tbuckley/cabot-search huggingface dataset:
Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer
Authors: Yu Kang, Archana S. Nagaraja, Guillermo N. Armaiz-Pena, Piotr L. Dorniak, Wei Hu, Rajesha Rupaimoole, Tao Liu, Kshipra M. Gharpure, Rebecca A. Previs, Jean M. Hansen, Cristian Rodriguez-Aguayo, Cristina Ivan, Prahlad Ram, Vasudha Sehgal, Gabriel Lopez-Berestein, Susan K. Lutgendorf, Steven W. Cole, Anil K. Sood
Journal: Clinical Cancer Research (2015)

Chronic adrenergic activation has been shown to associate with adverse clinical outcomes in cancer patients, but the underlying mechanisms are not well understood. The focus of the current study was to determine the functional and biologic effects of adrenergic pathways on response to chemotherapy in the context of ovarian cancer.Increased DUSP1 production by sympathetic nervous system mediators (e.g., norepinephrine) was analyzed by real-time quantitative RT-PCR and by Western blotting. In vitro chemotherapy-induced cell apoptosis was examined by flow cytometry. For in vivo therapy, a well-characterized model of chronic stress was used.Catecholamines significantly inhibited paclitaxel- and cisplatin-induced apoptosis in ovarian cancer cells. Genomic analyses of cells treated with norepinephrine identified DUSP1 as a potential mediator. DUSP1 overexpression resulted in reduced paclitaxel-induced apoptosis in ovarian cancer cells compared with control; conversely, DUSP1 gene silencing resulted in increased apoptosis compared with control cells. DUSP1 gene silencing in vivo significantly enhanced response to paclitaxel and increased apoptosis. In vitro analyses indicated that norepinephrine-induced DUSP1 gene expression was mediated through ADRB2 activation of cAMP-PLC-PKC-CREB signaling, which inhibits JNK-mediated phosphorylation of c-Jun and protects ovarian cancer cells from apoptosis. Moreover, analysis of The Cancer Genome Atlas data showed that increased DUSP1 expression was associated with decreased overall (P= 0.049) and progression-free (P= 0.0005) survival.These findings provide a new understanding of the mechanisms by which adrenergic pathways can impair response to chemotherapy and have implications for cancer management.
Evaluation of prostate-specific antigen as a surrogate marker for response of hormone-refractory prostate cancer to suramin therapy.
Authors: R Sridhara, M A Eisenberger, V J Sinibaldi, L M Reyno, M J Egorin
Journal: Journal of Clinical Oncology (1995)

PURPOSE We evaluated the surrogate role of serum prostate-specific antigen (PSA) using prospectively collected information from patients with hormone-refractory prostate cancer (HRPC) treated with suramin. MATERIALS AND METHODS Data from 103 patients were analyzed using survival analysis, exploratory analysis, and regression analysis. RESULTS There was a significant survival difference between groups of patients with a PSA decrease of &lt; or = 0% or greater than 0% (P = .018). There were no significant overall survival differences between groups of patients with PSA decreases less than 50% or &gt; or = 50% and less than 75% or &gt; or = 75%. Tree-based modeling did not define a specific threshold percentage PSA change as a response criterion. For a response of 1-year survival, sensitivity increased (0.91 v 0.69), but specificity decreased (0.37 v 0.62), with a 75% versus 50% PSA decrease used as classification criterion. Differences between the area under the receiver-operating curves (ROCs) with 50% and 75% PSA decreases as threshold values were small. For a response of 1-year survival, attributable proportions were 0.38 and 0.68, respectively, with 50% and 75% PSA decreases as threshold values. When pretreatment variables were assessed by Cox proportional hazards model, hemoglobin level was the most significant predictor of survival. When percentage PSA change was included in the model, hemoglobin level remained the most significant factor, but percentage PSA change was also a weak, but statistically significant, factor. PSA was a weak, but statistically significant, predictor of survival in Cox proportional hazards model with PSA as a time-variant covariate. CONCLUSION Reduction in PSA level has weak prognostic significance with respect to survival in HRPC patients, but, currently, PSA reduction cannot be used as a reliable response criterion to evaluate treatment efficacy in individual patients. Prospective, randomized studies, including prospective measurement of other indices related to symptomatic clinical benefits, are required.
A phase II study of cisplatin, 5 fluorouracil (5-FU), radiation (RT) and celecoxib in patients with resectable esophageal cancer (EC): Updated results from the Hoosier Oncology Group (HOG) study
Authors: R. Govindan, N. Fineberg, H. McLeod, K. Kesler, N. Hanna, C. Stoner, J. Vinson, R. Mantravadi, L. Einhorn
Journal: Journal of Clinical Oncology (2004)

4052 Background: EC commonly expresses cyclo-oxygenase II (COX-2). COX-2 inhibition results in decreased cell proliferation and potentiation of chemotherapy and radiation. We reported the preliminary results of a phase II study conducted by the HOG in patients (pts) with potentially resectable esophageal cancer (ASCO 2003, A 1168). Methods: All pts received cisplatin (75 mg/m2 d1, 29) and 5- FU (1000 mg/m2 d1–4, 29–32) with RT (50.4Gy beginning d1). Celecoxib was administered 200 mg po bid from d1 daily until surgery and then 400 mg po bid until disease progression or excessive toxicities or a maximum of 5 years. Esophagectomy was performed 4 –6 weeks after the completion of chemoradiation. The primary endpoint was pathological complete response (pCR). Secondary endpoints included response rate, toxicity, overall survival and correlation between COX-2 expression and pCR. Results: Thirty-one pts were enrolled from 3/01 to 7/02. Of the 22 pts (71%) who underwent surgery 6 had pCR (19% of those enrolled and 27% of those who underwent surgery). The two year survival rate (Kaplan-Meier estimate) for the entire study population was 31%±12% with a median survival of 17 months. COX-2 expression was performed and graded weak (0 or 1+) or strong (2+ or 3+) on 17 available baseline esophageal cancer tissue specimens. Out of 17 evaluable pre therapy specimens, 10 (59%) had strong COX-2 expression. The two-year survival rates for those with weak and strong baseline COX-2 expression were similar (0.38±0.20 Vs. 0.40 ± 0.15, p=0.473). However, the two year survival was significantly improved in patients who achieved pCR compared to those who did not (0.50±0.35 Vs. 0.26±0.11, p=0.027). Conclusions: 1) Baseline COX-2 expression in esophageal cancer tissues does not predict survival in patients with esophageal cancer treated with cisplatin, 5 FU, celecoxib and radiation treatment followed by surgery. 2) Pathological complete response following induction chemoradiation is associated with improved survival. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Lilly Aventis Ligand Pfizer
Abstract P346: Regulation of GRK5 in Myocytes Is Mediated by Nuclear Transcription Factor [ê]B: A New Clue in Heart Disease
Authors: Kazi N Islam, Walter J Koch
Journal: Circulation Research (2011)

G protein coupled receptor kinase-5 (GRK5) plays a key role in the heart and it’s expression is increased in heart failure. Moreover, a human mutation within its amino-terminus appears to play a role in therapeutic responses to β-blockers in heart failure patients. Nuclear transcription factor kappa B (NF-κB), a ubiquitous transcription factor, is involved in the regulation of numerous genes in various tissues and activation of NF-κB has also been shown to be associated with heart disease. Here, we investigated the role of NF-κB signaling in the regulation of the  GRK5  gene and GRK5 expression in neonatal rat ventricular myocytes (NRVMs). In analyzing the 5’-flanking DNA of  GRK5 , the presence of a potential NF-κB binding site was observed in the promoter. Phorbol myristate acetate (PMA), a known stimulator of NF-κB, increased the levels of GRK5 in NRVMs. Conversely, treatment of NRVMs with N-acetyl cysteine (NAC), a known inhibitor of NF-κB, decreased the levels of GRK5 compared to control cells. Utilizing electrophoretic mobility shift assay (EMSA) with nuclear extracts from NRVMs treated with or without PMA, it was found that proteins bound to the GRK5 promoter containing the putative NF-κB binding site. When an antibody specific for NF-κB was utilized, a super-shift of the proteins binding to the putative NF-κB binding site was observed. Furthermore, interaction of NF-κB with GRK5 was confirmed by shift Western blot. Chromatin immunoprecipitation (ChIP) showed dynamic recruitment of both p50 and p65 to the NF-κB site of GRK5 promoter after treatment of NRVMs with PMA. Treatment of myocytes with siRNA and subsequent knock-down of NF-κB p65 decreased the levels of GRK5 as judged by real time quantitative PCR. Finally, adenovirus mediated overexpression of a dominant negative IκB-α in NRVMs inhibited the levels of GRK5. Taken together, our present studies suggest that NF-κB plays a potential role in the regulation of GRK5 transcription in myocytes and this may translate to key expressional changes seen in heart disease.
Use of molecular signatures of gastric cancers derived from microarray analysis of paraffin-embedded specimens to predict the degree of response to CPT11/S-1 chemotherapy
Authors: S. Morita, M. Inokuchi, A. C. Hoffmann, J. Cooc, A. Omori, P. V. Danenberg, K. D. Danenberg, H. Uetake
Journal: Journal of Clinical Oncology (2008)

4566 Background: Microarray technology is potentially a powerful approach to identify genes expression signatures that predict the effects of chemotherapeutic drugs. In this study, we sought to determine whether gene expression profiles generated by DNA microarrays using RNA isolated from laser-capture microdisssected FFPE gastric cancer specimens could be used to distinguish different levels of drug response in gastric tumors treated with CPT-11 and S-1, a fluoropyrimidine-based drug combination that includes a DPD inhibitor. Methods: FFPE gastric cancer specimens were available from 23 patients with partial response (PR), 10 patients with stable disease (SD) and 5 patients with progesive disease (PR). Up to 5 10-micron sections of each were microdissected to isolate areas of tumor tissue. Following microdissection of paraffin-embedded specimens, RNA was isolated, amplified, labeled, and hybridized to Affymetrix U133 Plus 2.0 GeneChips. Differentially expressed gene lists between the tissues with the different levels of response were determined. Results: A T-test with unequal variance assumption identified 186 differentially expressed genes among the 3 response groups (p=0.001). Hierarchical clustering segregated the PR, SD and PD patients into distinct groups, and the results were confirmed with principal components analysis and leave-one-out analysis. Kaplan Meier survival analysis stratifying on these clusters revealed significant differences in survival (cluster 1, cluster 2 and cluster 3 had median survivals of 832, 404 and 128 days, respectively; p<0.001). Conclusion: The molecular signature of gastric cancers identifies predictive markers that distinguish patients who may expect different responses to CPT11/S-1 chemotherapy and thereby provides a guide to the use of therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Response Genetics, Inc. Response Genetics, Inc. Response Genetics, Inc.
Leveraging technology and data to facilitate development of cost-effective pathways.
Authors: B. S. Tom, I. Aksamit, C. B. Del Buono, L. Tuscher, D. K. Verrilli, Z. Wang, K. B. Whitlock, N. C. Leasure, K. A. Bergstrom
Journal: Journal of Clinical Oncology (2011)

e16587 Background: Oncologists and managed care organizations are challenged with incorporating an ever-growing array of evidence-based chemotherapy regimens into treatment strategies, while maintaining high-quality, cost-effective care. Creating pathways can aid in overcoming this challenge by increasing workflow efficiency, encouraging adherence to evidence-based regimens, and providing predictability in cost to the healthcare system. To assist community oncologists in this process, we have created a pathway development solution leveraging drug dispensing technology, clinical tools, and web-based reporting. Results of the first of 4 pilots will be presented. Methods: Our pilot began in 3/2009 with a 6 physician practice, aiming to create a pathway that standardized prescribing, while lowering costs to their largest commercial payer. Using our reporting solution, colon and breast cancer utilization and guideline compliance from the previous year were reviewed. Average cost and reimbursement per regimen using the payer’s fee schedule were then extrapolated and clinical tools were used to evaluate clinical evidence and support selection of the practice’s preferred regimens. Lastly, the cost and reimbursement impact of on-pathway prescribing was forecast to ensure their financial goals would be met. Following this process, the practice finalized and implemented pathways for the adjuvant (Adj) and 1st line metastatic (Met-1) treatment of colon and breast cancer. Results: The results from a 7-seven month, post-standardization period, are below (Table). Conclusions: Leveraging technology to allow practices to review utilization and guideline compliance, accessing clinical tools to aid in regimen selection, and forecasting cost and reimbursement trends from changed prescribing patterns are operative in assisting practices to develop cost-effective pathways. Baseline Post % Change Breast Adj No. of pts 55 27 No. of regimens 15 7 -53 Avg reimbursement/regimen $29,516 $27,528 -7 Met-1 N 21 8 No. of regimens 8 5 -38 Avg reimbursement/regimen $20,048 $15,786 -21 Colon Adj No. of pts 14 14 No. of regimens 4 3 -25 Avg reimbursement/regimen $44,931 $39,285 -13 Met-1 N 9 14 No. of regimens 4 5 +25 Avg reimbursement/regimen $29,975 $30,103 +0.4
Compositional MRI assessment of cartilage: what is it and what is its potential for sports medicine?
Authors: Ali Guermazi, Frank W Roemer
Journal: British Journal of Sports Medicine (2015)

Compositional MRI reveals biochemical and microstructural changes in cartilage well before changes are visible to the eye/arthroscopist. Compositional MRI focuses on early and potentially reversible injury stages, and may (1) help identify athletes at risk prior to the development of overt joint damage or (2) help to determine time to return to play in a postinjury scenario.1

Compositional MRI is not yet in clinical use, but it is being used with increasing frequency in osteoarthritis (OA) research for ‘pre-morphologic’ evaluation of cartilage (figure 1)2 and to assess biochemical response of joint tissue, primarily cartilage, to loading through physical activity.3 It has been used to image the biochemical response in knees after ACL reconstruction,4 meniscus surgery5 and cartilage repair6 (figure 2).



Figure 1 
Defining disease state of osteoarthritis. Adapted from Kwoh.11





Figure 2 
Knee of a patient 24 months after microfracture cartilage repair of the medial central femoral condyle. (A) Sagittal three-dimentional T1-weighted gradient echo MRI showing a normal morphological appearance of the cartilage repair tissue and native medial posterior femoral condyle …
National smoking bans improve health outcomes, Cochrane review shows
Authors: Jacqui Wise
Journal: BMJ (2016)

National smoking bans do reduce the harms of passive smoking, specifically cardiovascular disease, an updated systematic review from the Cochrane Library has found.1

Since the first version of this review in 2010, more countries have introduced national legislation to ban indoor smoking. The authors said that the updated review provided the most robust evidence yet that smoking bans have led to improved health outcomes.

A team of researchers based in Ireland included 77 studies, representing 21 countries, that investigated the effect of introducing a smoking ban on …
Membranes of Normal Hamster Lymphocytes and Lymphoid Cells Neoplastically Transformed by Simian Virus 40. II. Plasma Membrane Proteins Analyzed by Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis and Two-Dimensional Immune Electrophoresis2
Authors: R. Schmidt-Ullrich, D. F. H. Wallach, F. D. G. Davis
Journal: JNCI Journal of the National Cancer Institute (1976)

Journal Article Membranes of Normal Hamster Lymphocytes and Lymphoid Cells Neoplastically Transformed by Simian Virus 40. II. Plasma Membrane Proteins Analyzed by Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis and Two-Dimensional Immune Electrophoresis Get access R. Schmidt-Ullrich, R. Schmidt-Ullrich Search for other works by this author on: Oxford Academic PubMed Google Scholar D. F. H. Wallach, D. F. H. Wallach Search for other works by this author on: Oxford Academic PubMed Google Scholar F. D. G. Davis, II F. D. G. Davis, II Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 57, Issue 5, November 1976, Pages 1117–1126, https://doi.org/10.1093/jnci/57.5.1117 Published: 01 November 1976 Article history Received: 12 January 1976 Accepted: 02 April 1976 Published: 01 November 1976
Dynamic contrast-enhanced ultrasonography (DCE-US) with quantification for the early evaluation of metastatic renal cancer treated with tyrosine kinase inhibitors (TKI)
Authors: N. Lassau, S. Koscielny, L. Chami, B. Benatsou, L. Albiges, A. Roche, B. J. Escudier
Journal: Journal of Clinical Oncology (2008)

5049 Background: 1) To determine the best quantitative parameters of DCE-US at D15 for predicting the response at 3 months to TKI in patients with metastatic renal cancer. 2) To determine which parameters at D15 are correlated to Disease Free Survival (DFS) Methods: Thirty six patients with metastatic renal cancer, treated with TKI (sorafenib and sunitinib) were prospectively followed by DCE-US. DCE-US was performed before treatment and at day 15 and every 2 cycles. Contrast uptake was acquired using VRI perfusion software after SonoVue (Bracco) bolus injection. Time-intensity curves (TIC) were determined using linear raw-data from CHI-Q (Toshiba) software. Seven parameters were extracted from the modelized TICs: peak intensity (PI), areas under the curve (AUC), under the wash-in (AUWI), under the wash-out (AUWO), (corresponding all to the blood volume), time to peak intensity (TPI), slope of the wash-in (SWI) (both corresponding to the blood flow), mean transit time. CT-scan were performed before treatment and every 2 cycles. Patients were separate in good and bad responders according to the clinical benefit after 2 cycles according the RECIST criteria (good responders = PR+SD). The variation of each functional parameter of DCE-US was calculated between D0 and D15 and compared between good and bad responders using a non parametric test of Kruskal-Wallis. For the correlation with DFS, the difference between the 2 groups was test with a log-rank test. Results: To date, 31 patients have been followed-up at least 3 months: 21 good responders and 10 bad responders. A total of 118 DCE-US were performed. Among 7 parameters: 4 were significantly correlated to the response : AUC (p=0.04); PI (p=0.03), TPI (p=0.03), SWI (p=0.01). Three parameters were correlated to DFS : PI (P=0.002), SWI (p=0.008) and TPI (p=0.01) Conclusions: Quantitative functional evaluation by DCE-US performed at D 15 is able to predict the efficacy of TKI at 3 months in patients with RCC and is correlated to DFS. No significant financial relationships to disclose.
Maternal deaths have nearly halved in past 25 years
Authors: I. Torjesen
Journal: BMJ (2015)

The risk of a woman dying through pregnancy and childbirth has fallen by 44% over the past 25 years, but the world has missed the millennium development goal to cut maternal deaths by 75%, a report from United Nations agencies and the World Bank Group has shown.1

Just nine countries managed to achieve a 75% reduction in maternal death rates in the period from 1990 to 2015: Bhutan, Cape Verde, Cambodia, Iran, Laos, the Maldives, Mongolia, Rwanda, and Timor-Leste.

Worldwide, around 532 000 maternal deaths were …
Randomized phase II study (EORTC 08062) of amrubicin as single agent or in combination with cisplatin versus etoposide-cisplatin as first-line treatment in patients (pts) with extensive disease small cell lung cancer (ED SCLC).
Authors: M. O'Brien, J. Jassem, P. Lorigan, L. Bosquée, E. Marshall, F. Bustin, J. Stigt, A. C. Dingemans, B. Hasan, J. P. Van Meerbeeck
Journal: Journal of Clinical Oncology (2010)

7052 Background: Outcome for pts with ED SCLC remains poor, despite standard treatment with platinum and etoposide (E). Amrubicin (A) is a synthetic anthracycline and a potent topoisomerase II inhibitor, with less cardiotoxicity than doxorubicin, approved in Japan for the treatment of NSCLC and SCLC. Methods: Eligible pts had previously untreated, histologically confirmed ED SCLC,WHO performance status (PS) 0-2and measurable disease according to RECIST. Pts were randomized to 3 weekly cycles of either (1) A alone 45 mg/m2 d1-3, (2) cisplatin (C) 60 mg/m2 d1 and A 40 mg/m2 d1-3 or (3) E 100 mg/ m2 d1, d2-3 i.v/po and C 75 mg/m2 d1. The primary endpoint was overall response rate (ORR) aiming at ORR = 80% and powered to rule out an ORR < 55% in any experimental arm. Patients were stratified by center, gender and PS. To declare success, 19 responses out of 27 eligible pts who started treatment (ORR of at least 70%) were needed in each arm using a Fleming design. Results: The number of randomized/eligible pts who started treatment was 33/28 in Arm 1, 33/30 in arm 2 and 33/30 in arm 3, respectively. Major patient characteristics including age, sex and PS were well balanced between the arms. The median number of chemotherapy cycles received was 5, 6 and 6. Primary prophylaxis with pegfilgrastim was added in the later part of the trial in arms 1-3 (57%, 43%, 37%); grade (G) 3-4 hematological toxicity in arms 1-3 was neutropenia (73%, 73%, 69%); thrombocytopenia (17%, 15%, 9.4%), anemia (10%, 15%, 3.1%) and febrile neutropenia (17%,15%,14%). Early deaths including treatment related were 1, 3 and 3 pts respectively. Cardiac toxicity did not differ among the 3 arms. Out of 88 eligible pts who started treatment, the response rate assessed by investigators was 17 (61%), 23 (77%) and 19 (63%) for arm 1, 2 and 3, respectively. Conclusions: A + C was associated with the highest response rate and further evaluation of this combination is warranted. Independent central review is still on-going. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, AstraZeneca, Celgene, sanofi-aventis Celgene, Lilly Celgene, Lilly