5) and prevalent cartilage damage (aOR 15.3, 95% CI 4.9-47.4) CONCLUSION: Cartilage loss over 6 months is rare, but may be detected semiquantitatively at 3T MRI and is most commonly observed in Kellgren-Lawrence 3 knees. Predictors of patello-femoral cartilage loss were effusion and prevalent cartilage damage in the same subregion. Predictors of tibio-femoral cartilage loss were prevalent cartilage damage, BMLs and meniscal extrusion.

Osteopontin Alleles Are Associated with Clinical Characteristics in Systemic Lupus Erythematosus

Journal of Biomedicine & Biotechnology. 2011  |  Pubmed ID: 22131818

Variants of the osteopontin (OPN) gene have been associated with systemic lupus erythematosus (SLE) susceptibility and cytokine profiles in SLE patients. It is not known whether these alleles are associated with specific clinical phenotypes in SLE. We studied 252 well-characterized SLE patients from a multiethnic cohort, genotyping the rs11730582, rs28357094, rs6532040, and rs9138 SNPs in the OPN gene. Ancestry informative markers were used to control for genetic ancestry. The SLE-risk allele rs9138C in the 3' UTR region was associated with photosensitivity in lupus patients across all ancestral backgrounds (meta-analysis OR = 3.2, 95% CI = 1.6-6.5, P = 1.0 × 10⁻³). Additionally, the promoter variant rs11730582C demonstrated suggestive evidence for association with two hematologic traits: thrombocytopenia (OR = 2.1, P = 0.023) and hemolytic anemia (OR = 2.6, P = 0.036). These clinical associations with SNPs in the promoter and 3' UTR regions align with previously reported SLE-susceptibility SNPs in OPN and suggest potential roles for these variants in antibody-mediated cytopenias and skin inflammation in SLE.

Semiquantitative Assessment of Focal Cartilage Damage at 3T MRI: a Comparative Study of Dual Echo at Steady State (DESS) and Intermediate-weighted (IW) Fat Suppressed Fast Spin Echo Sequences

European Journal of Radiology. Nov, 2011  |  Pubmed ID: 20833493

The aim of the study was to compare semiquantitative assessment of focal cartilage damage using the dual echo at steady state (DESS)- and intermediate-weighted (IW) fat suppressed (fs) sequences at 3T MRI.