tbuckley/cabot-search huggingface dataset:
An experimental animal model of human tumor dormancy
Authors: George N. Naumov, David A. Sampson, Elise R. Bender, David Zurakowski, Evelyn Flynn, Raanan Berger, Sarah Short, Giannoula Klement, Judah Folkman, Nava Almog
Journal: Cancer Research (2004)

5133   It is well accepted that tumor growth is angiogenesis-dependent. It is also known that early  in situ  cancers can remain dormant for prolonged periods as microscopic lesions. As previously reported, human tumors contain angiogenic as well as non-angiogenic sub-populations of cancer cells ( Achilles et al. J. Natl. Cancer Inst., 2001 ). In order to study the timing of escape from the dormant phenotype ( i.e.  angiogenic switch) we isolated the angiogenic and non-angiogenic sub-populations of human breast adenocarcinoma, osteosarcoma, and glioblastoma. We developed an experimental animal model in which both phenotypes were xenographed in SCID mice. We hypothesized that dormancy is characterized by the absence or insufficiency of angiogenic activity. To test this hypothesis we compared the  in vivo  tumor growth of the angiogenic and non-angiogenic variants in both orthotopic and ectopic (subcutaneous) sites. Mice injected subcutaneously with the angiogenic variants initiated palpable tumors at 23 (median), 24 and 17 days for breast cancer, osteosarcoma, and glioblastoma, respectively. In contrast, mice injected with the non-angiogenic variants remained dormant for up to 10 months. The dormancy period of the non-angiogenic variants can be predicted. At 160 days the incidence for breast cancer was 4/5 mice (with a median time of 74 days to the angiogenic switch), osteosarcoma 1/8, and glioblastoma 1/5. Due to the timing of the angiogenic switch the dormancy period significantly varied between the examined cancer types. During this dormancy period, microscopic tumors remain avascular or with non-functional vasculature for a prolonged period. However, histology reveals high proliferative and apoptotic rates within the dormant tumors, suggesting a non-quiescent state. Interestingly, once the non-angiogenic tumors escape dormancy, there are no differences in growth rates when compared to their angiogenic counterparts. Similar  in vivo  growth patterns were confirmed in the appropriate orthotopic sites. This animal model presents an opportunity to test existing and novel anti-angiogenic therapeutic strategies that will regress already established tumors and/or will keep occult tumors in a state of prolonged dormancy by deactivating the angiogenic switch ( i.e.  angioprevention).
Abstract 11886: Targeting the PGE2/EP3 Pathway Differentiated Thrombosis From Hemostasis in Mice
Authors: Anne-Laure Charles, Peggy Tilly, Farid Slimani, Sabrina Gross, Jean-Etienne Fabre
Journal: Circulation (2011)

Hemostasis interrupts bleeding from disrupted blood vessels by activating platelet aggregation and coagulation. If uncontrolled, this process generates obstructive thrombi and the resulting endolum...
Impact of neoadjuvant chemotherapy to surgery interval on survival outcomes in breast cancer patients.
Authors: Rachel Ann Sanford, Xiudong Lei, Carlos Hernando Barcenas, Elizabeth Ann Mittendorf, Abigail Suzanne Caudle, Vicente Valero, Debu Tripathy, Sharon Hermes Giordano, Mariana Chavez-Mac Gregor
Journal: Journal of Clinical Oncology (2015)

1063 Background: Retrospective analyses have sought to identify the optimal interval between surgery and initiation of adjuvant chemotherapy in breast cancer, with conflicting results. No studies have examined the impact of the interval from conclusion of neoadjuvant chemotherapy to surgery. We evaluated the relationship between survival outcomes and the time interval between neoadjuvant therapy and surgery. Methods: Retrospective review of the prospectively maintained Breast Medical Oncology Institutional database at The University of Texas MD Anderson Cancer Center identified 1101 women diagnosed with stage I-III breast cancer between June 1995 and April 2007 who received any neoadjuvant chemotherapy. We examined the effect of the interval from completion of neoadjuvant chemotherapy to surgery, defined as < 4 weeks, 4-6 weeks, or > 6 weeks, on survival outcomes. Descriptive statistics and Cox proportional hazards models were used. Results: Three hundred thirty five of 1101 patients (30.4%) had surgery within 4 weeks of their last dose of neoadjuvant chemotherapy, 524 (47.6%) within 4-6 weeks, and 242 (22%) after more than 6 weeks. Median age was 50 years, median time to surgery was 33 days (range 8-159 days) and median follow-up was 94 months (range 3-178 months). Patients whose interval was < 4 weeks were more likely to have more advanced stage (p = 0.003) and higher grade (p = 0.04) disease. The 5-year overall survival (OS) estimate was 79%, 87%, and 81% in patients who received surgery in 0-4, 4-6, and > 6 weeks after neoadjuvant chemotherapy, respectively (p = 0.04). The three groups did not differ in five-year locoregional recurrence-free survival (LRFS) or recurrence-free survival (RFS). In multivariate analysis adjusting for important clinical and pathologic characteristics, compared with an interval of < 4 weeks, patients who underwent surgery at 4-6 weeks or at > 6 weeks had equivalent OS (4-6 weeks HR = 0.88, 95% CI 0.68 – 1.16; > 6 weeks HR = 1.12, 95% CI 0.83 – 1.53), LRFS and RFS. Conclusions: Our results suggest no relationship between the neoadjuvant chemotherapy to surgery interval and overall survival, LRFS, or RFS. This data should prove reassuring to clinicians coping with ever-increasing patient volumes.
Methylation reversal reveals Snk/PLK2 as a critical determinant of clinical outcome in ovarian cancer
Authors: Nelofar Syed, Helen Coley, Jalid Sehouli, Dominique Koensgen, Alexander Mustea, Peter Slozarek, Iain McNeish, Peter Schmid, Tim Crook
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

230 

To seek genes regulating chemotherapy sensitivity in ovarian cancer, we derived new cell lines with acquired resistance to paclitaxel and carboplatin. We show that paclitaxel resistance is predominantly epigenetic. Using methylation reversal/micro-array analysis, we have identified transcriptional down-regulation of the Polo-Like Kinase Snk/Plk2 as a major contributor to paclitaxel resistance. Bisulphite sequencing revealed aberrant methylation in the CpG island located at the 5’ end of the Snk/Plk2 gene in paclitaxel resistant cell lines compared to their drug sensitive parental cell lines, implying that methylation-dependent transcriptional silencing underlies the reduced expression of Snk/Plk2 mRNA. RNAi-dependent knock down of Snk/Plk2 resulted in decreased sensitivity to taxol and platinum, whereas ectopic expression abrogated resistance and conferred sensitivity to apoptosis and cytotoxicity caused by either drug. Over-expression of the Snk/Plk2 specific E2 ubiquitin ligase hVPS18 occurs in some paclitaxel resistant cell lines lacking epigenetic down-regulation of Snk/Plk2 mRNA and phenocopies Snk/Plk2 transcriptional silencing. In clinical cases of epithelial ovarian cancer, aberrant methylation of the Snk/Plk2 CpG island was significantly more common at relapse with drug-resistant disease than at initial presentation (p= 0.021). Moreover, the presence of methylated Snk/Plk2 in serum was strongly predictive of both disease recurrence and failure of second line chemotherapy. Together, our results implicate transcriptional silencing of Snk/Plk2 as a clinically important mechanism in a high proportion of epithelial ovarian cancers with acquired chemotherapy resistance and suggest that detection of methylated Snk/Plk2 DNA in serum may have utility as a biomarker of disease relapse and resistance to chemotherapy.
Genetic alterations associated with squamous cell lung carcinoma progression
Authors: Cathie Garnis, Stephen Lam, Calum Macaulay, Wan L. Lam
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

875 

Lung cancer is the leading cause of cancer deaths in North America. Despite advances in lung cancer treatment the overall 5 year survival rate for those diagnosed with lung cancer is bleak. In order to provide new treatment strategies that will ultimately result in increase survival rate we must determine the genetic alterations that drive this disease. Due to the genomic instability associated with late stage tumors the understanding of disease progression can only be achieved by studying both premalignant as well as invasive tumors. The objective of this study is to identify novel genetic alterations in the progression of squamous cell lung carcinoma. Using a tiling path bacterial artificial chromosome (BAC) array comprised of 32,433 over-lapping BAC clones that span the entire human genome we profiled 12 microdissected carcinoma in situ (CIS) and 12 invasive squamous cell lung carcinoma samples. The normalized hybridization data was run through a smoothing algorithm in the aCGH-Smooth program and the frequency of alteration for each BAC was then determined. Analysis of the premalignant lesions allowed for characterization of causal genetic alterations that are often masked by the genomic instability associated with later stage disease. Coupling pre-invasive lesions with tiling resolution arrayCGH technology provides the most comprehensive and informative analysis from which candidate genes can be selected.
Abstract 5050: Proteome-based combined treatment strategies synergizing antagonism of androgen receptor function in prostate cancer
Authors: Joo Hyoung Lee, James A. Mobley, Selvarangan Ponnazhagan
Journal: Cancer Research (2015)

Abstract Acquired resistance to second-generation androgen receptor (AR)-targeted therapies compels the development of novel therapeutic agents for castration-resistant prostate cancer (CRPC). We have recently reported a novel function of endostatin (ES) through direct binding and inhibition of AR in human prostate cancer (PCa) cells. Molecular characterization of the putative mechanisms of ES function on AR-positive PCa cells by global proteomic analysis revealed dramatic upregulation of CYP51A1 expression in LNCaP cells, suggesting that the increases in cholesterol biosynthesis and the resultant steroidogenesis may provide survival mechanism for PCa cells through the augmentation of androgen-AR axis. To validate this hypothesis, anti-proliferative effects of combined treatment of ES with Lovastatin or Fluconazole, inhibitor of HMG-CoA reductase or CYP5A1, were analyzed in vitro using AR-positive LNCaP cells. Results indicated a significantly enhanced ES-mediated growth inhibition on LNCaP cells by targeting both the ligand biosynthesis and receptor function. Proteomic profiling further indicated that ES significantly decreased the levels of AR, coactivator Ran (ARA24) and downregulated AR-driven expression of MCM complex 2, 3, 4 and 6, MDC1 and STMN1, suggesting that AR-targeted effects of ES include disruption of DNA replication, cell cycle propagation and cell division. We found that dual inhibition of AR nuclear transport and AR-mediated cell division by co-treatment of ES and Taxol greatly decreased PCa cell proliferation. Together, this interdisciplinary approach integrating proteomics with PCa cell function possibly suggests that antagonism of AR, which is the principal drug target for the PCa treatment, can be potentiated by the combination of ES with currently used chemotherapy agents and adjuvants. These findings further provide new insights into proteome-based approach as a useful tool to design and optimize effective therapeutic regimens for individual patients with CRPC. Citation Format: Joo Hyoung Lee, James A. Mobley, Selvarangan Ponnazhagan. Proteome-based combined treatment strategies synergizing antagonism of androgen receptor function in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5050. doi:10.1158/1538-7445.AM2015-5050
Abstract 771: Preclinical characterization of the selective FGFR inhibitor INCB054828
Authors: Phillip CC Liu, Liangxing Wu, Holly Koblish, Kevin Bowman, Yue Zhang, Ronald Klabe, Lynn Leffet, Darlise DiMatteo, Mark Rupar, Karen Gallagher, Michael Hansbury, Colin Zhang, Chunhong He, Paul Collier, Maryanne Covington, Richard Wynn, Swamy Yeleswaram, Kris Vaddi, Timothy Burn, Wenqing Yao, Reid Huber, Peggy Scherle, Gregory Hollis
Journal: Cancer Research (2015)

Abstract Aberrant signaling through Fibroblast Growth Factor Receptors (FGFR) has been reported in multiple types of human cancers. Genomic analyses of squamous cell lung, gastric and urothelial tumors have revealed recurrent genetic alterations in FGFR1, FGFR2 and FGFR3 genes, respectively. FGFR proteins contribute to the development of malignancies by promoting tumor cell proliferation, survival, and migration and supporting angiogenesis. Therefore targeting FGFR kinases may provide therapeutic benefit to patients with cancers that have genetic alterations in genes encoding components of the FGF-FGFR axis. INCB054828 is a potent inhibitor of FGFR1, FGFR2, and FGFR3 that has selective pharmacological activity against cancer cells with FGFR alterations. In vitro, INCB054828 potently inhibited the kinase activity of recombinant FGFR1, FGFR2 and FGFR3 enzymes and was highly selective against a panel of kinases including VEGFR2. In cellular assays, INCB054828 inhibited the autophosphorylation of FGFR proteins with low nanomolar IC50 values and blocked signal transduction by FGFR to downstream markers of pathway activation. Cancer cell lines that have genetic alterations in FGFR1, FGFR2 and FGFR3 were uniquely sensitive to growth inhibition by INCB054828, with IC50 values generally in the range of 3-50 nM, compared with cancer cell lines or normal cells without FGFR dependence (IC50 &amp;gt; 1500 nM). In vivo, once-daily oral administration of INCB054828 inhibited the growth of tumors that are dependent upon FGFR1, FGFR2 and FGFR3 activity at tolerated doses. Suppression of tumor growth was dose-dependent and correlated with pharmacodynamic inhibition of FGFR. Collectively, these preclinical studies demonstrate that INCB054828 potently and selectively inhibits models of FGFR-dependent cancers in vitro and in vivo, supporting the compound's clinical evaluation in patients harboring oncogenic FGFR activation. Citation Format: Phillip CC Liu, Liangxing Wu, Holly Koblish, Kevin Bowman, Yue Zhang, Ronald Klabe, Lynn Leffet, Darlise DiMatteo, Mark Rupar, Karen Gallagher, Michael Hansbury, Colin Zhang, Chunhong He, Paul Collier, Maryanne Covington, Richard Wynn, Swamy Yeleswaram, Kris Vaddi, Timothy Burn, Wenqing Yao, Reid Huber, Peggy Scherle, Gregory Hollis. Preclinical characterization of the selective FGFR inhibitor INCB054828. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 771. doi:10.1158/1538-7445.AM2015-771
Substitution of atenolol for propranolol in a case of propranolol- related depression
Authors: G N McNeil, P K Shaw, D S Dock
Journal: American Journal of Psychiatry (1982)

The authors describe a 62-year-old woman with symptoms of major depression presumed to be secondary to propranolol use. The patient responded poorly to imipramine; however, her symptoms cleared rapidly when atenolol was substituted for propranolol.
Abstract 20634: Extended Selection Criterias for Heart Transplant Candidates, a Single Center 10 Years Experience.
Authors: Chiara Nalli, Mario Senechal, Bernard Cantin, Marie-Heleene Leblanc, Sebastien Bergeron, Guy Proulx, Christine Bourgault, Eric Charbonneau, Daniel Doyle, Francois Dagenais, Eric Dumont, Pierre Voisine, Mathieu Bernier
Journal: Circulation (2010)

Background: The past 30 years of cardiac transplantation (CT) have lead to better medical management of recipients . Many of the original contraindications such as age, diabetes, weight and renal f...
GCF2 interacts with Dishevelled and regulates activation of Rho A
Authors: Hideo Ohtsuka, Masaya Oikawa, Jennifer Rieker, Alfred C. Johnson
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1745 

GC-binding factor 2 (GCF2) is known as a transcriptional repressor that decreases activity of several genes. GCF2 can directly bind to the GC-rich sequence of the EGFR promoter and repress the transcriptional activity of EGFR. GCF2 mRNA is differentially expressed in many human tissues and cell lines. GCF2 mRNA is expressed as a 4.2 kb mRNA in most human tissues with the highest expression level in peripheral blood leukocytes. Additional transcripts of 2.9 and 2.4 kb are found in skeletal muscles and smooth muscles. The only transcript detected in cancer cell lines was 4.2 kb with high levels found in Burkitts’ lymphoma cell lines. GCF2 is found in both nuclear and cytoplasmic compartments in cells. In addition to its function as a transcriptional repressor of several genes, we now show that the GCF2 can directly interact with other proteins such as flightless-1 (Fli-1). Viable mutations of the Drosophila Fli-1 locus cause ultrastructural defects in the indirect flight muscles. Fli-1 has highly conserved homologues in human. The human Fli-1 protein consists of leucine-rich repeat domain and a gelsolin-like domain that is known to bind with actin. Many findings on the function of Fli-1 are consistent with a role for fli-1 in providing a direct link between molecules involved in signal transduction pathways and the actin cytoskeleton. We hypothesized that GCF2, together with Fli-1, plays a role in regulating cytoskeleton, cell migration, and/or morphology. In this study, we found that GCF2 represses the activation of small GTPase, RhoA, which is known as a key molecule in the regulation of the actin cytoskeleton. The expression of GCF2 in MCF-7 cells was transiently knocked down using the siRNA technique. Activated RhoA was detected with the GST-RBD pull-down assay. RhoA was markedly activated by repression of GCF2. To further investigate the mechanism for this repressive function, co-immunoprecipitation experiments were performed. We were able to identify dishevelled (Dvl), which is the key mediator for the Wnt-noncanonical pathway, as a binding partner with GCF2. Additionally, we found that all of the human Dvl family members; Dvl-1, Dvl-2, and Dvl-3, could bind to GCF2. Thus, we have found that GCF2 interacts with Dvl protein and regulates the activation of small GTPase, RhoA. These results strongly suggest that GCF2 plays a role in the Wnt-noncanonical planar cell polarity (PCP) signaling pathway. Consequently, GCF2 may regulate the cytoskeleton or migration via Dvl and RhoA.
A higher principle is at stake than simply freedom of speech
Authors: D. F Marks
Journal: BMJ (1996)

EDITOR,—John Roberts and Richard Smith suggest that the American Journal of Respiratory and Critical Care Medicine and the American Journal of Respiratory Cell and Molecular Biology should reverse their recent ban on research sponsored by the tobacco industry.1 They suggest that if some studies are systematically suppressed then we will reach false conclusions: “Because peer review cannot guarantee the validity of a study and because bias operates very subtly, many journals, including this one, print authors' funding sources alongside papers. By …
Dissemination of the multidrug-resistant extended-spectrum β-lactamase-producing Escherichia coli O25b-ST131 clone and the role of house crow (Corvus splendens) foraging on hospital waste in Bangladesh
Authors: B. Hasan, B. Olsen, A. Alam, L. Akter, Å. Melhus
Journal: Clinical Microbiology and Infection (2015)
Mortality in Portugal associated with the heat wave of August 2003: Early estimation of effect, using a rapid method
Authors: P J Nogueira, J M Falcão, M T Contreiras, E Paixão, J Brandão, I Batista
Journal: Eurosurveillance (2005)

During the first two weeks of August 2003, Portugal was affected by a severe heat wave. Following the identification in Portugal of the influence of heat waves on mortality in 1981 and 1991 (estimated excess of about 1900 and 1000 deaths respectively), the Observatorio Nacional de Saude (ONSA) - Instituto Nacional de Saude Dr. Ricardo Jorge, together with the Vigilancia Previsao e Informacao - Instituto de Meteorologia, created a surveillance system called iCARO, which has been in operation since 1999. iCARO identifies heat waves with potential influence on mortality [1]. Before the end of the 2003 heat wave, ONSA had produced a preliminary estimate of its effect on mortality. The results based on daily number of deaths from 1 June to 12 August 2003 were presented within 4 working days. Data was gathered from 31 National Civil registrars, covering the district capitals of all 18 districts of mainland Portugal, and representing approximately 40% of the mainland's mortality. The number of deaths registered in the period 30 July to 12 August was compared with the ones registered during 3 comparison periods: (in July): 1-14 July, 1-28 July, and 15-28 July). 15-28 July, the period best resembling the heat wave in time and characteristics, produced an estimation of 37.7% higher mortality rate then the value expected under normal temperature conditions. From this value, an estimate of 1316 death excess was obtained for mainland Portugal. The main purpose of this article is to present the method used to identify and assess the occurrence of an effect (excess mortality) during the heat wave of summer 2003.
A Randomized Trial of Prasugrel Versus Clopidogrel in Patients With High Platelet Reactivity on Clopidogrel After Elective Percutaneous Coronary Intervention With Implantation of Drug-Eluting Stents
Authors: Dietmar Trenk, Gregg W. Stone, Meinrad Gawaz, Adnan Kastrati, Dominick J. Angiolillo, Ulrike Müller, Gert Richardt, Joseph A. Jakubowski, Franz-Josef Neumann
Journal: Journal of the American College of Cardiology (2012)
Website of the week: Intelligence, schizophrenia, and the corporate industry
Authors: Marcus Müllner
Journal: BMJ (2001)

According to a paper in this week's BMJ (p 819), better childhood mental ability predicts a longer life. Hundreds of promising sites on the web will allow you to measure your intelligence, creativity, sexuality, or emotional intelligence www.selfgrowth.com/test.html is just one of the many collections of links. I tried several of these tests: some are fun, some are annoying (I wasted at least 15 minutes of my time on one, and the test finally didn't analyse my intelligent answers), and some are predictable (usually the creativity tests—click everything that would put off an average person, then you will always get a high score). If you like such tests try the Mensa workout (www.mensa.org). It's on the home page of Mensa, a society for bright people that welcomes “people from every walk of life whose IQ is in the top 2% of the population.”

I also encountered a mental health IQ test (www.mhasp.org/coping/mh_iq.html), which is, as you may imagine, a tool to create awareness of the issue of mental health. Furthermore, a higher IQ seems to protect you from schizophrenia. The source of this statement is a free encyclopaedia of mental health information (www.mentalhealth.com/book/p42-sc5.html#Head_5), but don't expect a thrilling site. It is hard to say how much of the information is grounded in the available evidence, but it is obvious that the authors took great pains to compile this website and make it accessible free of charge while refusing corporate sponsorship. Then look at one of the sites sponsored by “an unrestricted educational grant” (such as www.mhsource.com/schizophrenia). This provides almost everything you could expect from a website: a neat layout, interactivity, streaming audio and conference series slide shows. However, I would ask all doctors who enjoy this audiovisual pleasure to visit www.nofreelunch.org.