tbuckley/cabot-search huggingface dataset:
Using novel protein antibodies on tissue microarrays (TMAs) for breast cancer prognostication
Authors: G. T. Budd, E. Tso, B. Yoder, T. Choueiri, P. Elson, S. Tarr, M. Skacel, R. Tubbs, A. Dawson, D. Hicks
Journal: Journal of Clinical Oncology (2004)

9629 Background: Estrogen receptor (ER) and progesterone receptor (PR) are important prognostic and predictive factors for breast cancer patients (pts). Murine monoclonal antibodies (MuAb) are currently used in immunohistochemistry (IHC) assays to determine ER/PR status. Rabbit monoclonal antibodies (RAb) may have greater affinity for human antigens than MuAb. We compared the concordance of MuAb- and RAb-based IHC assays of ER and PR and the prognostic value of these and other factors in pts with Stage I-III breast cancer. Methods: TMAs were produced from formalin-fixed paraffin-embedded tissue sections of primary breast cancer pts. IHC assays were performed for the following: ER/PR status using RAb SP1CLONE (Labvision™) and using MuAb (Ventana™), fascin (a tumor cell motility protein) using clone 55K-2 (DAKO/M3567™), cytokeratin 5/6 (CK5/6) using clone D5/164B (Roche Biomed/1273396™), and HER2 using CB11. These were correlated with stage, progression-free (PFS) and overall survival (OS). ER/PR positivity was defined as ≥5% estimated proportion of positive-staining tumor cells. Results: 199 pts were evaluable for ER/PR. The concordance rate for RAb- and MuAb- assessed ER status was 90% (180/199). The level of agreement for RAb- and MuAb- assessed PR status was 81% (162/199). ER/PR positivity by RAb correlated with each other, HER2 negativity and earlier stage. In 159 pts with evaluable follow up, pts with ER positivity by RAb had better 5-year PFS (p<.001) and OS (p=.03), similar to ER positivity by MuAb. Pts with PR positivity by RAb had superior 5-year PFS (p=.001) and OS (p=.04) and correlated better with survival than PR positivity by MuAb. Fascin was expressed in 34 pts. Using univariate analysis, fascin expression correlated with higher stage, negative ER/PR, shorter PFS and OS. CK5/6 positivity did not correlate with any variable, except ER/PR positivity by RAb. After multivariate analysis, significant factors for PFS were stage, HER2, and PR by RAb, and for OS were stage, HER2, and fascin positivity. Conclusion: 1) The RAb for PR may be superior to the MuAb in predicting prognosis. 2) Fascin deserves further investigation as a prognostic factor. No significant financial relationships to disclose.
Effect of anti-IgE therapy on microRNAs in the lungs of mice with allergen-driven airway remodeling
Authors: William Henderson, Jun Xue, Federico Farin, Richard Beyer, Theo Bammler
Journal: European Respiratory Journal (2012)

Rationale: Current therapies have had limited effect on structural airway changes in patients with asthma. We recently found that anti-IgE therapy significantly decreased established airway hyperresponsiveness and subepithelial fibrosis in a mouse asthma model (Henderson et al., AJRCCM 183: A4066, 2011). MicroRNA (miRNA or miR)s, small non-coding RNAs, are key regulators of gene expression that may serve as novel biomarkers and therapeutic targets in disease states.

Study Aim: Determine the effect of anti-IgE therapy on miRNA expression in a mouse asthma model with airway remodeling.

Methods: Mice periodically given OVA (days 14-163) were treated with 100 µg monoclonal rat IgG1 anti-IgE (R35-92, Pharmingen) (OVA/anti-IgE group), rat IgG1 isotype control antibody (OVA/IgG1 group), or saline (OVA/Saline group) days 73-75, and then once weekly until day 163 when lung miRNA was isolated. MiRNA transcriptional profiling was carried out using Affymetrix GeneChip miR 2.0 arrays with data analysis by Bioconductor limma package. MiRNAs whose expression was changed >1.5-fold (p<0.05) were considered differentially expressed.

Results: 21 miRNAs were significantly changed in the OVA/Saline group vs saline-treated controls including upregulation of profibrotic miR-21 and miR-155. MiRs 467e, 511, and 744* were downregulated and the antifibrotic miR-16* upregulated in the OVA/anti-IgE group vs the OVA/IgG1 group.

Conclusions: The ameliorating effect of anti-IgE treatment on established airway remodeling in this asthma model is likely mediated by its differential effects on gene expression in the lung. Our data direct attention to key miRNAs that may serve as biomarkers for this remodeling process.
Direct Protection Against Acetaminophen Hepatotoxicity by Propylthiouracil
Authors: Tadataka Yamada, Shelly Ludwig, John Kuhlenkamp, Neil Kaplowitz
Journal: Journal of Clinical Investigation (1981)

Hepatotoxicity caused by acetaminophen can be prevented by enzyme-catalyzed conjugation of its reactive metabolite with glutathione (GSH). Since we have shown in previous studies that 6-N-propyl-2-thiouracil (PTU) can substitute for GSH as a substrate for the GSH S-transferases, we examined the possibility that PTU might also protect against acetaminophen hepatotoxicity by direct chemical interaction with the reactive metabolite of acetaminophen. In an in vitro system consisting of [(3)H]acetaminophen, liver microsomes from phenobarbital-pretreated rats, and an NADPH-generating system, we found that PTU had a dose-dependent additive effect with GSH on inhibition of acetaminophen covalent binding. PTU administration also resulted in a dose-dependent decrease in both GSH depletion and covalent binding in vivo in acetaminophen-treated mice. To examine the possible mechanisms by which PTU exerts its protective effect, we studied the action of PTU on both acetaminophen conjugation and metabolic activation. PTU had no effect upon acetaminophen pharmacokinetics in phenobarbital-pretreated rats, as examined by measuring acetaminophen concentration in bile, urine, and blood after an intraperitoneal dose, nor did it alter the total amount of polar conjugates formed. Microsomes from PTU-treated rats were unaltered in cytochrome P-450 concentrations and p-nitroanisole-O-demethylase, benzo-alpha-pyrene hydroxylase, and cytochrome c-reductase activities. Furthermore PTU did not decrease acetaminophen-GSH adduct formation in vitro, suggesting that there was no reduction in drug activation. However, in bile from [(35)S]PTU and [(3)H]acetaminophen treated rats, as well as in incubates of the two drugs with liver microsomes, a new (35)S- and (3)H-containing product could be identified. By both thin layer chromatography and high pressure liquid chromatography this new product, which co-eluted with [(3)H]acetaminophen, was separated from unreacted [(35)S]PTU. The formation of this product in vitro was a function of PTU concentration and reached a maximum of 0.06 mumol/min per mg protein at 0.5 mM PTU. In vivo, the total biliary excretion of this product over 4 h (116 nmol) equaled the net reduction in acetaminophen metabolite covalent binding in the liver of phenobarbital-pretreated rats (108 nmol). We conclude that PTU, independent of its antithyroid effect, diminishes hepatic macromolecular covalent binding of acetaminophen reactive metabolite both in vivo and in vitro, and it does so by detoxifying the reactive metabolite through direct chemical interaction in a manner similar to GSH. These observations may define the mechanism by which PTU is protective against liver injury caused by acetaminophen.
Identification of AMPK Phosphorylation Sites Reveals a Network of Proteins Involved in Cell Invasion and Facilitates Large-Scale Substrate Prediction
Authors: Bethany E. Schaffer, Rebecca S. Levin, Nicholas T. Hertz, Travis J. Maures, Michael L. Schoof, Pablo E. Hollstein, Bérénice A. Benayoun, Max R. Banko, Reuben J. Shaw, Kevan M. Shokat, Anne Brunet
Journal: Cell Metabolism (2015)
Diagnosis of Basal-Like Breast Cancer Using a FOXC1-Based Assay
Authors: Tor W. Jensen, Tania Ray, Jinhua Wang, Xiaodong Li, Wesley Y. Naritoku, Bingchen Han, Frank Bellafiore, Sanjay P. Bagaria, Annie Qu, Xiaojiang Cui, Clive R. Taylor, Partha S. Ray
Journal: JNCI Journal of the National Cancer Institute (2015)

Diagnosis of basal-like breast cancer (BLBC) remains a bottleneck to conducting effective clinical trials for this aggressive subtype. We postulated that elevated expression of Forkhead Box transcription factor C1 (FOXC1) is a simple and accurate diagnostic biomarker for BLBC. Accuracy of FOXC1 expression in identifying BLBC was compared with the PAM50 gene expression panel in gene expression microarray (GEM) (n = 1992) and quantitative real-time polymerase chain reaction (qRT-PCR) (n = 349) datasets. A FOXC1-based immunohistochemical (IHC) assay was developed and assessed in 96 archival formalin-fixed, paraffin-embedded (FFPE) breast cancer samples that also underwent PAM50 profiling. All statistical tests were two-sided. A FOXC1-based two-tier assay (IHC +/- qRT-PCR) accurately identified BLBC (AUC = 0.88) in an independent cohort of FFPE samples, validating the accuracy of FOXC1-defined BLBC in GEM (AUC = 0.90) and qRT-PCR (AUC = 0.88) studies, when compared with platform-specific PAM50-defined BLBC. The hazard ratio (HR) for disease-specific survival in patients having FOXC1-defined BLBC was 1.71 (95% CI = 1.31 to 2.23, P < .001), comparable to PAM50 assay-defined BLBC (HR = 1.74, 95% CI = 1.40 to 2.17, P < .001). FOXC1 expression also predicted the development of brain metastasis. Importantly, unlike triple-negative or Core Basal IHC definitions, a FOXC1-based definition is able to identify BLBC in both ER+ and HER2+ patients. A FOXC1-based two-tier assay, by virtue of being rapid, simple, accurate, and cost-effective may emerge as the diagnostic assay of choice for BLBC. Such a test could substantially improve clinical trial enrichment of BLBC patients and accelerate the identification of effective chemotherapeutic options for this aggressive disease.
Human papillomaviruses and associated malignancies.
Authors: R M Alani, K Münger
Journal: Journal of Clinical Oncology (1998)

The human papillomaviruses (HPVS) are small DNA tumor viruses that infect epithelial cells and induce proliferative lesions. Substantial epidemiologic data along with in vitro and in vivo studies have led to the implication of particular HPVs with the development of epithelial malignancies. Greater than 90% of all cervical carcinomas are positive for HPV infection. Most of these lesions are caused by infection with mucosal-associated high-risk HPV subtypes. Much work has been undertaken in basic science laboratories to determine the molecular basis for HPV-associated malignancies. Although many significant advances have been made in understanding the biologic properties of these viruses using in vitro analyses, the field has been greatly hindered until recently by the inability to propagate the virus in culture. In this review, we discuss the basic biologic properties of HPVs and the current understanding of the mechanisms of cellular transformation by malignancy-associated viral subtypes. We place particular emphasis on discussion of the HPV oncogenes, E6 and E7. We also discuss premalignant and malignant disorders of squamous and mucosal epithelia, which have been associated with HPV infections, and the current understanding of the mechanism of HPV-associated carcinogenesis in these settings. We focus these discussions on cervical carcinogenesis and briefly review the particulars regarding HPV-associated malignancies in normal and immunocompromised hosts. We end with a discussion of potential targeted molecular therapies for HPV-associated malignancies that may result from the current knowledge of HPV-related cellular growth dysregulation and carcinogenesis.
The role of SorLA in neurotrophic activity and complex behavior
Authors: Simon Glerup, Mart Saarma, Anders Nykjaer
Journal: Molecular Neurodegeneration (2013)

SorLA binds amyloid precursor protein (APP) in the trans-Golgi network and protects it against proteolysis by both the alpha-and beta-secretases, preventing the generation of toxic amyloid-beta peptide.We have recently found that SorLA also affects neuronal function in a different manner by acting as sorting receptor for the neurotrophic factor GDNF and its receptors GFRα1 and RET, directing them from the cell surface to endosomes.Through this mechanism, GDNF is targeted to lysosomes and degraded while GFRα1 and RET recycles, creating an efficient GDNF clearance pathway.SorLA thereby influences a number of neuronal systems known to depend on GDNF activity including the dopaminergic system and the hippocampus.Accordingly, mice with altered SorLA expression exhibit altered reward and memory function, and a behavioral phenotype characterized by altered anxiety, hyperactivity, and response to psychostimulants.
Prevalence of preinvasive bronchial lesions in patients with lung cancer
Authors: Alaa Mohamed, Ali AbdelAzim, Kiyoshi Shibuya
Journal: European Respiratory Journal (2013)

In suppot with field cancerisation theory, some patients with lung cancer (LC) will also have synchronous invasive or pre-invasive bronchial lesions; we used autofluorescence bronchoscopy (AFB) to assess the prevalence of synchronous lesions in patients with LC. All patients with abnormal sputum cytology, underwent white light and AFB. From 335 patients with abnormal sputum cytology referred for AFB, lung cancer was detected in 91 patients (89 male and 2 female) age (mean±SD, 67±8 years). 77 have squamous cell carcinoma (SqCC), 13 had adenocarcinoma and one patient with small cell lung cancer (SCLC). Synchronous lesions detected in 26 (29%) patients, 25 (33%) of patients with SqCC, one with adenocarcinoma, no synchronous lesion detected in one patient with SCLC. The most severe detected synchronous lesion was adenocarcinoma in one patient, Carcinoma insitu (CIS) in 4 patients, severe dysplasia in 3 patients, moderate dysplasia in 10 patients, and mild dysplasia in 8 patients. Synchronuos lesions wrer more frequently detected in current smokers (35%), than in ex-smokers (20%) and non-smokers (15%). In conclusion, we recommend the use of AFB for preoperative evaluation of patients with lung cancer as synchronous lesions is a frequent finding. In summary; synchronous preinvasive lesions is frequent in patients with LC and AFB should be included in pre-operative evaluation of these patients.
Reduced submaximal exercise performance in COPD patients at moderate altitude (2590m)
Authors: Michael Furian, Sara E. Hartmann, Tsogyal D Latshang, Deborah Flueck, Sebastian D. Segitz, Christian Murer, Philipp Scheiwiler, Severine Mueller-Mottet, Silvia Ulrich, Malcolm Kohler, Marc J. Poulin, Konrad E. Bloch
Journal: European Respiratory Journal (2014)

Background Chronic obstructive pulmonary disease (COPD) is associated with exercise intolerance at sea level and further limitations are expected at altitude. We quantified exercise performance of COPD patients travelling to moderate altitude and analyzed responsible mechanisms.

Methods 37 patients with COPD, (mean±SD FEV1 54±15%) performed submaximal, constant-load bicycle spiroergometry to exhaustion in Zurich (490m) at 60% of maximal work rate (63±30watts), and on the 2nd day after arrival at Davos Jakobshorn (2590m). Performance was compared between altitudes.

Results At 2590m exercise endurance was reduced by 57%, and this was associated by a reduced oxygen uptake and PaO2 compared to 490m.

View this table:

Results of exercise tests





Conclusion In COPD patients, exposed to hypobaric hypoxia at 2590m submaximal exercise endurance was reduced by more than half compared to 490m. The exercise limitation at altitude was related to hypoxemia due to low barometric pressure but not to ventilatory limitation.

Grant:Swiss National Science Foundation.
Randomized Clinical Trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in Stage IB Non-Small Cell Lung Cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633
Authors: G. M. Strauss, J. Herndon, M. A. Maddaus, D. W. Johnstone, E. A. Johnson, D. M. Watson, D. J. Sugarbaker, R. L. Schilsky, M. R. Green
Journal: Journal of Clinical Oncology (2004)

7019 Background: The value of adjuvant chemotherapy in resectable lung cancer remains controversial. The International Adjuvant Lung Trial (IALT) reported a modest but statistically significant survival advantage with cisplatin-based adjuvant chemotherapy in stages IA to III NSCLC. On the other hand, Adjuvant Lung Project Italy (ALPI) failed to demonstrate benefit for adjuvant chemotherapy in patients of similar stage. CALGB 9633 was designed to test the effectiveness of adjuvant chemotherapy in patients with T2N0M0, stage IB NSCLC. NCCTG and RTOG also participated. Methods: Within 4–8 weeks of resection, patients were randomized to adjuvant chemotherapy with paclitaxel 200 mg/m2 over 3 hours and carboplatin AUC 6, each administered on day one every three weeks for four cycles, or to observation. Eligibility: age >18 years, histologically documented NSCLC, T2 primary lesion, lobectomy or pneumonectomy, absence of tumor in N1 or N2 nodes sampled at surgery or mediastinoscopy. All p-values are two-sided. Results: Between 9/15/96 and 11/26/03, 344 patients were randomized. Median follow-up is currently 34 months. Median age was 61 years (range 34–81 years), and 64% were male. Groups were well balanced with regard to age, gender, race, ethnicity, histology, tumor differentiation, and resection type. 80% underwent mediastinoscopy prior to surgery. Lobectomy was performed in 89%. Adjuvant chemotherapy was well tolerated, and there were no chemotherapy-related toxic deaths. Grade III or IV neutropenia occurred in 36%. There have been 36 deaths from any cause among 173 patients in the chemotherapy group compared to 52 deaths among 171 patients in the observation group (HR=0.62; 95% CI: 0.41–0.95, p=0.028). Overall survival at 4 years is 71% (95% CI: 62%–81%) and 59% (95% CI: 50%–69%) in chemotherapy and observation groups, respectively. There was also a significant advantage in failure-free survival favoring the chemotherapy group (HR=0.69; 95% CI: 0.48–0.98; p=0.035). With regard to lung cancer mortality, there have been 19 lung cancer deaths in the chemotherapy group and 34 deaths in the control group (HR=0.51; 95% CI: 0.29–0.89; p=0.018). At 4 years, lung cancer mortality was 15% (95% CI: 8%–21%) and 26% (95% CI: 18%–34%) in chemotherapy and control groups, respectively. Conclusions: Adjuvant chemotherapy significantly reduces all-cause and lung cancer mortality in stage IB NSCLC. This is the first randomized trial to demonstrate significantly improved survival for a carboplatin-based adjuvant chemotherapy regimen in a uniform population with NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis
Complete Molecular Response (CMR) Rate with Nilotinib in Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) without CMR After ≥ 2 Years on Imatinib: Preliminary Results From the Randomized ENESTcmr Trial of Nilotinib 400 Mg Twice Daily (BID) Vs Imatinib
Authors: Timothy P. Hughes, Jeffrey H. Lipton, Brian Leber, Nelson Spector, Francisco Cervantes, Ricardo Pasquini, Nelma Clementino, Anthony P. Schwarer, Francois-Xavier Mahon, Delphine Rea, David T. Yeung, Suzanne Kamel-Reid, Israel Bendit, John Reynolds, Lisa Williams, Tomasz Szczudlo, Susan Branford
Journal: Blood (2011)
Dose-escalation study using up to twice the standard dose of cetuximab in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST study): Preliminary data
Authors: S. Tejpar, M. Peeters, Y. Humblet, H. Gelderblom, J. Vermorken, F. Viret, B. Glimelius, F. Ciardiello, O. Kisker, E. Van Cutsem
Journal: Journal of Clinical Oncology (2006)

3554 Background: Response to the epidermal growth factor receptor (EGFR) inhibitor, cetuximab appears to correlate with the intensity of the associated skin reaction. This randomized multicenter study investigated the effect of cetuximab dose escalation on EGFR activation and downstream signaling in skin and tumor biopsies, on activity and skin reactions in patients (pts) with EGFR-expressing mCRC, failing prior irinotecan (I). Methods: Pts with ≥1 measurable lesion suitable for biopsy were eligible and were randomized 22 days after starting treatment with cetuximab (initial dose 400mg/m 2 then 250mg/m 2 /week(w)) plus I (2-weekly regimen 180 mg/m 2 ) if they had not experienced &gt;grade 1 skin reaction, any other &gt;grade 2 cetuximab-related toxicity and were not intolerant to I. Pts were randomized to standard cetuximab dose (arm A; 250 mg/m 2 /w) or dose-escalation (arm B; cetuximab dose increased by 50 mg/m 2 q 2 w up to 500 mg/m 2 , until &gt;grade 2 toxicity or tumor response). Pts not randomized (arm C) continued with the standard regimen after day 22. Skin and tumor biopsies were taken pre- and during treatment. Results: Of 273 screenedpts, 221 were EGFR-expressing and 166 were recruited. 45 pts were randomized to arm A, 44 to arm B and 76 were in arm C. By August 2005, 18 pts had reached the highest dose (500mg/m 2 /w), with no concerns over safety. All baseline and second biopsies are available. Safety results are presented for the first 36 pts in arm B. M/F 23/13, median age 60 y (34–79), median Karnofsky performance score 90 (80–100). All pts reported here had received cetuximab for at least 6 weeks. Maximum dose reached at w 6: 350mg/m 2 /w (300mg/m 2 in 36 pts at w 4; 350mg/m 2 in 31 pts at w 6). Relevant grade 3/4 toxicities were diarrhea (2.8%) and fatigue (5.6%). No grade 3/4 skin reactions occurred. Conclusions: Cetuximab at a dose of 350 mg/m 2 is well tolerated in pts who have had no or mild skin reactions in response to standard dose treatment. Further dose escalation is possible. No early increase of skin toxicity is observed. Analysis of efficacy and pharmacokinetics/dynamics is ongoing. [Table: see text]
Mitochondrial Targeting of Human<i>O</i>6-Methylguanine DNA Methyltransferase Protects against Cell Killing by Chemotherapeutic Alkylating Agents
Authors: Shanbao Cai, Yi Xu, Ryan J. Cooper, Michael J. Ferkowicz, Jennifer R. Hartwell, Karen E. Pollok, Mark R. Kelley
Journal: Cancer Research (2005)

Abstract DNA repair capacity of eukaryotic cells has been studied extensively in recent years. Mammalian cells have been engineered to overexpress recombinant nuclear DNA repair proteins from ectopic genes to assess the impact of increased DNA repair capacity on genome stability. This approach has been used in this study to specifically target O6-methylguanine DNA methyltransferase (MGMT) to the mitochondria and examine its impact on cell survival after exposure to DNA alkylating agents. Survival of human hematopoietic cell lines and primary hematopoietic CD34+ committed progenitor cells was monitored because the baseline repair capacity for alkylation-induced DNA damage is typically low due to insufficient expression of MGMT. Increased DNA repair capacity was observed when K562 cells were transfected with nuclear-targeted MGMT (nucl-MGMT) or mitochondrial-targeted MGMT (mito-MGMT). Furthermore, overexpression of mito-MGMT provided greater resistance to cell killing by 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) than overexpression of nucl-MGMT. Simultaneous overexpression of mito-MGMT and nucl-MGMT did not enhance the resistance provided by mito-MGMT alone. Overexpression of either mito-MGMT or nucl-MGMT also conferred a similar level of resistance to methyl methanesulfonate (MMS) and temozolomide (TMZ) but simultaneous overexpression in both cellular compartments was neither additive nor synergistic. When human CD34+ cells were infected with oncoretroviral vectors that targeted O6-benzylguanine (6BG)–resistant MGMT (MGMTP140K) to the nucleus or the mitochondria, committed progenitors derived from infected cells were resistant to 6BG/BCNU or 6BG/TMZ. These studies indicate that mitochondrial or nuclear targeting of MGMT protects hematopoietic cells against cell killing by BCNU, TMZ, and MMS, which is consistent with the possibility that mitochondrial DNA damage and nuclear DNA damage contribute equally to alkylating agent–induced cell killing during chemotherapy.