ABSTRACT
Nearly half the patients identified as having health care facility-onset Clostridioides difficile infections on a hematopoietic cell transplant unit had an alternative clinical explanation for diarrhea, including conditioning regimen toxicity or other medications. Our study supports that targeted diagnostic stewardship interventions should be explored and that additional risk-adjustments considered for facilities with oncology hematopoietic cell transplant wards in the National Healthcare Safety Network LabID Clostridioides difficile infection standardized infection ratio model.
Subject(s)
Clostridioides difficile , Clostridium Infections , Cross Infection , Hematopoietic Stem Cell Transplantation , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Clostridium Infections/epidemiology , Patients , Health Facilities , Cross Infection/diagnosis , Cross Infection/prevention & control , Cross Infection/epidemiologyABSTRACT
BACKGROUND: The well-documented association between acute mental status changes and sepsis development and progression makes acute mental status an attractive factor for sepsis screening tools. However, the usefulness of acute mental status within these criteria is limited to the frequency and accuracy of its capture. The Glasgow Coma Scale (GCS) score-the acute mental status indicator in many clinical sepsis criteria-is infrequently captured among allogeneic hematopoietic cell transplant recipients with suspected infections, and its ability to serve as an indicator of acute mental status among this high-risk population is unknown. OBJECTIVE: We evaluated the GCS score as an indicator of acute mental status during the 24 hours after suspected infection onset among allogeneic hematopoietic cell transplant recipients. METHODS: Using data from the first 100 days posttransplant for patients transplanted at a single center between September 2010 and July 2017, we evaluated the GCS score as an indicator of documented acute mental status during the 24 hours after suspected infection onset. From all inpatients with suspected infections, we randomly selected a cohort based on previously published estimates of GCS score frequency among hematopoietic cell transplant recipients with suspected infections and performed chart review to ascertain documentation of clinical acute mental status within the 24 hours after suspected infection onset. RESULTS: A total of 773 patients had ≥1 suspected infections and experienced 1,655 suspected infections during follow-up-625 of which had an accompanying GCS score. Among the randomly selected cohort of 100 persons with suspected infection, 28 were accompanied with documented acute mental status, including 18 without a recorded GCS. In relation to documented acute mental status, the GCS had moderate to high sensitivity and high specificity. DISCUSSION: These data indicate that, among allogeneic hematopoietic cell transplant recipients with suspected infections, the GCS scores are infrequently collected and have a moderate sensitivity. If sepsis screening tools inclusive of acute mental status changes are to be used, nursing teams need to increase measurement of GCS scores among high sepsis risk patients or identify a standard alternative indicator.
Subject(s)
Glasgow Coma Scale/standards , Sepsis/etiology , Transplantation, Homologous/adverse effects , Glasgow Coma Scale/statistics & numerical data , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Odds Ratio , Retrospective Studies , Sepsis/classification , Sepsis/psychology , Transplantation, Homologous/methods , Transplantation, Homologous/statistics & numerical dataABSTRACT
Spikes in symptom severity are noted for adolescents with attention deficit/hyperactivity disorder (ADHD) at the transitions to middle and high school that are attributed to developmental maladjustment. This study evaluated the effectiveness of high-intensity (HI; 412 hr, $4,373 per participant) versus low-intensity (LI; 24 hr, $97 per participant) skills-based summer intervention delivered to adolescents with ADHD by local school district staff. Participants were 325 ethnically diverse rising sixth and ninth graders with ADHD randomized to HI versus LI (n = 218) or recruited into an untreated comparison group (n = 107). Group × Time 1-year outcome trajectories were compared using linear mixed models. Both interventions possessed high fidelity and were viewed by families as enjoyable and beneficial. Youth attendance was higher for HI (~80%) versus LI (~45%). Parent training attendance was uniform across groups (~50%). Parent and student attendance did not impact trajectories. Primary benefits of HI over LI were to note taking (d = .50), parent contingency management (d = .43), and parent-rated ADHD symptoms (d = .40-.46; ninth grade only). Secondary analyses suggested that HI may produce additional benefits compared to no treatment for home organization skills (HI vs. untreated d = .54), parent-teen conflict (HI vs. untreated d = .39), and grade point average (HI vs. untreated d = .47, ninth grade only). Summer HI treatment was superior to LI in engagement and uptake of certain skills. However, the extent to which these medium benefits on a limited number of outcomes justify high costs compared to LI remains an open question. Delivering treatment during the summer instead of school year may limit generalizability.
Subject(s)
Attention Deficit Disorder with Hyperactivity/psychology , Attention Deficit Disorder with Hyperactivity/therapy , Behavior Therapy/methods , Schools/standards , Adolescent , Cohort Studies , Female , Humans , Male , SeasonsABSTRACT
Fire safety is a concern in space travel, particularly with the current plans of increasing the length of the manned space missions, and of using spacecraft atmospheres different than in Earth, such as microgravity, low-velocity gas flow, low pressure and elevated oxygen concentration. In this work, the spread of flame over a thermoplastic polymer, polymethyl methacrylate (PMMA), was conducted in the International Space Station and on Earth. The tests consisted of determining the opposed flame spread rate over PMMA cylinders under low-flow velocities ranging from 0.4 to 8 cm/s and oxygen concentrations from 15% to 21%. The data show that as the opposed flow velocity is increased, the flame spread rate first increases, and then decreases, different from that on Earth. The unique data are significant because they have only been predicted theoretically but not been observed experimentally before. Results also show that flame spread in microgravity could be faster and sustained at lower oxygen concentration (17%) than in normal gravity (18%). These findings suggest that under certain environmental conditions there could be a higher fire risk and a more difficult fire suppression in microgravity than on Earth, which would have significant implications for spacecraft fire safety.
ABSTRACT
The flammability of combustible materials in spacecraft environments is of importance for fire safety applications because the environmental conditions can greatly differ from those on earth, and a fire in a spacecraft could be catastrophic. Moreover, experimental testing in spacecraft environments can be difficult and expensive, so using ground-based tests to inform microgravity tests is vital. Reducing buoyancy effects by decreasing ambient pressure is a possible approach to simulate a spacecraft environment on earth. The objective of this work is to study the effect of pressure on material flammability, and by comparison with microgravity data, determine the extent to which reducing pressure can be used to simulate reduced gravity. Specifically, this work studies the effect of pressure and microgravity on upward/concurrent flame spread rates and flame appearance of a burning thin composite fabric made of 75% cotton and 25% fiberglass (Sibal). Experiments in normal gravity were conducted using pressures ranging between 100 and 30 kPa and a forced flow velocity of 20 cm/s. Microgravity experiments were conducted during NASA's Spacecraft Fire Experiment (Saffire), on board of the Orbital Corporation Cygnus spacecraft at 100 kPa and an air flow velocity of 20 cm/s. Results show that reductions of ambient pressure slow the flame spread over the fabric. As pressure is reduced, flame intensity is also reduced. Comparison with the concurrent flame spread rates in microgravity show that similar flame spread rates are obtained at around 30 kPa. The normal gravity and microgravity data is correlated in terms of a mixed convection non-dimensional parameter that describes the heat transferred from the flame to the solid surface. The correlation provides information about the similitudes of the flame spread process in variable pressure and reduced gravity environments, providing guidance for potential on-earth testing for fire safety design in spacecraft and space habitats.
ABSTRACT
BACKGROUND: Academic impairment is among the most troubling domains of impairment for adolescents with Attention Deficit/Hyperactivity Disorder (ADHD). METHOD: This investigation presents results of a yearlong academic intervention delivered to adolescents with ADHD (N = 218) by engaging school staff as interventionists through behavioral consultation with an outside mental health professional. RESULTS: The intervention was coordinated successfully in some cases, but not in others. The principal challenge to intervention coordination was sustaining monthly contact between consultants and interventionists (38.5% success rate) and scheduling in-person consultation meetings with interventionists (40.0% success rate). Implementation of the intervention was enhanced when the student (a) attended a public (vs. private) school, (b) had an IEP or Section 504 plan in place, (c) was in middle school (vs. high school), (d) had a parent who communicated regularly with the school, and (e) had a special education support staff member or counselor (vs. teacher or administrator) as a school interventionist. CONCLUSIONS: Considering these data, recommendations are provided for effective coordination of academic interventions for adolescents with ADHD.
ABSTRACT
AIM: The purpose of this study was to describe the prognostic significance of ALDH7A1 in surgically treated non-small-cell lung carcinoma. (NSCLC). MATERIALS & METHODS: We immunohistochemically analyzed ALDH7A1 expression in surgically resected NSCLC from 89 patients using a tissue microarray. RESULTS: ALDH7A1 staining was positive in 43 patients and negative in 44 patients, with two tumor sections missing. For stage I NSCLC patients, ALDH7A1 positivity was associated with decreased recurrence-free and overall survival. Multivariate analysis demonstrated that ALDH7A1-expressing NSCLC tumors had a significantly higher incidence of lung cancer recurrence compared with patients with ALDH7A1-negative tumors, although there was no association with overall survival. CONCLUSION: For patients with NSCLC, low ALDH7A1 expression was associated with a decreased incidence of cancer recurrence. Specifically in stage I patients, negative staining for ALDH7A1 was associated with improved recurrence-free and overall survival, suggesting a predictive role in surgically treated patients.
Subject(s)
Aldehyde Dehydrogenase/biosynthesis , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Neoplasm Recurrence, Local/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/surgery , Disease-Free Survival , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Lung Neoplasms/drug therapy , Lung Neoplasms/surgery , Male , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Staging , PrognosisABSTRACT
Research shows that certain antihypertensives taken during midlife confer Alzheimer's disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including cerebrospinal fluid (CSF) amyloid-ß (Aß) levels and ACE activity, arterial function, and cognition in participants with a parental history of AD. This four month randomized, double-blind, placebo-controlled, pilot clinical trial evaluated the effects of ramipril, a blood-brain-barrier crossing ACE-I, in cognitively healthy individuals with mild, or Stage I hypertension. Fourteen participants were stratified by gender and apolipoprotein E ε4 (APOE ε4) status and randomized to receive 5 mg of ramipril or matching placebo daily. Participants were assessed at baseline and month 4 on measures of CSF Aß(1-42) and ACE activity, arterial function, and cognition. Participants were middle-aged (mean 54 y) and highly educated (mean 15.4 y), and included 50% men and 50% APOE ε4 carriers. While results did not show a treatment effect on CSF Aß(1-42) (p = 0.836), data revealed that ramipril can inhibit CSF ACE activity (p = 0.009) and improve blood pressure, however, there were no differences between groups in arterial function or cognition. In this study, ramipril therapy inhibited CSF ACE activity and improved blood pressure, but did not influence CSF Aß1-42. While larger trials are needed to confirm our CSF Aß results, it is possible that prior research reporting benefits of ACE-I during midlife may be attributed to alternative mechanisms including improvements in cerebral blood flow or the prevention of angiotensin II-mediated inhibition of acetylcholine.
Subject(s)
Alzheimer Disease/prevention & control , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Ramipril/therapeutic use , Adult , Aged , Alzheimer Disease/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Ankle Brachial Index , Apolipoproteins E/genetics , Arteries/physiopathology , Biomarkers/cerebrospinal fluid , Blood Pressure/physiology , Brachial Artery/diagnostic imaging , Cognition/physiology , Data Interpretation, Statistical , Double-Blind Method , Family , Female , Humans , Male , Middle Aged , Neuropsychological Tests , Peptidyl-Dipeptidase A/cerebrospinal fluid , Pilot Projects , Ultrasonography , tau Proteins/cerebrospinal fluidABSTRACT
Women are at a higher risk than men to develop mood disorders and depression. The increased risk is associated with fluctuating estrogen levels that occur during reproductive cycle events, particularly during the menopausal transition, a time characterized by drastic fluctuations in estrogen levels and increases in new onset and recurrent depression. Conversely, recent data show that hormone therapy, particularly transdermal estradiol formulations, may prevent mood disorders or even serve as a treatment regimen for women with diagnosed mood disturbances via estrogen regulation. While the exact mechanism is unknown, there is compelling scientific evidence indicating the neuromodulatory and neuroprotective effects of estrogen, which are directly relevant to mood symptomotology. Specifically, affective regulation has been linked to neural structures rich in estrogen receptors and estrogenic regulation of neurotransmitters. While a wealth of basic science, observational and clinical research support this rationale, potential mediating variables, such as estrogen formulation, proximity of administration to menopause, and the addition of progestins should be considered. Furthermore, the nature of postmenopausal exogenous hormone formulations in relation to premenopausal endogenous levels, as well as the ratio of estrone to estradiol warrant consideration.
ABSTRACT
Both inflammation and oxidative injury are features of Alzheimer's disease (AD), but the contribution of these intertwined phenomena to the loss of working memory in this disease is unclear. We tested the hypothesis that highly reactive γ-ketoaldehydes that are formed both by non-enzymatic free radical catalyzed lipid peroxidation and by cyclooxygenases may be causally linked to the development of memory impairment in AD. We found that levels of γ-ketoaldehyde protein adducts were increased in the hippocampus of brains obtained postmortem from patients with AD compared to age-matched controls, but that levels of γ-ketoaldehyde protein adducts in the cerebellum were not different in the two groups. Moreover, immunohistochemistry revealed that adducts localized to hippocampal pyramidal neurons. We tested the effect of an orally available γ-ketoaldehyde scavenger, salicylamine, on the development of spatial working memory deficits in hApoE4 targeted replacement mice, a mouse model of dementia. Long-term salicylamine supplementation did not significantly alter body weight or survival, but protected against the development of age-related deficits in spatial working memory in 12-14 month old ApoE4 mice. These findings suggest that γ-ketoaldehyde adduct formation is associated with damage to hippocampal neurons in patients with AD and can contribute to the pathogenesis of spatial working memory deficits in hApoE4 mice. These data provide a rational basis for future studies exploring whether γ-ketoaldehyde scavengers may mitigate the development of cognitive dysfunction in patients with AD.
Subject(s)
Aldehydes/therapeutic use , Apolipoprotein E4/genetics , Memory Disorders/genetics , Memory Disorders/prevention & control , Memory, Short-Term/drug effects , Age Factors , Aged , Aged, 80 and over , Alzheimer Disease/complications , Alzheimer Disease/genetics , Analysis of Variance , Animals , Body Weight/drug effects , Body Weight/genetics , Cerebellum/metabolism , Disease Models, Animal , Female , Hippocampus/metabolism , Humans , Male , Maze Learning/drug effects , Memory Disorders/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Motor Activity/drug effects , Psychomotor Performance/drug effects , Single-Chain Antibodies/therapeutic useABSTRACT
Early detection may help improve survival from lung cancer. In this study, our goal was to derive and validate a signature from the proteomic analysis of bronchial lesions that could predict the diagnosis of lung cancer. Using previously published studies of bronchial tissues, we selected a signature of nine matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) mass-to-charge ratio features to build a prediction model diagnostic of lung cancer. The model was based on MALDI MS signal intensity (MALDI score) from bronchial tissue specimens from our 2005 published cohort of 51 patients. The performance of the prediction model in identifying lung cancer was tested in an independent cohort of bronchial specimens from 60 patients. The probability of having lung cancer based on the proteomic analysis of the bronchial specimens was characterized by an area under the receiver operating characteristic curve of 0.77 (95% CI 0.66-0.88) in this validation cohort. Eight of the nine features were identified and validated by Western blotting and immunohistochemistry. These results show that proteomic analysis of endobronchial lesions may facilitate the diagnosis of lung cancer and the monitoring of high-risk individuals for lung cancer in surveillance and chemoprevention trials.
Subject(s)
Lung Neoplasms/diagnosis , Neoplasm Proteins/analysis , Proteomics/methods , Aged , Blotting, Western , Early Detection of Cancer/methods , Female , Humans , Immunohistochemistry , Lung Neoplasms/metabolism , Male , Middle Aged , Neoplasm Proteins/metabolism , Reproducibility of Results , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methodsABSTRACT
Preclinical analyses strongly implicate the phosphatidylinositol 3' kinase-Akt-mammalian target of the rapamycin (P13K-Akt-mTOR) signaling pathway in smooth muscle tumorigenesis and differentiation, indicating that this pathway may be a suitable molecular target for the development of anticancer chemotherapeutic agents. The purpose of this study is to define the frequency and patterns of expression of 3 proteins in this pathway (mTOR, Akt, and PI3-K) in smooth muscle tumors of the uterine corpus, and to establish whether the expression of any of these proteins has independent prognostic significance. The expression patterns of mTOR, pan-Akt, and PI3-K were evaluated by immunohistochemistry in 31 uterine leiomyosarcomas and 10 leiomyomata, and the results were correlated with clinicopathologic parameters. Cases were scored by multiplication of staining intensity (on a 0 to 3+scale) and the extent/distribution of immunoreactivity (on a 0 to 4+ scale) for potential scores that ranged from 0 to a maximum of 12. Cases with scores of 4+to 12+(moderate, 4+ to 8+; high, 9+ to 12+ immunoreactivity) were considered positive. Associated peritumoral normal myometrium was present in 27 cases. All 31 leiomyosarcomas were pan-Akt positive, with 80.6% of the positive cases displaying high scores, whereas all 10 leiomyomata and 27 normal myometria were entirely pan-Akt negative. High pan-Akt scores were associated with high tumor grade but not with advanced stage or outcome. Every tumoral and nontumoral sample that was evaluated showed immunoreactivity for mTOR. PI3-K was positive in 20 (64.5%) of the 31 leiomyosarcomas but in none of the leiomyomata. High scores of PI3-K were associated with late pathologic stage (P=0.0022). High PI3-K scores, high pan-Akt scores, and PI3-K positivity were not independently associated with reduced disease-specific survival on multivariate analysis. Our findings suggest that relative to the normal myometrium, there is indeed dysregulation of the P13K-Akt-mTOR pathway in uterine smooth muscle tumors and especially in uterine leiomyosarcomas. Pan-Akt, mTOR, and PI3-K expression lacked independent prognostic significance in this pilot study, but additional and larger analyses are required. If corroborated in other laboratories, the expression patterns of proteins in this pathway, especially pan-Akt, may be of diagnostic use.
Subject(s)
Biomarkers, Tumor/analysis , Phosphatidylinositol 3-Kinase/biosynthesis , Proto-Oncogene Proteins c-akt/biosynthesis , Smooth Muscle Tumor/pathology , TOR Serine-Threonine Kinases/biosynthesis , Uterine Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , Middle Aged , Neoplasm Staging , Prognosis , Signal Transduction/physiology , Smooth Muscle Tumor/metabolism , Uterine Neoplasms/metabolismABSTRACT
Inflammatory myofibroblastic tumor is a rare mesenchymal neoplasm that harbors an anaplastic lymphoma kinase (ALK) gene rearrangement in the majority of cases. It is composed of fibroblastic-myofibroblastic cells with a characteristic inflammatory infiltrate that consists predominantly of plasma cells. In contrast, IgG4-related sclerosing disease is a recently described multisystem disorder with a histological appearance similar to inflammatory myofibroblastic tumor. The plasma cell infiltrate is characteristic in IgG4-related sclerosing disease and has been studied as a tool to render this diagnosis. Histologically, the two disorders overlap, although there are significant clinical differences. This study analyzes the histological appearance of 36 inflammatory myofibroblastic tumors, compares them with IgG4-related sclerosing disease, and assesses the plasma cell profile using immunohistochemistry to determine the range and proportion of IgG4 plasma cells. The majority of patients were children and young adults, mainly with solitary masses and no clinical manifestations of IgG4-related sclerosing disease. ALK-1 positivity was present in 23 cases (64%). None showed obliterative phlebitis or prominent lymphoid aggregates. Of 36 inflammatory myofibroblastic tumors, 15 cases showed an IgG4/IgG ratio ≥0.10, a cutoff described in the literature as supportive of IgG4-related sclerosing disease and up to 33 IgG4-positive plasma cells per high-power field indicating a mild-to-moderate increase as compared with IgG4-related sclerosing disease. Currently, the diagnostic recognition of inflammatory myofibroblastic tumor is based on clinicopathological features and diagnostic adjuncts, such as ALK-1 reactivity and genetic tests. Although inflammatory myofibroblastic tumor and IgG4-related sclerosing disease are distinct entities, a subset of inflammatory myofibroblastic tumors exhibit an IgG4/IgG ratio that is within the range for IgG4-related sclerosing disease. Therefore, the ratio alone cannot be used as a reliable discriminator between these two entities and other clinical and pathologic features must always be taken into account.
Subject(s)
Granuloma, Plasma Cell/immunology , Immunoglobulin G/analysis , Myofibroblasts/immunology , Plasma Cells/immunology , Scleroderma, Systemic/immunology , Adolescent , Adult , Anaplastic Lymphoma Kinase , Biomarkers/analysis , Child , Child, Preschool , Diagnosis, Differential , Female , Granuloma, Plasma Cell/pathology , Humans , Immunohistochemistry , Infant , Male , Myofibroblasts/pathology , Plasma Cells/pathology , Predictive Value of Tests , Receptor Protein-Tyrosine Kinases/analysis , Scleroderma, Systemic/pathology , Young AdultABSTRACT
The distinction between sarcomatoid carcinoma (SC) and bona fide sarcoma can be difficult using conventional immunohistochemical markers. Epithelial-mesenchymal transition (EMT) has been proposed as a histogenetic mechanism for the development of SC. Expression of selected markers of EMT (Twist and Slug) was compared with other markers of epithelial differentiation in SC and spindle cell sarcoma to determine the utility of these antigens in this differential diagnosis. Twenty-seven cases of SC (excluding those of gynecologic origin) were stained by immunohistochemistry for cytokeratins (AE1/AE3, 5D3, CK5/6, and 34betaE12), p63, claudin-1, claudin-7, epithelial cadherin, placental cadherin, epithelial cell adhesion molecule/epithelial-specific antigen, 14-3-3sigma, Twist, and Slug. A comparison group of 21 spindle or pleomorphic spindle cell sarcomas was also studied. Immunohistochemical stains were scored in a semiquantitative manner and subsequent exploratory analyses were performed using logistic regression and chi2 tests. Only cytokeratin AE1/AE3 specifically labeled SC in a statistically significant manner. Other epithelial-specific markers tested did not distinguish SC from sarcoma primarily owing to low sensitivity. However, when positive, immunostains such as CK5/6, membranous epithelial cadherin, and nuclear p63 may aid in the distinction of SC from sarcoma. EMT markers were expressed in most cases of both SC and sarcoma, and were not useful in making a differential diagnosis between these neoplasms.
Subject(s)
Carcinoma, Transitional Cell/diagnosis , Epithelial Cells/pathology , Mesenchymal Stem Cells/pathology , Sarcoma/diagnosis , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/metabolism , Carcinoma, Transitional Cell/pathology , Cell Differentiation , Diagnosis, Differential , Epithelial Cells/metabolism , Gene Expression , Humans , Immunohistochemistry , Keratins/biosynthesis , Mesenchymal Stem Cells/metabolism , Sarcoma/pathology , Snail Family Transcription Factors , Transcription Factors/biosynthesis , Twist-Related Protein 1/biosynthesisABSTRACT
BACKGROUND: Clusterin is a glycoprotein that has been implicated in many processes, including apoptosis, cell cycle regulation, and DNA repair. Previous studies have examined the prognostic value of clusterin expression in various malignancies. In the present study, we examined clusterin staining in tumors resected from patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Tumor specimens were obtained for 113 patients with completely resected NSCLC from paraffin-embedded tissue microarrays and stained with an antibody specific for clusterin. Staining patterns were observed and graded based on intensity and then correlated with clinical data. RESULTS: Positive cytoplasmic clusterin staining was observed in 44 patients, and weak/negative staining was observed in 62 patients. Patients who had tumors that stained positive for cytoplasmic clusterin had significantly longer survival in multivariate analysis (hazard ratio 0.487, 95% confidence interval 0.27-0.89). A correlation was also observed for recurrence-free survival, which approached statistical significance (hazard ratio 0.345, 95% confidence interval 0.12-1.02). In univariate analysis, patients with clusterin-positive tumors had a 63% 3-year survival, whereas patients with clusterin-negative tumors had a 42% 3-year survival (P = 0.0108); clusterin-positive tumors also had significantly less recurrence (P = 0.0231). CONCLUSIONS: Cytoplasmic clusterin staining is present in a substantial number of NSCLC tumors and may be a biomarker for longer survival in patients with surgically resected NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Clusterin/metabolism , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/surgery , Cytoplasm/metabolism , Cytoplasm/pathology , Female , Humans , Immunohistochemistry , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Male , Microarray Analysis , Neoplasm Staging , Survival AnalysisABSTRACT
Reports of sex steroid receptor expression in chordoma suggest that these tumors may be responsive to hormone manipulation therapy. Immunohistochemical stains for estrogen receptor (ER)-alpha, ER-beta, progesterone receptor (PR), androgen receptor (AR), and cyclooxygenase 2 (COX-2), were performed on a tissue microarray containing 21 samples of chordoma. Most chordomas expressed COX-2, ER-beta, and AR, whereas ER-alpha and PR stains were negative in all cases. ER-beta expression did not correlate with AR expression (P = .4142; McNemar test). There were no statistically significant correlations between the expression of any of these markers and anatomic location of tumor, patient sex, patient age, or disease-free survival. Chordomas commonly express COX-2, AR, and ER-beta. These findings may have therapeutic implications concerning the use of agents that inhibit or modulate these signaling molecules.
Subject(s)
Chordoma/metabolism , Cyclooxygenase 2/metabolism , Receptors, Androgen/metabolism , Receptors, Estrogen/metabolism , Adult , Aged , Disease-Free Survival , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Female , Humans , Immunohistochemistry , Male , Middle Aged , Sacrum , Skull Neoplasms/metabolism , Spinal Neoplasms/metabolismSubject(s)
Access to Information/legislation & jurisprudence , Confidentiality/legislation & jurisprudence , Employment/legislation & jurisprudence , Nursing Staff/legislation & jurisprudence , Humans , Job Application , Pennsylvania , Personnel Selection/legislation & jurisprudence , Public Health/legislation & jurisprudenceABSTRACT
Human exposure to dithiocarbamates results from their uses as pesticides, in manufacturing, and as pharmaceutical agents. Neurotoxicity is an established hazard of dithiocarbamate exposure and has been observed in both humans and experimental animals. Previous studies have shown that the neurotoxicity of certain dithiocarbamates, including N,N-diethyldithiocarbamate (DEDC), disulfiram, and pyrrolidine dithiocarbamate, can manifest as a primary myelinopathy of peripheral nerves. Because increased levels of copper in peripheral nerves and elevated levels of lipid peroxidation products accompany DEDC-induced lesions, it has been suggested that the disruption of copper homeostasis and increased oxidative stress may contribute to myelin injury. To further assess the biological impact of DEDC-mediated lipid peroxidation in nerves, the changes in protein expression levels resulting from DEDC exposure were determined. In addition, protein carbonyl content in peripheral nerves was also determined as an initial assessment of protein oxidative damage in DEDC neuropathy. Rats were exposed to DEDC by intra-abdominal osmotic pumps for eight weeks and proteins extracted from the sciatic nerves of DEDC-exposed animals and from non-exposed controls. The comparison of protein expression levels using two-dimensional difference gel electrophoresis demonstrated significant changes in 56 spots of which 46 were identified by MALDI-TOF/MS. Among the proteins showing increased expression were three isoforms of glutathione transferase, important for the detoxification of reactive alpha,beta-unsaturated aldehydes generated from lipid peroxidation. The increased expression of one isoform, glutathione transferase pi, was localized to the cytoplasm of Schwann cells using immunohistochemistry. An immunoassay for nerve protein carbonyls demonstrated a significant increase of approximately 2-fold for the proteins isolated from DEDC-exposed rats. These data support the ability of DEDC to promote protein oxidative damage in peripheral nerves and to produce sufficient lipid peroxidation in either myelin or another component of the Schwann cell to elicit a protective cellular response to oxidative stress.
Subject(s)
Demyelinating Diseases/chemically induced , Demyelinating Diseases/metabolism , Ditiocarb/toxicity , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Peripheral Nervous System/metabolism , Animals , Chromatography, High Pressure Liquid , Databases, Factual , Demyelinating Diseases/pathology , Electrophoresis, Polyacrylamide Gel , Fluoresceins , Fluorescent Dyes , Globins/metabolism , Immunoassay , Immunohistochemistry , Male , Neural Networks, Computer , Neural Pathways/physiology , Oxidative Stress/physiology , Peripheral Nervous System/pathology , Rats , Rats, Sprague-Dawley , Sciatic Nerve/pathology , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Weight Gain/drug effectsABSTRACT
BACKGROUND: Platelet derived growth factor (PDGF) and PDGFR-beta are expressed and have been found to have prognostic value in several human cancers. Data in non-small-cell cancer cell lines have suggested that PDGFR is a therapeutic target for drug development. In the current study PDGFR-beta expression and prognostic value in small cell lung cancer (SCLC) was investigated. METHODS AND MATERIALS: Paraffin-embedded tissue blocks from 53 patients with limited and extensive stage SCLC were obtained for immunohistochemical staining. Tumors from each patient were sampled 3 times and stained with PDGFR-beta specific antibody. Patients were divided into low and high staining groups based on intensity. RESULTS: There was high intensity PDGFR-beta staining in 20 patients with SCLC. Another 29 expressed low intensity PDGFR-beta staining, with only 4 patients showing no PDGFR-beta staining. There was no statistically significant difference in 5 year overall survival between patients with low levels of PDGFR-beta staining vs. those with high level staining SCLC tumors (p = 0.538). CONCLUSIONS: The present study found that the majority of SCLC patients express, at least, a low level of PDGF-beta. However, the level of PDGFR-beta expression was not a statistically significant predictor of 5 year overall survival in SCLC.