Can Organizational Practices Inadvertently Silence Potential Whistleblowers?

This study examines how employee perceptions of organizational ethics, safety practices, and manager-subordinate relationships might influence employees’ silence in regards to workplace hazards using a sample of 178 workers in the mining, manufacturing, and petrochemical industries. The findings support a model in which employee perceptions of endangerment by their organization and fear of retaliation for whistleblowing mediate the relationship between manager-subordinate relationships and the practice of withholding negative (and sometimes vital) information from organizational management. Results suggest that even with high quality superior/subordinate relationships, employees may still withhold important information due to the overall perception of the current safety climate

Phase II Trial of Simple Oral Therapy with Capecitabine and Cyclophosphamide in Patients with Metastatic Breast Cancer: SWOG S0430

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139899/1/onco0179.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139899/2/onco0179-sup-0001.pd

Adjuvant therapy of osteosarcoma—A Phase II trial

BACKGROUND The objective of this study was to estimate the time to treatment failure and survival rate of the three-drug combination of doxorubicin, cisplatin, and ifosfamide as primary and postoperative, adjunctive treatment for teenagers and adults with osteosarcoma (OS). METHODS Sixty-three eligible patients with nonmetastatic OS of the extremities were registered from 24 institutions from February, 1992 through December, 1996. Chemotherapy was comprised of doxorubicin at a dose of 75 mg/m 2 and cisplatin at a dose of 120 mg/m 2 , alternating with doxorubicin at a dose of 50 mg/m 2 and ifosfamide at a dose of 8 g/m 2 . Four cycles were given prior to surgical resection, and four cycles were given after surgery. Outcome measures included the time to treatment failure, overall survival, toxicity, and centralized assessment of tumor necrosis. RESULTS Thirty-one of 63 eligible patients died, for a 5-year overall survival rate of 58% (95% confidence interval [95% CI], 46–71%). The median time to treatment failure was 19 months (95% CI, 12–41 months). A good pathologic response (≥ 90% necrosis) to neoadjuvant chemotherapy was observed in 48% of patients who underwent surgery. There was no correlation noted between response to neoadjuvant chemotherapy and patient outcome. Grade 4 hematologic toxicities were frequent (89%), although serious nonhematologic toxicities other than nausea and emesis were uncommon. CONCLUSIONS The regimen and schedule used in the current study did not improve outcomes compared with prior trials of doxorubicin and cisplatin alone. New, more effective drugs are needed for the treatment of patients with OS. The identification and utilization of molecular markers to predict outcome and response to therapy would facilitate clinical management, limiting exposure to toxic therapies for patients with favorable molecular profiles and identifying those patients who may fail with current approaches as candidates for clinical trials. Cancer 2004;100:818–25. © 2004 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34384/1/20021_ftp.pd

Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human Natural Killer cells

It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions

Characterization of killer immunoglobulin-like receptor genetics and comprehensive genotyping by pyrosequencing in rhesus macaques

<p>Abstract</p> <p>Background</p> <p>Human killer immunoglobulin-like receptors (KIRs) play a critical role in governing the immune response to neoplastic and infectious disease. Rhesus macaques serve as important animal models for many human diseases in which KIRs are implicated; however, the study of KIR activity in this model is hindered by incomplete characterization of <it>KIR </it>genetics.</p> <p>Results</p> <p>Here we present a characterization of <it>KIR </it>genetics in rhesus macaques (<it>Macaca mulatta)</it>. We conducted a survey of <it>KIRs </it>in this species, identifying 47 novel full-length <it>KIR </it>sequences. Using this expanded sequence library to build upon previous work, we present evidence supporting the existence of 22 <it>Mamu-KIR </it>genes, providing a framework within which to describe macaque <it>KIRs</it>. We also developed a novel pyrosequencing-based technique for <it>KIR </it>genotyping. This method provides both comprehensive <it>KIR </it>genotype and frequency estimates of transcript level, with implications for the study of <it>KIRs </it>in all species.</p> <p>Conclusions</p> <p>The results of this study significantly improve our understanding of macaque <it>KIR </it>genetic organization and diversity, with implications for the study of many human diseases that use macaques as a model. The ability to obtain comprehensive KIR genotypes is of basic importance for the study of KIRs, and can easily be adapted to other species. Together these findings both advance the field of macaque KIRs and facilitate future research into the role of KIRs in human disease.</p

KIR Polymorphisms Modulate Peptide-Dependent Binding to an MHC Class I Ligand with a Bw6 Motif

Molecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogens and tumors. Here we identify Mamu-A1*00201 (Mamu-A*02), a common MHC class I molecule in the rhesus macaque with a canonical Bw6 motif, as a ligand for Mamu-KIR3DL05. Mamu-A1*00201 tetramers folded with certain SIV peptides, but not others, directly stained primary NK cells and Jurkat cells expressing multiple allotypes of Mamu-KIR3DL05. Differences in binding avidity were associated with polymorphisms in the D0 and D1 domains of Mamu-KIR3DL05, whereas differences in peptide-selectivity mapped to the D1 domain. The reciprocal exchange of the third predicted MHC class I-contact loop of the D1 domain switched the specificity of two Mamu-KIR3DL05 allotypes for different Mamu-A1*00201-peptide complexes. Consistent with the function of an inhibitory KIR, incubation of lymphocytes from Mamu-KIR3DL05+ macaques with target cells expressing Mamu-A1*00201 suppressed the degranulation of tetramer-positive NK cells. These observations reveal a previously unappreciated role for D1 polymorphisms in determining the selectivity of KIRs for MHC class I-bound peptides, and identify the first functional KIR-MHC class I interaction in the rhesus macaque. The modulation of KIR-MHC class I interactions by viral peptides has important implications to pathogenesis, since it suggests that the immunodeficiency viruses, and potentially other types of viruses and tumors, may acquire changes in epitopes that increase the affinity of certain MHC class I ligands for inhibitory KIRs to prevent the activation of specific NK cell subsets

Top Ten Tips Palliative Care Clinicians Should Know About Prognostication in Oncology, Dementia, Frailty, and Pulmonary Diseases

Prognostication has been described as "Medicine's Lost Art." Taken with diagnosis and treatment, prognostication is the third leg on which medical care rests. As research leads to additional beneficial treatments for vexing conditions like cancer, dementia, and lung disease, prognostication becomes even more difficult. This article, written by a group of palliative care clinicians with backgrounds in geriatrics, pulmonology, and oncology, aims to offer a useful framework for consideration of prognosis in these conditions. This article will serve as the first in a three-part series on prognostication in adults and children

Top Ten Tips Palliative Care Clinicians Should Know About Prognostication in Oncology, Dementia, Frailty, and Pulmonary Diseases

Prognostication has been described as "Medicine's Lost Art." Taken with diagnosis and treatment, prognostication is the third leg on which medical care rests. As research leads to additional beneficial treatments for vexing conditions like cancer, dementia, and lung disease, prognostication becomes even more difficult. This article, written by a group of palliative care clinicians with backgrounds in geriatrics, pulmonology, and oncology, aims to offer a useful framework for consideration of prognosis in these conditions. This article will serve as the first in a three-part series on prognostication in adults and children