tbuckley/cabot-search huggingface dataset:
Identification of estrogenic tamoxifen metabolite(s) in tamoxifen-resistant human breast tumors.
Authors: V J Wiebe, C K Osborne, W L McGuire, M W DeGregorio
Journal: Journal of Clinical Oncology (1992)

PURPOSE We have shown previously that acquired tamoxifen resistance in an in vivo experimental model is associated with reduced tamoxifen accumulation, isomerization of trans-4-hydroxytamoxifen, and tamoxifen-stimulated tumor growth. The purpose of this study is to isolate and verify the presence of estrogenic tamoxifen metabolites in human breast tumors using high-performance liquid chromatography (HPLC) and mass-spectrometry (MS) techniques. PATIENTS AND METHODS In the present study, we used HPLC and MS to identify the presence of estrogenic metabolites in tumor samples excised from athymic nude mice and in human breast tumors isolated from patients receiving adjuvant tamoxifen therapy. RESULTS We identified the presence of metabolite E, a known estrogenic metabolite of tamoxifen, in tamoxifen-resistant MCF-7 human breast tumors implanted in athymic nude mice, as well as in tumors from patients with clinical resistance. Additionally, we separated another estrogenic metabolite, bisphenol, by HPLC, and this was also tentatively confirmed by MS analysis. CONCLUSION These data suggest that cellular tamoxifen metabolism to estrogenic metabolites may in part contribute to stimulating the growth of hormone-responsive breast tumors following prolonged exposure to tamoxifen. Further evaluation of the relationship between cellular metabolism and acquired tamoxifen resistance is warranted.
Effect of Immune Manipulation on Natural Immune Responses to Murine Mammary Tumor Antigens2
Authors: Phyllis B. Blair, Mary-Ann Lane
Journal: JNCI Journal of the National Cancer Institute (1977)

The virus-host relationship in BALB/cfC3H virgin female mice neonatally infected with an oncogenic virus (mammary tumor virus) (MuMTV) was significantly altered by a brief immunosuppressive treatment during young adult life. Natural immune responses were augmented and changed. The ability of lymphoid cells to attack target cells expressing MuMTV-associated antigens was significantly increased, and a new component, a non-T-cell reactivity, was added to the T-cell reactivity found in normal females. Serum blocking factors were both quantitatively and qualitatively altered.
Abstract 124: Parthenogenetic Stem Cell-derived Cardiomyocytes Express Major Histocompatibility Complex-I only after Inflammatory Stimulation
Authors: Satish Galla, Michael Didie, Vijayakumar Muppala, Ralf Dressel, Wolfram Hubertus Zimmermann
Journal: Circulation Research (2014)

Background: Pluripotent parthenogenetic stem cells (PSCs) can be directed towards a cardiac fate and utilized in tissue engineered heart repair. In vivo applications of tissue engineered allografts are compromised by expression of mismatching major histocompatibility complex proteins (MHC; encoded in the murine H2 locus). Here we investigated whether PSC-derived cardiomyocytes (CM) express MHC-I. Methods: Mouse PSCs (A3-line from B6D2F1 strain with haploidentical H2K d -locus) expressing a CM-specific neomycin-resistance and GFP were differentiated and purified for CM by addition of G418 (85% purity by FACS for actinin). To simulate heart muscle biology in vitro, we made use of engineered heart muscle (EHM) constructed from PSC-derived CM (75%), growth-inhibited murine embryonic fibroblasts (MEF (25%); NMRI mice), and collagen type I. MHC class-I H2K d (MHC-I) expression was assessed on CM and Non myocytes before EHM assembly and from enzymatically digested EHMs (cultured for 10 days) by FACS. Interferon gamma (IFNγ) was added for 48 h to stimulate MHC-I expression. As a reference, we investigated MHC-I expression in CM from neonatal mice and adult mouse hearts by FACS and by immunofluorescence staining. Results: EHM showed a positive ionotropic response to beta-adrenergic stimulation which could be reduced by muscarinergic stimulation. A3-CM, in contrast to Non myocytes, showed negligible expression of MHC-I (1±0.5% vs. 60±10% positive cells; n=3). EHM culture did not change MHC-I expression in CM. IFNγ treatment resulted in a marked increase of MHC-I-expression in CM monolayer culture (40±6%; n=3) and in EHM (30±8%; n=3). For comparison, 30% (n=2) neonatal CM expressed MHC-I while MHC-I was not detectable in adult CM. Conclusion: PSC-derived CM show a similarly low expression of MHC-I as adult CM and respond with MHC-I upregulation to IFNγ stimulation. This suggests a mature immunological response in PSC-CM with important implications for in vivo applications, i.e., MHC-I matching will likely be a prerequisite for successful allografting of PSC-EHM.
Investigations of Cigarette Smoke Dosages in Inhalation Experiments With Syrian Hamsters. II. Uptake of Cigarette Smoke by the Animals; Comparisons of the Influence of the Gas Phase and the Whole Smoke of Different Cigarettes
Authors: H.-J. Klimisch, W. Dontenwill
Journal: JNCI Journal of the National Cancer Institute (1977)

An increased CO2 content (CO2 enrichment) in the smoke-air mixture was measured in an inhalation chamber containing Syrian hamsters. Since these additional CO2 concentrations originated from the animals' expiratory air, the level of CO2 (CO2 enrichment) was considered a function of the respiratory capacity. Results obtained with this method of characterizing the respiratory behavior of hamsters in inhalation experiments led us to conclude that the vapor phase of cigarettes reduced respiration up to 45% and the whole smoke, up to 60%. Qualitative and quantitative differences in the composition of the vapor phase and particulate phase as offered in animal inhalation experiments for comparing different cigarettes did not induce measurable differences in the respiratory behavior. Therefore, such inhalation experiments were found to be suitable for comparing the relative effects of different cigarette types. Estimations on the inhaled amounts of TPM led to results that were similar to those obtained in experiments with radioactively labeled smoke.
Abstract 17097: M2 Macrophage Polarization Promotes Neovascularization in vivo
Authors: Mohamed Ameen Ismahil, Justin R Kingery, Tariq Hamid, Sumanth D Prabhu
Journal: Circulation (2011)

Following myocardial infarction (MI), resident and recruited macrophages remove necrotic and apoptotic cells, secrete cytokines, and modulate angiogenesis at the infarct site. In response to microenvironmental stimuli, macrophages adopt either pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes; however, the role of macrophage polarity in tissue neovascularization is unclear. We hypothesized that macrophage polarity with regard to activation state plays a critical role in neovascularization during wound healing. Peritoneal macrophages were isolated from adult C57Bl/6 mice (n = 7) using thioglycollate-elicitation, and polarization was induced to either M1, using LPS 1 μg/ml and IFN-γ 4 ng/ml, or M2, using IL-4 20 ng/ml or IL-10 20 ng/ml. Successful macrophage polarization was confirmed by immunofluorescence for M1- and M2-specific surface markers. In syngeneic mice, Matrigel plugs (0.6 ml/plug) were injected subcutaneously in vivo, either alone or with M1 or M2 macrophages (~20,000 cells/plug) or supernatant derived from M1 or M2 cultures (0.3 ml/plug) and plug neovascularization was assessed after 10 days. In addition, we also performed in vitro scrape wound healing assays using cultured mouse cardiac endothelial cells (MCECs) and human umbilical vein endothelial cells (HUVECs) and tube formation assays with HUVECs. Supernatant derived from M2 macrophages induced faster wound healing over 16 h in cultured MCECs or HUVECs, and increased HUVEC tube formation and tube length. However, in vitro wound closure and tube formation was delayed by supernatant derived from M1 cells (n = 5). In vivo neovascularization in the Matrigel plug was quantified morphologically and by flow cytometry. The presence of M2 macrophages, or supernatant derived from M2 macrophages, resulted in increased neovessel length and number, with recruitment of significantly greater numbers of CD31+ cells to the Matrigel plug, as compared with M1 or inactivated macrophages and their associate culture supernatant (p &lt; 0.05, n = 6). We conclude that M2 macrophage polarization promotes angiogenesis in vivo via paracrine effects on vessel recruitment. Strategies to induce M2 polarization in vivo may augment wound healing after MI.
The TNF-derived TIP peptide reduces lung dysfunction in experimental influenza A virus infection
Authors: Rudolf Lucas, Guang Yang, Supriya Sridhar, Zachary Traylor, Hamid Hossain, Bernhard Fischer, Trinad Chakraborty, Ian Davis
Journal: European Respiratory Journal (2011)

Background: Permeability edema during Influenza A virus (IAV) infection is characterized by reduced alveolar liquid clearance (ALC) and pulmonary endothelial hyperpermeability. Mortality after IAV infection is mainly due to secondary pneumococcal infections and occurs after antibiotic therapy, which can release the toxin pneumolysin (PLY) in the lungs.

Aims: To investigate whether the TNF-derived TIP peptide, which reduces PLY-induced edema, can blunt IAV-induced ALC dysfunction and combined IAV/PLY-induced barrier dysfunction.

Methods: ALC is assessed in BALB/c mice infected i.n. for 2d with 10,000 FFU/mouse (strain H1N1-A/WSN/33), using the BSA dilution method. We measure IAV/PLY-induced changes in transendothelial resistance (TER) in monolayers of human lung microvascular endothelial cells (HL-MVEC; ECIS).

Results: IAV infection reduces basal ALC by 50±5%, which is prevented by co-instillation of the TIP peptide (2.5 mg/kg; n=11). The combination of PLY (7.5 ng/ml) and UV-inactivated IAV (1 virus/cell) causes a significant drop in normalized TER in HL-MVEC monolayers from 100 to 40±3% of baseline. The TIP peptide (50 μg/ml), as well as Ro32-4032 (10 nM), a specific inhibitor of PKC-α, implicated in both ALC dysfunction and hyperpermeability, restore TER to 86±4 and 80±6% of ctrl, respectively (n=4). IAV-treatment increases PKC-α activation by 110±7% over basal in HL-MVEC, an effect significantly blunted by the TIP peptide (23±1% over basal, n=4).

Conclusions: The TIP peptide represents a therapeutic candidate for the treatment of IAV-associated lung dysfunction, since it interferes with both IAV infection-associated ALC and barrier dysfunction, upon reducing PKC-α activation.
Glucocorticoid Receptors and Actions in Subpopulations of Cultured Rat Bone Cells
Authors: Theresa L. Chen, David Feldman
Journal: Journal of Clinical Investigation (1979)

We have previously shown that bone cells possess glucocorticoid receptors and that, in addition to being inhibitory to cell growth, glucocorticoid treatment potentiates the ability of parathyroid hormone (PTH) to stimulate cyclic AMP (cAMP) formation. This study extends those observations to specific subpopulations of bone cells and explores the mechanism of the cAMP augmentation. Subpopulations of cultured bone cells derived from 20-d-old fetal rat calvaria were enriched for “osteoblast-like” (OB) and “osteoclast-like” (OC) cells by sequential collagenase digestion. OC cells released during the first 30 min of collagenase digestion were characterized by low alkaline phosphatase activity, a cAMP response to salmon calcitonin (CT), but only a small cAMP response to bovine PTH. In contrast, OB cells released between 30 and 120 min of collagenase digestion, possessed high alkaline phosphatase activity, responded with a large cAMP rise to PTH, but exhibited no response to CT. Glucocorticoid receptors, with similar properties, were demonstrated in both populations (Kd ≅ 5 nM, Nmaximum ≅ 400 fmol/mg cytosol protein). Dexamethasone equivalently inhibited cell growth and alkaline phosphatase activity in both populations. Dexamethasone potentiation of cAMP generation occurred after PTH but not CT stimulation. A greater enhancement of cAMP generation observed in OB cells appears to result from two glucocorticoid actions: (a) stimulation of adenylate cyclase and (b) inhibition of phosphodiesterase. Only the latter mechanism was found in OC cells. Dexamethasone-treated cells showed an increase in both sensitivity and maximal response of cAMP to PTH. The possible relationship of these actions to the mechanism of glucocorticoid-induced osteopenia is discussed.
Pilot study of reliability of PHQ-9 questionnaire for evaluation of depression in hospitalized asthmatic patients
Authors: Saeid FallahTafti, Ali Cheraghvandi, Mitra Safa, Firouzeh Talischi
Journal: European Respiratory Journal (2012)

In chronic pulmonary disease patients, consideration of physical signs of illness such as difficulty breathing, etc. as well as psychiatric conditions which occur due to lack of adaptability with disease are important. In this study it was tried to evaluate a short and comprehensive questionnaire for screening for psychiatric disease and the PHQ-9 for depression and GAD-7 for anxiety were evaluated.

This was a cross-sectional study with completion of questionnaire by one interviewer. All asthma patients hospitalized at Masih Daneshvari Hospital during the summer of 2011 who were able to respond to questionnaire and agreed to participate were included in the study. Demographic information was also collected. Data was entered into the computer and analyzed via SPSS 12 software.

In total 20 patients participated for the pilot study with mean age of 58±18 years and 70% were female. Fifty six percent were illiterate and average years of illness were 9±5 years. Depression and anxiety was found more in women compared to men which a larger study for significance evaluation is needed. The Cronbach alpha values for PHQ-9 were 0.645 and for GAD-7 0.837.

The shortness of the questionnaires makes them practical. A larger study is in progress by researchers for determining validity and reliability of the two questionnaires and comparison with the GHQ-12.
Risk factors for acquired drug-resistant tuberculosis
Authors: Evelina Lesnic, Vasile Zlepca, Viorica Uzdris
Journal: European Respiratory Journal (2013)

According to WHO estimates Moldova leads among 27 countries with highest level of MDR-TB, with 27% in new cases and 51% in previously treated, causing 76% of TB-deaths. Patients with treatment failure have the highest rate of MDR. Aim risk factors study for acquired drugresistant-TB (DR-TB). Design Case-control study included 121 new pulmonary TB cases with sensible strains at DST, distributed in study group (SG)- 67 cases failed after 5 months DOT and DST detected DR-TB and control group-54 cases cured. Results Men were 69%vs59%, RR=1.5, average age 39,3vs 41,2yrs, urban residence 68%vs57%, RR=1.2. TB contact was established in 41%vs.27%, RR=1.3. Social risk factors: unemployment 79%vs71% RR=1.1, single status 73%vs26%, RR=2.1, low life conditions 78%vs44%, RR=2.3, migration 15%vs13%, RR=1.1 detention 12%vs0%, RR=1.9. Active smokers were 87%vs28%, RR=4,2, cronic alcool consumers 79%vs11%, RR=4.4. TB- related factors: late detection 63%vs52% RR=1.2, onset-complications 43%vs24% RR=1.4, associated diseases 36%vs21%, RR=1.2. Severe extensive forms 93%vs45%, RR=5.3, lung destructions 83%vs61%. At detection microscopic positive 82%vs73%. Negativation rate at 2nd month 47%vs69%.At 5th month 95% of SG were microscopic positive, DST revealing monoresistance-13%, poliresistance-28%, MDR-TB 59%. All cases started DOT, but 12% of SG were individualized treated, due to adverse reactions 12%vs 2%, RR=1.9, anti-TB treatment non-adherented were 91%vs.0%, RR=10.9. Conclusions:High risk factors for acquired DR-TB: treatment non-adherence, extensive severe TB, alcohol consumption, smoking. Completely observed standard treatment, social support, population awareness about TB will diminish the rate of acquired drugresistant-TB.
c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases.
Authors: C Carlomagno, F Perrone, C Gallo, M De Laurentiis, R Lauria, A Morabito, G Pettinato, L Panico, A D'Antonio, A R Bianco, S De Placido
Journal: Journal of Clinical Oncology (1996)

PURPOSE We studied retrospectively the interaction between c-erbB2 overexpression and adjuvant tomoxifen in node-negative breast cancer patients enrolled in the Gruppo Universitario Napoletano 1 (GUN-1) trial. PATIENTS AND METHODS c-erbB2, evaluated by immunohistochemistry in 145 of 173 patients randomly assigned to 2-year adjuvant tamoxifen or no further therapy, was considered overexpressed if greater than 10% of the cells showed specific membrane staining. The role of each prognostic variable and their independent effect were studied using the Cox model. Disease-free (DFS) and overall (OAS) survival curves were estimated by the Kaplan-Meier method. RESULTS As of November 30, 1994, the median follow-up period was 12 years. c-erbB2 was overexpressed in 43 of 145 patients (29.7%), which directly correlated with tumor size and inversely with estrogen receptor (ER) level. At univariate analysis, overexpression of c-erbB2 did not affect either DFS or OAS; tamoxifen had a greater effect on reducing the risk of recurrence than of death. Addition of c-erbB2 to a multivariate Cox model that contained menopausal status, tumor size, nuclear grade, and treatment as covariates did not affect the significance of the model for DSF or OAS, whereas addition of the first-order interaction between c-erbB2 and tamoxifen was statistically significant both for DFS and OAS. The same result was obtained when the model contained ER status and ER-tamoxifen interaction. Indeed, adjuvant tamoxifen significantly prolonged DFS and OAS in c-erbB2-negative cases, whereas it had no effect on DFS and OAS in c-erbB2-positive patients. CONCLUSION In early-stage breast cancer patients, overexpression of c-erbB2 is a marker of lack of efficacy of adjuvant tamoxifen.
Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma.
Authors: J A Sparano, R I Fisher, M Sunderland, K Margolin, M L Ernest, M Sznol, M B Atkins, J P Dutcher, K C Micetich, G R Weiss
Journal: Journal of Clinical Oncology (1993)

PURPOSE To compare the response rate, survival, and toxicity of treatment with high-dose intravenous (IV) bolus interleukin-2 (IL-2) plus interferon alfa-2a (IFN-alpha) with high-dose IL-2 alone in patients with advanced melanoma in a randomized phase III trial design. PATIENTS AND METHODS Eighty-five patients with advanced melanoma were randomly assigned to receive IL-2 6 X 10(6) U/m2 per dose every 8 hours as tolerated for a maximum of 14 doses on days 1 through 5 and 15 through 19, or IL-2 4.5 X 10(6) U/m2 per dose, plus IFN-alpha 3 X 10(6) U/m2 using an identical schedule. A planned interim analysis was performed after 85 patients were entered, which forms the basis for this report. RESULTS Partial response (PR) occurred in two of 44 patients (5%; 95% confidence interval, 1% to 15%) receiving IL-2 alone, compared with four of 41 patients (10%; 95% confidence interval, 3% to 23%) receiving IL-2/IFN-alpha (P = .30). There were no complete responses (CRs). The median duration of response was 11.5 months (range, 2.0 to 15.7+). There was no significant difference in the median survival duration for patients receiving IL-2 alone (10.2 months) compared with patients receiving IL-2/IFN-alpha (9.7 months). The median and mean number of doses of IL-2 were equivalent in both groups, as was toxicity. There were three treatment-related deaths, two in the IL-2-alone arm and one in the IL-2/IFN-alpha arm. The trial was terminated after the first interim analysis based on predefined early-stopping rules, which included termination if the response rate in the IL-2/IFN-alpha arm was less than 25%. CONCLUSION Using the preparation, dose, and schedule of IL-2 in our trial, IFN-alpha failed to enhance significantly the response rate to high-dose IL-2 in the treatment of patients with advanced melanoma.
Bioactivity of 14C-labeled endotoxin in aggregates, shed blebs and whole bacteria: Potency comparison in the LAL assay, cell cultures, and mouse bioassays
Authors: Peter S. Thorne, Kimberly A. Hoppe, Suzana Hadina, Andrea Adamcakova-Dodd, Jerrold P. Weiss
Journal: European Respiratory Journal (2011)

It is unknown if endotoxin reactivity in the LAL assay varies by its presentation or if this parallels differences in potency  in vitro  and  in vivo . We compared endotoxin responses in the LAL assay, in cell cultures and  in vivo  when presented in different forms.  Lipooligosaccharide (LOS) from  Neisseria meningitidis  sero B was metabolically labeled and incorporated into intact bacteria, purified membrane blebs, and aggregates ( 14 C-LOSagg).  14 C-LOS content of each was quantified as LOS-specific  14 C-3-OH fatty acids. Equivalent escalating doses of  14 C-LOS-containing bacteria, blebs, or LOSagg were tested in the LAL assay,  in vivo  in C3HeB/FeJ mice following intranasal instillation (monitoring induced airway inflammation), and  in vitro  using HEK293 cells ± CD14, MD-2, TLR4 (monitoring extracellular accumulation of IL-8). Doses of  14 C-LOS were measured by scintillation counting (our  gold standard) .  Potency varied depending on LOS presentation. Ranked reactivity was: in the LAL assay, blebs > LOSagg > bacteria; by airway inflammation, bacteria > blebs > LOSagg; by activation of HEK cells, LOSagg > blebs > bacteria. Differences in potency reached 10-fold for  in vitro  and  in vivo  inflammation. Across the range of doses, the ratio of LOS concentration determined by the LAL assay to the gold standard was 1.0-1.3 for blebs, 0.3-0.7 for aggregates and 0.1-0.2 for whole bacteria.  How endotoxin is presented significantly affects endotoxin reactivity in the LAL, cell culture and whole animal assays. Compared to the  gold standard  measure, the LAL assay substantially underestimated the content of the LOS preparations for LOSagg and bacteria.
Epigenetic Activation of TWIST1 by MTDH Promotes Cancer Stem–like Cell Traits in Breast Cancer
Authors: Yajun Liang, Jing Hu, Jiatao Li, Yingjie Liu, Jingyi Yu, Xueqian Zhuang, Lili Mu, Xiangyin Kong, Dengli Hong, Qifeng Yang, Guohong Hu
Journal: Cancer Research (2015)

Cancer stem-like cells (CSC) are a cell subpopulation that can reinitiate tumors, resist chemotherapy, and give rise to metastases. Metadherin (MTDH) contributes widely to tumor growth, drug resistance, relapse, and metastasis, but its molecular mechanisms of action are not well understood. Here, we report that MTDH drives CSC expansion by promoting the expression of TWIST1, a transcription factor critical for cancer cell stemness and metastasis. MTDH activates TWIST1 expression indirectly by facilitating histone H3 acetylation on the TWIST1 promoter, a process mediated by the histone acetyltransferase CBP. Mechanistic investigations showed that MTDH interacts with CBP and prevents its ubiquitin-mediated degradation, licensing its transcriptional activation of TWIST1. In clinical specimens of breast cancer, MTDH expression correlates positively with TWIST1 expression and CSC abundance. Overall, our work revealed that MTDH promotes CSC accumulation and breast tumorigenicity by regulating TWIST1, deepening the understanding of MTDH function in cancer.