tbuckley/cabot-search huggingface dataset:
Tolerability profile of ZD4054 is consistent with the effects of endothelin A receptor-specific antagonism
Authors: G. Liu, R. Dreicer, J. Hou, Y. Chen, G. Wilding
Journal: Journal of Clinical Oncology (2005)

4628 Background: Preclinical studies show ZD4054 to be an orally active, potent, specific endothelin A receptor (ETA) antagonist with potential utility in cancer. The anti-cancer effects of endothelin-1 (ET-1) antagonists appear to be mediated via ETA blockade, while inhibition of the endothelin B receptor (ETB) may adversely affect beneficial processes e.g. apoptosis and systemic clearance of ET-1. Specific ETA blockade is therefore considered optimal. This study aimed to assess the tolerability of ZD4054 in subjects with androgen independent prostate cancer (HRPC) with or without metastasis. Methods: ZD4054 was given orally, once daily in tablet form to men with HRPC (n = 16) in a phase IIa, open-label, multicentre, dose-escalation study. The starting dose was 10 mg (n = 3) and doses were escalated to 15 mg (cohort subsequently expanded [n = 9]) and 22.5 mg (n = 4). Results: Therapy was well tolerated. Dose-limiting toxicities were encountered at 22.5 mg; one patient had grade 3 dyspnea and peripheral edema and a second patient had grade 3 headache and intraventricular haemorrhage. At the 15 mg dose level, enrolment was subsequently expanded to further determine the safety and tolerability of ZD4054. No dose-limiting toxicity was seen at 15 mg. The most frequent adverse events in patients receiving 15 mg ZD4054 were headache, peripheral edema, fatigue, nasal congestion and nausea. Although 3 patients developed significant weight gain the average weight change was 0.7 kg (range -1 to 4 kg [15 mg cohort]). An average hemoglobin decrease of 0.8 g/dL was observed. Conclusions: On the basis of these preliminary data, the maximum tolerated daily oral dose of ZD4054 in HRPC patients was identified as 15 mg. The observed tolerability profile of ZD4054 is consistent with effects arising from specific ETA antagonism. As a result of this specificity, ZD4054 has the potential to block the pathological processes in malignancy that are mediated by ETA while allowing the beneficial processes mediated by ETB to proceed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca Aventis, Celgene AstraZeneca
Identification of polo-like kinase 1 (PLK1) in aggressive prostate cancer by paradigm analysis.
Authors: Phillip G. Febbo, Theodore C. Goldstein, Robert Baertsch, Jack Youngren, Yulia Newton, Adrian Bivol, Eric Jay Small, Joshua M. Stuart
Journal: Journal of Clinical Oncology (2013)

5006 Background: Integrative analysis that combines expression data, copy number variation, sequence, and epigenetic data with thousands of known biological interactions can help identify strong biological associations and novel “genotype to phenotype” associations. Methods: We performed multi-dataset differential expression analysis with Statistical Analysis of Microarrays (SAM) and gene set enrichment analysis (GSEA) across 10 publicly-available PCa microarray datasets to identify genes and pathways differentially expressed between local (n=471) and metastatic (n=220) PCa. We used PARADIGM, an integrated pathway analysis method, on PCa tumor samples with mRNA expression, copy number variation, and TMPRSS2:ERG fusion status data to infer differential fusion gene-related “activities” for pathway features (genes, protein complexes, etc) within a “Superimposed Pathway” representing a comprehensive collection of genetic interactions currently containing 20,314 known interactions among 16,362 concepts representing 6916 proteins, 7345 complexes, 1449 families, 55 RNAs, 15 miRNAs and 582 processes. Results: Out of the 7571 genes tested (those genes having data in two or more studies), the meta-analysis on gene expression revealed 210 (1.8% FDR) positively associated with PCa metastasis and 403 (0.94% FDR) negatively associated genes (threshold was p&lt;0.001, 2-tailed Student’s t-test). GSEA highlighted cell proliferation, cell cycle control, and DNA damage repair pathways with metastatic tumors. The PARADIGM analysis identified a network containing 914 features connected by 1137 edges. PLK1 was identified as both highly expressed in metastatic PCa and as one of the fourteen hubs in the largest (596-feature) sub-network identified by PARADIGM. PLK1 was also associated with high Gleason Sum and recurrent disease in independent local PCa datasets. Conclusions: Using an approach pioneered by members of our SU2C/PCF supported PCa Dream Team, integrated analysis across multiple PCa datasets associates PLK1 activity with aggressive PCa and suggests it may provide a novel treatment target for at least a genetic sub-set of advanced PCa.
Colistin resistance gene mcr-1 in extended-spectrum β-lactamase-producing and carbapenemase-producing Gram-negative bacteria in Germany
Authors: Linda Falgenhauer, Said-Elias Waezsada, Yancheng Yao, Can Imirzalioglu, Annemarie Käsbohrer, Uwe Roesler, Geovana Brenner Michael, Stefan Schwarz, Guido Werner, Lothar Kreienbrock, Trinad Chakraborty
Journal: The Lancet Infectious Diseases (2016)
DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys
Authors: Yu-Ting Chang, Ching-Chin Yang, Szu-Yu Pan, Yu-Hsiang Chou, Fan-Chi Chang, Chun-Fu Lai, Ming-Hsuan Tsai, Huan-Lun Hsu, Ching-Hung Lin, Wen-Chih Chiang, Ming-Shiou Wu, Tzong-Shinn Chu, Yung-Ming Chen, Shuei-Liong Lin
Journal: Journal of Clinical Investigation (2016)

Renal erythropoietin-producing cells (REPCs) remain in the kidneys of patients with chronic kidney disease, but these cells do not produce sufficient erythropoietin in response to hypoxic stimuli. Treatment with HIF stabilizers rescues erythropoietin production in these cells, but the mechanisms underlying the decreased response of REPCs in fibrotic kidneys to anemic stimulation remain elusive. Here, we show that fibroblast-like FOXD1+ progenitor-derived kidney pericytes, which are characterized by the expression of α1 type I collagen and PDGFRβ, produce erythropoietin through HIF2α regulation but that production is repressed when these cells differentiate into myofibroblasts. DNA methyltransferases and erythropoietin hypermethylation are upregulated in myofibroblasts. Exposure of myofibroblasts to nanomolar concentrations of the demethylating agent 5-azacytidine increased basal expression and hypoxic induction of erythropoietin. Mechanistically, the profibrotic factor TGF-β1 induced hypermethylation and repression of erythropoietin in pericytes; these effects were prevented by 5-azacytidine treatment. These findings shed light on the molecular mechanisms underlying erythropoietin repression in kidney myofibroblasts and demonstrate that clinically relevant, nontoxic doses of 5-azacytidine can restore erythropoietin production and ameliorate anemia in the setting of kidney fibrosis in mice.
Abstract 13673: DICOM-Based Strain Shows Low Variability Compared to Strain from Polar Source Images in a Heterogenous Population
Authors: Shafkat Anwar, Kazuaki Negishi, Allen Borowski, Patrick Gladding, Zoran Popovic, Francine Erenberg, James D Thomas
Journal: Circulation (2012)

Introduction: Two-dimensional Strain (2D S) is a powerful technique to evaluate myocardial deformation. We compared S from images in raw Polar (P) format with the same images in DICOM (D) in adult & pediatric patients to test agreement. Methods: 110 patients (55/110 pediatric, 80/110 normal LV function) had echocardiograms with a General Electric (GE) Vivid 7 or E9. 4,3 & 2-chamber LV apical views yielding 330 datasets were analyzed with EchoPAC (GE, v. 10.8.1) in P & Velocity Vector Imaging (VVI, Siemens, v. 3.5) in D by 3 blinded readers. Variability in measurements was tested with 2-way analysis of variance with calculation of intra- & interobserver standard error of measurement (SEMintra, SEMinter) and minimum discernable difference (MDDintra, MDDinter) for 95% confidence interval. Results: Mean Global Longitudinal S (GLS) by EchoPAC (P) was -18.1 +/- 4.4 & VVI (D) -15.3 +/- 4.1. D yielded lower absolute GS by mean of 2.8 (± SD 2.7, p < 0.0001), Fig. 1. SEMintra & SEMinter were similar for P & D, Fig....
Poor access to clinical trials among community cancer patients requiring chemotherapy for recurrent or progressive disease: Limitations of current cancer cooperative groups
Authors: L. A. Meyer, J. A. Lee, M. A. Mathiason, K. A. Frisby, K. C. Bruden, C. M. Meyer, J. K. Keller, R. S. Go
Journal: Journal of Clinical Oncology (2006)

6076 Background: Data on clinical trial accrual among cancer patients treated in the community are limited. In a prospective study at our community-based cancer center, we found that the accrual rate was only 4% for newly diagnosed patients and protocol limitations accounted for 68% of non-accrual (Go RS, et al. Cancer 2006). We would like to determine the availability of trials for adult cancer patients with recurrent or progressive disease treated in the community and the accrual rate. Methods: We retrospectively identified this specific group of patients who received chemotherapy at our institution between November 2004 and October 2005 and collected data on the number, types, and sources of trials that were available. Results: We identified a total of 140 patients. There was an equal number of females (52.9%) and males, with a median age of 66 years (range, 38–89) at the time of chemotherapy. Fifty trials were available, with about half for the following cancers: lung (14%), pancreatic (12%), renal (10%), head and neck (8%), prostate (6%), and breast (6%). No trials were available for bladder, colorectal, and gastroesophageal cancers. The proportions of phase I, II, and III trials were 4%, 62%, and 34%, respectively. The sources of trials were: ECOG (56%), Wisconsin Oncology Network (14%), Intergroup (12%), GOG (10%), RTOG (2%), CTSU (2%), our institution (2%), and pharmaceutical companies (2%). Only 69 (49.3%) patients had trials appropriate for their type and stage of cancers. Among those patients with available trials, 24 (34.8%) were eligible to participate and 6 were enrolled, for an overall accrual rate of 4.3%. There were no differences in age and sex among subgroups in terms of trial availability, eligibility, and accrual. Conclusions: At our institution, enrollment of cancer patients with recurrent or progressive disease in clinical trials is as low as for newly diagnosed patients. Over 80% of the patients were denied access to a trial because of protocol unavailability and ineligibility. Current cancer cooperative groups do not provide adequate trials for patients in the community. No significant financial relationships to disclose.
Murine peripheral blood prognostic biomarkers for tumor survival following combination aCTLA-4 and aPD-1 treatment
Authors: Ian Hilgart-Martiszus, Michael McNamara, William Redmond
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immune checkpoint inhibitors, particularly those targeting CTLA-4 and PD-1, are transforming the way cancer is treated. However, these therapies do not benefit all patients and frequently cause significant immune-related adverse events. Therefore, prognostic biomarkers that
Deletion of NF-kB p50 alters murine glioblastoma tumor-associated macrophage polarization, reduces tumor growth and prolongs survival
Authors: Theresa Barberi, Allison Martin, Sarah Harris-Bookman, Michael Lim, Alan D Friedman
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Glioblastoma multiforme (GBM) is a uniformly fatal brain tumor. The GBM microenvironment includes abundant tumor-associated macrophages (TAMs) that predominantly assume a pro-tumor “M2” phenotype rather than a pro-inflammatory “M1” phenotype. TAMs suppress T cell
Effects of paternal tobacco use on different parameters of a newborn child
Authors: Syed Ali Arsalan, Aneel Roy Bhagwani, Imroz Arif Farhan, Sadaf Kanwal, Haleema Hashmi, Syed Ali Abbas, Syed Arshad Husain
Journal: European Respiratory Journal (2011)

Introduction:  There has been significant research done on the effects of maternal smoking on pregnancy but not much data is available regarding the role of paternal smoking and its effect on the vitals of a newborn child. We therefore tried to evaluate the effects of paternal tobacco use on newborn child.   Methods:  A prospective study carried out in gynecology and obstetrics department of our hospital. A questionnaire based interview was conducted with the delivering females in the month of October 2010 in terms of tobacco use of their spouse during pregnancy. The neonatal vitals were assessed and previous abortion history was also inquired.   Results:  Age of the delivering females was 28.34 years ±4.095 S.D. Females delivered was n=100. Tobacco use was found among spouses of n=25 females. Out of them n=14 were smokers and n=11 chewed tobacco. Among females whose husbands smoked (n=14) previous abortion history was found in n=6 (42.85%) females out of which n=2 females were exposed to tobacco smoke during those earlier pregnancies, as compared to females with non smoking husbands (n=86) previous abortion was noted in n=19 (20.09%). Among females whose husbands chewed tobacco (n=11) previous abortion history was found in n=3 females. Among n=2 preterm neonates n=1 had paternal smoking history. Out of n=7 neonates with respiratory distress n=2 had paternal smoking history, n=1 (out of n=2) had delayed sucking and n=1 had delayed micturation.   Conclusion:  Our results suggest that paternal tobacco consumption might have risks to the newborn child & ongoing pregnancy. Paternal smoking may have a biological correlation with such outcomes. Further research should be carried out in this aspect.
Modulation of immune cell infiltrate with sunitinib to improve anti-PD1 therapy in preclinical tumor model
Authors: Patricia Rayman, C Marcela Diaz-Montero, Yu Yang, Brian Rini, Paul Elson, James Finke
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Combined therapy using the checkpoint blockade anti-PD1 antibody and the TKI, sunitinib, has been investigated in metastatic renal cell carcinoma (mRCC). Here we examined the impact of sunitinib plus anti-PD1 therapy on tumor growth in the renal cell carcinoma mouse model RENCA.
Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b–Mediated Malignant Progression
Authors: Manuel Picon-Ruiz, Chendong Pan, Katherine Drews-Elger, Kibeom Jang, Alexandra H. Besser, Dekuang Zhao, Cynthia Morata-Tarifa, Minsoon Kim, Tan A. Ince, Diana J. Azzam, Seth A. Wander, Bin Wang, Burcu Ergonul, Ram H. Datar, Richard J. Cote, Guy A. Howard, Dorraya El-Ashry, Pablo Torné-Poyatos, Juan A. Marchal, Joyce M. Slingerland
Journal: Cancer Research (2016)

Abstract Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing human-derived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell–like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment. Cancer Res; 76(2); 491–504. ©2016 AACR.
Non invasive ventilation (NIV) in conscious sedation with remifentanil
Authors: Alfonso Pecoraro, Ginevra Del Giudice
Journal: European Respiratory Journal (2011)

Background: NIV use in acute hypercapnic respiratory failure (AHRF) patients who refused orotracheal intubation is an open question. Agitation is a frequent reason of NIV failure.

Aim: We have evaluated the safety and tolerance of NIV in patients under conscious sedation induced by remifentanil.

Methods: Thirty (11F19M) consecutive COPD patients with AHRF admitted to our Semi-intensive care Unit were unable to tolerate NIV treatment. Patients were submitted to remifentanil sedation (continous perfusion 0.1±0,03 μg/kg/min). We assessed the changes in arterial blood gas, tolerability and adverse events at the time of admission, after 30 min and 60 min of NIV use.

Results: PaO2/FiO2 ratio improved after 60 min (p <0,0001). PaO2 increased from 46±7 (pre-NIV) to 61±4mmHg (post-NIV). PaCO2 decreased from 67±4 (pre-NIV) to 45±3 mmHg (post-NIV). We documented hypotension in 2 patients (7,6%) treated by dose adjustments. No bradycardia and respiratory depression were observed. We have not documented any unforeseeable event. No patient died during admission.

Conclusions: In selected population remifentanil is well tolerate in AHRF patients treated with NIV.
Vitamins B6 and B12 supplementation to prevent chemotherapy-induced neuropathy (CiN): Interim analysis of the taxane cohort
Authors: C. F. Verschraegen, M. Royce, S. J. Lee, S. Movva, L. Susan, G. Michael
Journal: Journal of Clinical Oncology (2009)

e20621 Background: Chemotherapy-induced neuropathy (CiN) is common with heavy metals, taxanes, and vinca alcaloids. Pyridoxine (Vit B6) is used for diabetic neuropathy and cyanocobalamine (Vit B12) is required for synthesis of myelin and maintenance of the integrity of neuronal tissue. We hypothesized that supplementing patients (pts) with these 2 vitamins will prevent CiN. There were 3 pt cohorts depending on the chemotherapy regimen. Pts receiving any taxane enrolled in the taxane cohort (N=46), pts receiving vincristine or vinblastine enrolled in the vinca cohort (N=7), and all other pts receiving a platinum enrolled in the heavy metal cohort (N=25). The taxane cohort is reported here. Methods: Pts starting treatment with a taxane were randomized to a 1/6 of 100% of the daily recommended dose of a multivitamin/day (placebo) versus the same plus Vit B6, 50 mg tid, and Vit B12, 1 mg q 3–4 weeks (MV+Vit), during 4 cycles of chemotherapy. No other supplements were allowed. Taxane Fact G and a formal neurologic examination were performed prior to, and after 2 &amp; 4 cycles of chemotherapy. Statistical methods were based on least squared means with ANCOVA and t-test (Cella, JCO, 2008). Results: To date, 46 pts treated with taxanes were randomized; 22 to placebo and 24 to MV+Vit. 13 and 16 pts completed 2 cycles and 8 and 6 pts completed 4 cycles, respectively. On the neuro examination, the only significant difference between placebo and MV+Vit was in the cold sensation (p=0.0097). The physical well being and the neuro modules of the Taxane Fact G significantly worsened after 4 cycles of chemotherapy in the placebo group (p=0.0289 and 0.0173, respectively), but this significant trend was not observed in the MV+Vit group (p=0.8318 and p=0.0866). The study will accrue 76 pts per cohort. Conclusions: The preliminary trends in this study suggest that vitamin supplementation with Vit B6 and B12 may reduce CiN during taxane-based chemotherapy. No significant financial relationships to disclose.
A pilot study of pi-class glutathione S-transferase expression in breast cancer: correlation with estrogen receptor expression and prognosis in node-negative breast cancer.
Authors: L Gilbert, L J Elwood, M Merino, S Masood, R Barnes, S M Steinberg, D F Lazarous, L Pierce, T d'Angelo, J A Moscow
Journal: Journal of Clinical Oncology (1993)

Previous studies have indicated that RNA levels for pi-class glutathione S-transferase (GST pi), a phase II, drug-metabolizing enzyme, were inversely related to estrogen receptor (ER) and progesterone receptor (PR) levels in human breast tumors. Because GST pi also is expressed in normal breast epithelium, an immunohistochemical assay that uses affinity-purified polyclonal antibodies to GST pi was developed to examine the possible relationship between GST pi expression in breast cancer cells and hormone receptor expression, as well as prognosis, in patients with primary breast cancer.A strong inverse correlation between GST pi expression and ER (two-sided P [P2] = .002) and PR status (P2 = .023) was found in our study of 189 patients with primary breast cancer. GST pi expression was not related to tumor size, nodal metastasis, nuclear grade, histology, or age of the patient. In node-negative breast cancer (n = 72), increased GST pi expression was associated with decreased disease-free survival (DFS) and overall survival (OS). When GST pi expression was divided into categories of negative (no GST pi-positive tumor cells), intermediate (1% to 70% GST pi-positive tumor cells), and high (> 70% GST pi-positive tumor cells), the relative risk of tumor recurrence in patients with node-negative breast cancer was increased 3.39-fold for each successive category of expression (P2 = .0045; 95% confidence interval, 1.46 to 7.87) and the relative risk of death was increased 4.49-fold for each successive category (P2 = .0003; 95% confidence interval, 2.02 to 10.42). The actuarial 5-year OS was 100%, 79%, and 51%, and the DFS was 94%, 77%, and 44%, for the negative, intermediate, and high tumor groups, respectively. Among the factors studied in multivariate analysis (ER status, PR status, nuclear grade, and tumor size), GST pi expression was the factor that most accurately predicted shorter DFS and OS in node-negative patients.GST pi expression is inversely related to hormone receptor status in breast cancer. This pilot study also suggests that increased GST pi expression may be an important predictor of early recurrence and death in node-negative breast cancer patients that merits additional investigation.