bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post Operative Analgesia for Breast Surgery: Intercostal Nerve Block Versus Subcutaneous Infiltration.
Authors: Syed A. , Devkaran A. , Mehta S. , Michail M. , Bradpiece H. 
Published: December 2010

Abstract
BackgroundPost operative analgesia is often underestimated in breast surgery resulting in long term sequelae. Opiates and epidural analgesia may produce complications and limits early rehabilitation. We compare the effects of intercostal nerve block with subcutaneous infiltration as post operative analgesia in breast surgery.MethodsAll patients who undergo breast surgery were assigned to two groups. They either receive intercostal nerve block or subcutaneous infiltration of 0.5% bupivacaine at the end of surgery. Pain score using visual analogue scale and the total amount of morphine consumption were recorded. Personnel taking measurements were kept blind.ResultsThere were 70 patients included in the study. Of these, three patients (two from Group A and one from Group B) were excluded because of post operative haematoma and drain related complications. 33 patients had intercostal nerve block and 34 patients received subcutaneous infiltration. The groups were comparable with respect to age and type of breast surgery. There were significant differences in the visual analogue pain scores at the early post operative period in the study group (P value of &lt; 0.05).Table 1Pain ScoreGroup A Median (range)Group B Median (range)No. of patientsP valueWith in 4 hr of surgery2 (1-8)2 (1-9)330.7521st post op 8am2 (1-6)3 (1-8)330.0091st post op 6pm2 (1-6)2 (1-10)330.0112nd post op 8am1 (1-5)2 (1-8)120.2442nd post op 6pm1 (1-4)1.5 (1-5)110.2213rd post op 8am1 (1-4)1 (1-6)90.1373rd post op 6pm1 (1-7)2 (1-4)90.347 ConclusionsWe have demonstrated in our study that intercostal nerve block provides effective post operative analgesia in breast surgery patients. The accessibility of intercostal nerves in the operative field makes blockade feasible. Contrary to the misconception, incidence of pneumothorax is very rare. It should therefore be used more widely in view of its simplicity.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5052.
Phosphorylation of the Mutant K303R Estrogen Receptor α at Serine 305 Impacts Aromatase Inhibitor Sensitivity.
Authors: Barone I. , Beyer A. , Covington K. , Tsimelzon A. , Ando' S. , Fuqua S. 
Published: December 2010

Abstract
Aromatase inhibitors (AIs) are challenging tamoxifen as the treatment of choice for both early and advanced breast cancer in postmenopausal women with estrogen receptor (ER) α-positive diseases. However, resistance frequently occurs. Previously, we identified a lysine to arginine transition at residue 303 (K303R) in ERα in premalignant breast lesions and invasive breast cancers, which confers estrogen hypersensitivity and resistance to the AI Anastrozole (Ana) when transfected in MCF-7 breast cancer cells. To identify genes whose expression was associated with the development of aromatase inhibitor resistance (AIR), we performed microarray analysis, and found a marked increase in the gene expression of different IGF family members in the mutant cells. Immunoblot analysis also revealed elevated constitutive phosphorylation of the IGF-1R/IRS-1/Akt pathway in K303R-expressing cells. Treatment with IGF-1R and Akt inhibitors drastically inhibited proliferation of the K303R-mutant expressing cells, while wild-type ERα-expressing clones showed little reduction of growth by these inhibitors, confirming the increased IGF signaling activation in the mutant cells.Post-translational modifications of ERα, such as phosphorylation, tightly regulate its function, and the K303R mutation resides at a major post-translational modification site, serine (S) residue 305. We found that the mutant was more efficiently phosphorylated than the WT receptor by Akt in vitro, and that the mutant cells exhibited enhanced S305 phosphorylation in vivo. Mutation of S305 to alanine (A) to destroy this phosphorylation site prevented in vitro and in vivo Akt-mediated phosphorylation.The ERα S305 residue is an important site that modifies response to tamoxifen; thus, we questioned whether the S305 site could also influence AI response. To address the role of S305 phosphorylation on AIR, we generated pools of stable transfectants expressing exogenous WT, K303R, or K303R/S305A mutant receptors, and then evaluated for the effects of Ana in soft agar assays. Expression of the K303R/S305A mutant resulted in a significant reduction in the basal non-stimulated growth and sensitivity to Ana compared to K303R ERα-expressing pools, thus mimicking the same response profile of wild-type ERα clones. A selective blocking peptide (S305 peptide, residues 298-308) able to antagonize this phosphorylation reversed AIR. Blockade of S305 phosphorylation also resulted in a specific inhibition of IGF-1R/IRS-1/Akt activation, but only in the mutant cells.Our data suggest that the K303/S305 residues of the ERα mutation may be a novel determinant of aromatase inhibitor response in breast cancer, and blockade of S305 ERα phosphorylation represents a new therapeutic strategy to overcome resistance to hormonal therapies in tumors with the ERα mutation.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5053.
Combining HSP90 Inhibition with Standard Therapies for HER2 Positive Breast Cancer.
Authors: Qadir Z. , Qadir Z. , Crown J. , Crown J. , Jensen M. , Clynes M. , Slamon D. , O'Donovan N. 
Published: December 2010

Abstract
Background: HSP90 is required for the stability and activity of HER2 and downstream proteins, such as Akt, which play a key role in cell survival. We aimed to assess the anti-tumor effects of the HSP90 inhibitor NVP-AUY922 in HER-2 positive breast cancer cell lines.Methods: HER2 positive breast cancer cell lines with varied sensitivity to trastuzumab (Sensitive: BT474, SKBR3, MDA-MB-361; acquired resistance: BT474Res, SKBR3Res; innate resistance: HCC1419, HCC1954, MDA-MB-453) were treated with the HSP90 inhibitor NVP-AUY922 (Novartis) and trastuzumab. IC50s were determined using the acid phosphatase assay. HER2, Akt and HSP90 levels were determined by immunoblotting after treatment with NVP-AUY922. Combinations of NVP-AUY922 with trastuzumab were tested in BT474, BT474Res, SKBR3, SKBR3Res, HCC1954, and MDA-MB-361 cells. Combinations with docetaxel, cisplatin and 5'-deoxy-5-fluorouridine (5-DFUR) were tested in BT474, SKBR3, HCC1954, MDA-MB-453 and MDA-MB-361 cells.Results: All of the HER2 positive cells were sensitive to NVP-AUY922, with IC50s ranging from 5.5 to 16.4 nM and NVP-AUY922 treatment reduced HER2 and Akt levels in a dose dependent manner. Combined treatment with NVP-AUY922 (10 nM) and trastuzumab (10 nM) showed significantly greater inhibition of growth than either trastuzumab or NVP-AUY922 alone in BT474 and BT474Res cell lines (p&lt;0.005). In SKBR3, SKBR3Res, HCC1954, MDA-MB-453 and MDA-MB-361 cells, dual treatment with NVP-AUY922 and trastuzumab did not significantly increase response compared to NVP-AUY922 alone (Table 1). Combinations of docetaxel, cisplatin or 5-DFUR with NVP-AUY922 were antagonistic in all cell lines tested (CI values &gt;1).Conclusions: This study demonstrates that NVP-AUY922 has anti-tumour activity in HER2 positive breast cancers regardless of sensitivity to trastuzumab. The antagonistic interactions observed for combinations of NVP-AUY922 with chemotherapy do not favour clinical evaluation of concurrent administration of NVP-AUY922 with chemotherapy. However, alternative scheduling or combinations with other targeted therapies warrants further investigation.Table 1: Percentage growth in response to NVP-AUY922 and trastuzumab. BT474BT474ResSKBR3SKBR3ResHCC1954MDA-MB-361Trastuzumab53.3 +/- 4.990.4 +/- 7.669.5 +/- 16.179.5 +/- 8.2102.9 +/- 15.558.4 +/- 3.3AUY92255.0 +/- 1.192.6 +/- 11.933.3 +/- 9.719.1 +/- 6.152.2 +/- 13.88.2 +/- 6.2Tras+AUY92222.0 +/- 2.3*59.7 +/- 17.5*30.6 +/- 7.518.3 +/- 4.347.2 +/- 3.42.5 +/- 2.2
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5055.
Hyperthermia Sensitizes Breast Cancer Stem Cells to Radiation Therapy.
Authors: Atkinson R. , Zhang M. , Diagaradjane P. , Krishnan S. , Rosen J. , Rosen J. , Chang J. , Chang J. 
Published: December 2010

Abstract
Background In cancer, metastatic disease and recurrence are hypothesized to result, at least in part, from the residual cancer stem cells (CSCs), also referred to as tumor-initiating cells(TICs), which evade initial treatment. In several genetically engineered mouse models that resemble human breast cancer, the tumor subpopulation CD29+/CD24+/lin- has been shown to be more tumorigenic as compared to other subpopulations by in vitro and in vivo assays. We and others have demonstrated that the tumorigenic CD29+/CD24+/lin- subpopulation repairs radiation-induced DNA strand breaks more efficiently than the other subpopulations. Therefore, we hypothesized that hyperthermia, a documented means of inhibiting DNA repair, may radiosensitize CSCs to radiation therapy(RT) by delaying and inhibiting the repair of DNA strand breaks. Methods To test this hypothesis, we assayed for tumorigenic CD29+/CD24+/lin- cells in p53null mouse mammary tumor model with and without radiation, and in combination with hyperthermia (42°C) administered as optically-activated gold nanoparticles. We then determined if there was a decrease in functional CSCs by FACS analysis and limiting dilution transplantation assays. Results These studies confirmed that CD29+/CD24+/lin- cells were more radiation resistant and that their relative proportion was increased after RT, as compared to the other cell populations. However, the addition of hyperthermia increased the sensitivity of the CD29+/CD24+/lin- subpopulation to radiation. Radiation treatment alone in vivo resulted in a decrease in tumor size, but the percentage of tumorigenic cells increased as compared to untreated controls. In contrast, following post-treatment with 20 minutes of local hyperthermia, using intravenously administered optically activated gold nanoparticles, a larger regression in tumor size was observed, without a concomitant increase in the percentage of CD29+/CD24+/lin- tumorigenic cells. Using the functional limiting dilution transplantation assay to assay for CSCs, we showed that 48 hours after treatment cells derived from tumors treated with RT exhibited an increased frequency of TICs as compared to untreated controls, and tumors treated with radiation and hyperthermia. In addition, clonogenic survival assays of this tumorigenic subpopulation had consistent results with the in vivo data. Conclusion These results suggest that localized hyperthermia serves as a simple strategy to selectively sensitize the radioresistant subpopulation of CSCs to enhance their response to radiation therapy. The mechanisms responsible for these effects of hyperthermia are currently under investigation. Supported by grant NCI R01 CA112305 and CA16303.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 506.
Marked Synergism In Vitro with the Histone Deacetylase Inhibitor LBH-589 and Classical Agents: Potential New Leads for Combination Therapy.
Authors: Budman D. , Calabro A. , Tai J. 
Published: December 2010

Abstract
Background: Clinical studies of new agents with targeted effects have been tempered by the poor single agent activity in solid tumors of most of these agents with the exception of trastuzumab and lapatinib. In addition, off-target effects may also play a role in their anti-cancer activities so their putative mechanism of action may not be applicable. As a consequence, a combinatorial approach of combining agents has been employed in the clinic with little regard of whether or not the combination may display synergy or antagonism. As over 400 drugs are in development, the clinical trials mechanism can only evaluate a paucity of agents. Methods: We have employed median effect analysis of drugs applied to human cancer cells in short term log phase culture, combined with curve shift analysis, to identify potential interesting combinations(such as tyrosine kinase dual Her2/EGFR inhibitors with capecitabine)and to discard antagonistic combinations (AntiCancer Drugs. 17: 921-928, 2006). This technique allows schedule to be examined and up to three agents combined simultaneously. The following human breast cancer cell lines were used: MCF7/wt (ER+), MCF7/adr (ER-, Her2+ multiply resistant), BT474 (ER+, Her2+), SK-BR3 (ER-, P53 mutant, Her2+), HCC-1395 (triple negative), and HTB-25 (triple negative). LBH-589 (gift of Novartis USA)is a histone deacetylase inhibitor in clinical trials with broad biological effects including perturbation of survivin, pro-apoptotic effects, induction of differentiation, and non cycle dependent effects (Int J Ca 121: 1138, 2007). Results: This agent was combined with more classical agents. Synergism (CI at Fa50 &lt; 1.0) was noted for doublets combined with either carboplatin (6/6 cell lines) docetaxel(5/6 cell lines), 5'DFUR (6/6 cell lines), doxorubicin (5/6 cell lines), and the triplets examined. Her2 antagonists such as trastuzumab or GW282974X (lapatinib analogue) were not enhanced by co-treatments with LBH-589. CI values are shown for the triplets. Only SK-BR3 demonstrated resistance with one combination.Conclusions: This data suggests several innovative combinations which might have greater efficacy than traditional therapy. A doublet of LBH589 with gemcitabine or a triplet are most attractive. Supported in part by the Don Monti Foundation, the Donna Dennis Foundation, and NCI CA 35279.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5061.
BIBW 2992, a Novel Irreversible EGFR/HER1 and HER2 Tyrosine Kinase Inhibitor for the Treatment of Patients with HER2-Negative Metastatic Breast Cancer after Failure of No More Than Two Prior Chemotherapies.
Authors: Harbeck N. , Schmidt M. , Harter P. , Possinger K. , Jonat W. , Lück H. , Beckmann M. , Fasching P. , Schütte J. , Solca F. , Uttenreuther-Fischer M. , Taton M. , Lahogue A. , Awada A. , De Grève J. , Canon J. , Dirix L. , Fleischer F. , Neven P. , Gottschalk N. , Piccart M. , Schuler M. 
Published: December 2010

Abstract
Background: BIBW 2992 (Tovok™*) is a novel, oral, irreversible inhibitor of the epidermal growth factor receptor (EGFR)/ human epidermal growth factor receptor (HER)1 and HER2 inhibitor. It has promising preclinical activity in HER2-negative MDA-MB-453 and triple-negative SUM 149-PT cell lines, and showed clinical Phase I activity. First results of a Phase II study of BIBW 2992 in patients with HER2-negative, hormone receptor (HR)-positive or triple-negative breast cancer who have progressed following no more than two prior lines of chemotherapy are presented. The trial was conducted as a multi-institutional, open-label study in Germany and Belgium.Methods: Eligible patients had stage IIIB or IV HER2-negative metastatic breast cancer (MBC), with progression following no more than two prior lines of chemotherapy. No prior EGFR-targeted therapy was allowed and measurable disease, Eastern Cooperative Oncology Group performance status of 0–2 and an adequate organ function were required. Patients received 50 mg BIBW 2992 once-daily until disease progression. Tumor assessment was performed every other treatment course (one course is 28 days). The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors criteria in patients with HR-positive and triple-negative MBC. The latter was changed to clinical benefit, i.e. objective response (OR) or stable disease (SD) on treatment for at least four cycles for patients with triple-negative disease. Safety data were collected and analyses are still ongoing.Results: A total of 56 patients were enrolled with 50 actually starting treatment on the trial, including 29 patients with triple-negative and 21 patients with HER2-negative and HR-positive MBC. No ORs were observed in either cohort. Three patients in the triple-negative cohort had SD for at least 4 treatment cycles, one of them for 12 cycles. The most frequently observed side-effects at snapshot date (on 49 patients) are diarrhea (Common Terminology Criteria for Adverse Events Grade 3 in 18 patients [36.7%]) and Grade 3 skin rash in two patients [4.1%]). These were managed by symptomatic treatments and dose reductions.Conclusion: Long-term oral administration of BIBW 2992 was safe in HER2-negative MBC patients. Side effects mainly affected the skin and gastrointestinal tract, and were manageable. Clinical benefit was achieved in a fraction of triple-negative MBC patients.*Trade name not FDA approved.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5062.
Vimentin: A Novel Chemopreventive Target for Breast Cancer Metastasis.
Authors: Thaiparambil J. , Bender L. , Kline E. , Ganesh T. , Snyder J. , Liotta D. , Marcus A. 
Published: December 2010

Abstract
Background: Cancer metastasis is the major cause of death in nearly all tumor types; however, most treatments target the primary tumor and not the highly invasive metastatic cells. We propose to prevent cancer metastasis by precisely targeting the cancer invasion machinery. To do this we disrupt a novel target-the vimentin cytoskeleton. Vimentin is overexpressed in nearly all invasive solid tumors and is critical for cell migration. Here we show that Withania sominifera root extracts (WRE) and one of its primary constituent, Withaferin A (WFA), targets vimentin to inhibit cancer cell motility and migration while having negligible effects on viability. WFA is a steroidal natural product with 4-rings (A-D) connected to a lactone ring. We test the hypothesis that WFA is an anti-invasive compound that disrupts vimentin function with limited toxicity.Material and Methods: We employ cutting-edge live cell confocal imaging studies in combination with traditional molecular biology techniques to dissect the precise mechanism of how WRE or WFA inhibits cancer cell migration and invasion. We have employed a wounding model and Matrigel invasion assay to determine the anti-migratory and anti-invasive properties of WRE and WFA using MDAMB-231 cells. We have used GFP-vimentin to visualize the changes in vimentin dynamics. Effect of WRE and WFA on cell cycle was analyzed by Flow cytometry.Results: Our results show WFA has weak anti-proliferative activity at low concentrations but potently inhibits breast cancer migration and invasion in a dose-dependent manner. High resolution confocal images reveal that in WFA-treated cells, vimentin fails to invade the lamellipodia resulting in decreased cell migration. This is supported by live cell confocal imaging showing that at high doses WFA treatment depolymerizes GFP: vimentin. Furthermore, treatment with WFA results in aberrant vimentin phosphorylation, likely resulting in a net depolymerized phenotype. In order to determine if the vimentin-binding A ring of WFA is critical for its anti-invasive efficacy, we synthesized and tested A-ring modified analogs of WFA. All three analogs showed severely reduced potency in inhibiting cancer cell migration and invasion, suggesting that the A ring is critical for its anti-invasive activity.Discussion: The present study shows that WRE or WFA inhibits breast cancer cell migration at nanomolar concentrations by disrupting vimentin at concentrations that have minimal effect on proliferation. We believe its strong anti-migratory activity make this an appropriate compound as an anti-metastatic chemopreventative. Ultimately, we envision WFA can be used as a vimentin-targeting chemopreventative in high-risk metastatic patients and has the potential to be used with traditional cytotoxics.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5063.
Constitutive Activation of Src Kinase as a Mechanism of Acquired Resistance to Dasatinib in Triple Negative Breast Cancer.
Authors: Corkery B. , Corkery B. , Crown J. , Crown J. , Roche S. , O'Connor R. , Tryfanopoulos D. , Tryfanopoulos D. , Clynes M. , O'Donovan N. 
Published: December 2010

Abstract
Background: Dasatinib, a multi-target inhibitor of tyrosine kinases including Src, Bcr-Abl, PDGFR, and ephrin A receptor kinases, preferentially inhibits growth in triple negative breast cancer (TNBC) cell lines compared to other breast cancer subtypes. Previous studies have shown that dasatinib is a substrate for the drug efflux pumps, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). We sought to develop a model of acquired resistance to dasatinib to investigate potential mechanisms of resistance.Materials and Methods: Resistance to dasatinib in MDA-MB-231 was achieved by continuous exposure to incrementally increasing concentrations of dasatinib (200 - 500 nM). IC50 values and combination assays were measured using the acid phosphatase assay. Parental and resistant cells were treated with dasatinib (1 µM) for 2 hours and accumulation of dasatinib in cells was quantified by liquid chromatography–mass spectrometry (LC-MS). The effect of the P-gp/BCRP inhibitor, elacridar, on dasatinib sensitivity was also assessed. Src and phospho-Src (P-Src) levels were assessed by western blot.Results: The MDA-MB-231-Das cell line displayed significant resistance to dasatinib (IC50 &gt; 5 µM) compared to the parental MDA-MB-231 cells (IC50 39.3 ± 14.2 nM). There was no significant difference in the doubling time of the parental and MDA-MB-231-Das cells (Table 1). In addition, the growth rate of the resistant cells did not significantly decrease in response to dasatinib treatment, in contrast to the parental cell line. No difference in accumulation of dasatinib was observed in the parental and resistant cells. Furthermore, inhibition of P-gp and BCRP with elacridar did not enhance response to dasatinib in either cell line. P-Src levels were not altered in the resistant cell line. However, P-Src levels did not decrease in response to dasatinib treatment in the MDA-MB-231-Das cells, whereas a dose dependent decrease in P-Src levels was observed for the parental cells.Discussion: Src kinase has been implicated in aberrant signalling through multiple receptors involved in tumorigenesis, and is a putative target for response/resistance to dasatinib. We developed a novel triple negative breast cancer model of acquired resistance to dasatinib, and examination of Src phosphorylation suggests that constitutive activation of Src is a potential mechanism of resistance.Table 1 Doubling time (± standard deviation (hrs)) and growth rate of MDA-MB-231 and MDA-MB-231-Das cells with and without dasatinib (D) treatment. ControlD 50 nMD 100 nMMDA-MB-231 (parental)17.6 ± 1.232.2 ± 3.3*46.8 ± 5.1*Growth rate (%)100.054.737.6MDA-MB-231-Das (Dasatinib-resistant)19.1 ± 2.421.0 ± 0.221.2 ± 3.1Growth rate (%)100.091.090.1
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5066.