tbuckley/cabot-search huggingface dataset:
Abstract 812: Assessing combinations of FDA approved chemotherapy in childhood sarcoma cell lines
Authors: Diana Yu, Christopher Cubitt, Daniel Sullivan, Damon Reed
Journal: Cancer Research (2014)

Abstract Background: Sarcomas are a heterogeneous group of mesenchymal malignant tumors that make up approximately 15% of all childhood tumors and represent the fourth most common group of malignancies in children, remaining common in young adults with cancer as well. While over 35 agents have been FDA approved for adult carcinomas in the past 3 years, little progress has been made in incorporating new agents into the chemotherapy plans for pediatric sarcomas in the past few decades. A system to rapidly evaluate many agents and combinations of agents which can immediately be translated into clinical trials in a clinically relevant manner is needed. Methods: Here, we seek to examine the therapeutic activity of single agent and combinations of FDA approved chemotherapy agents using high-throughput screening platforms, based on well-established childhood cancer cell line models for most prevalent forms of pediatric bone sarcomas (osteosarcoma and Ewing sarcoma). Taking into consideration past lessons learned from in vitro experiments, we designed stringent screening conditions that assess the candidate compounds at clinically-relevant concentrations and time of exposures that mimic the in vivo pharmacokinetics in an effort to maximize the translational potential of these results to the clinical setting. Fifty-four agents, mainly FDA approved but also including agents with promising mechanism of action or preclinical data were screened across 5 cell lines for each histology. Caspace glo and cell titer glo assays were used to determine apoptosis and cell viability at the maximal achievable serum concentration from phase I studies and at two lower concentrations. Promising agents were then studied in 2 drug combinations to evaluate for synergy with careful attention to metabolism pathways, existing clinical data for combinations, and non-overlapping toxicities. Combinations of FDA approved agents with promising therapeutic efficacy and predicated non-overlapping toxicities will be translated to the clinic using the established Sunshine Project network. Results: Our screening results indicate that a number of FDA approved chemotherapy agents, evaluated at clinically relevant concentrations and exposure times, significantly reduced cell viability and induced up regulation of caspase3/7 activities across all cell lines. These findings suggest promising opportunities for developing combinational approach to treating childhood bone sarcomas and can be utilized to explore other pediatric tumors with existing cell lines. Citation Format: Diana Yu, Christopher Cubitt, Daniel Sullivan, Damon Reed. Assessing combinations of FDA approved chemotherapy in childhood sarcoma cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 812. doi:10.1158/1538-7445.AM2014-812
Abstract A30: Small molecule kinase inhibitor mediated modulation of immunotherapy in melanoma
Authors: Robert Suriano, Neha Tuli, Jan Geliebter, Raj K. Tiwari, Marc Wallack
Journal: Cancer Research (2015)

Abstract As the BRAFV600E mutation is observed in over 60% of melanomas, the development of the small inhibitor, PLX4032, which specifically targets mutated BRAF, represents a novel therapeutic approach. This targeted inhibition of BRAF effectively blocks activation of key signaling molecules of the mitogen activated protein kinase (MAPK) pathway, such as Mek and Erk, thus halting cell proliferation. In addition, since MAPK signaling targets the micropthalmia transcription factor (MITF), which is linked to the expression of various melanoma associated antigens (MAAs), we hypothesize that the inhibition of BRAFV600E can modulate the expression of MAAs thus serving as a viable target for immunotherapy of melanoma. Our lab has developed a vaccinia virus based immunotherapeutic vaccine using patient derived melanoma cell lines which express various MAAs. The melanoma cell lines have been characterized as far as the status of the BRAFV600E mutation and were found to be either homozygous or heterozygous for the mutation and are responsive to PLX4032, as evidenced by inhibition of two key MAPK pathway molecules, namely Mek and Erk. Phenotypically, the cells invasive and migratory properties were also modulated upon treatment with PLX4032. Interestingly was the observation that upon treatment with PLX4032, the expression of various MAAs was enhanced. Expression of gp100, MART-1, and tyrosinase increased both on the RNA level as well as on the protein level. The expression of MMAs were well maintained in vivo following the analysis of melanoma cell xenografts in BALB/c nude mice. We conclude that an effective multivalent immunotherapeutic vaccine requires the use of various MAAs and since PLX4032 upregulates expression of MAAs, further studies are warranted to determine the clinical effectiveness of combining BRAFV600E inhibitors with our melanoma cell line derived preparation. Citation Format: Robert Suriano, Neha Tuli, Jan Geliebter, Raj K. Tiwari, Marc Wallack. Small molecule kinase inhibitor mediated modulation of immunotherapy in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A30.
Abstract 3870: Effects of carbon ion beam, alone or in combination with cisplatin, on triple-negative breast cancer stem-like cells
Authors: Sei Sai, Kumiko Karasawa, Guillaume Gueal Vares, Toshiyuki Shirai
Journal: Cancer Research (2014)

Abstract Aims To investigate whether a carbon ion beam alone or in combination with cisplatin has beneficial effects compared to X-ray by targeting putative triple negative (TN) breast cancer stem cells (CSCs). Materials and Methods Human breast CSCs sorted from MDA MB231 cells were treated with carbon ion or X-ray irradiation alone or in combination with cisplatin, and then colony, spheroid and tumor formation assays, RT-PCR Array analysis as well as immunofluorescence γH2AX foci assay were performed. Results The colony, spheroid formation as well as tumorigenicity assays confirmed that CD44+/CD24- and CD44+/ESA+ cells exactly have CSC properties compared to CD44-/CD24- and CD44-/ESA- cells. CSCs were more highly enriched after X-ray or cisplatin compared to carbon ion beam. Carbon ion beam combined with cisplatin significantly suppressed colony and spheroid formation compared to that of X-ray combined with cisplatin as well as carbon ion alone. RT-PCR Array analysis showed that expression of DNA repair, apoptosis and autophagy related genes were differently altered between carbon ion beam and X-ray irradiation alone or in combination with cisplatin, and carbon ion beam combined with cisplatin more highly induced apoptosis and autophagy compared to X-ray combined with cisplatin. Immunofluorescence assay showed that not only the number but also the size of γH2AX foci in CSCs were lager 24 h after carbon ion beam combined with cisplatin compared to that of X-ray combined with cisplatin as well as carbon ion alone. Conclusion Carbon ion beam combined with cisplatin has superior potential to kill TN breast CSCs with unrepairable severe DNA damage and enhanced apoptosis as well as autophagy. Citation Format: Sei Sai, Kumiko Karasawa, Guillaume Gueal Vares, Toshiyuki Shirai. Effects of carbon ion beam, alone or in combination with cisplatin, on triple-negative breast cancer stem-like cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3870. doi:10.1158/1538-7445.AM2014-3870
When I use a word . . .: Cheque your spelling
Authors: J Aronson
Journal: BMJ (2000)

> ![Graphic][1]</img> Eye halve a spelling chequer;It came with my pea sea.It plainly marques four my revue Miss steaks eye khan knot sea. This poem, which has recently been circulating by email marked “Sauce unknown,” shows how important it is to check a hard copy of your word processed material. But I often see evidence that writers don't do this simple thing. Take, for instance, a reference to “Hypocrites” (in an article on ancient Greek medicine), or to “Ciba space” (drug companies on the internet?), and the description of an argument as being “full of significant floors” (wrong on many levels or just basically wrong?). The editor also tells me of a surfeit of … [1]: /embed/inline-graphic-1.gif
Abstract 15741: Long Term Survival Following Transcatheter Aortic Valve Replacement: Results From a Single US High Volume Center
Authors: Ricardo O Escarcega, Rebecca Torguson, Marco A Magalhaes, Nevin C Baker, Sa’ar Minha, Michael J Lipinski, Thibault Lhermusier, Hideaki Ota, Lowell Satler, Augusto Pichard, Itsik Ben-Dor, Ron Waksman
Journal: Circulation (2014)

Introduction: Mortality following Transcatheter aortic valve replacement (TAVR) has been reported up to 5 years. However, mortality after 5 years remains unclear. Hypothesis: We aim to determine the mortality in patients undergoing TAVR &gt;5 years follow up. Methods: From our institution’s prospectively collected TAVR database we analyzed all patients undergoing TAVR to a maximum follow up of 8 years. We divided our population into transapical TAVR (TA-TAVR) and transfemoral TAVR (TF-TAVR) groups. A Kaplan-Meier survival analysis was conducted. Results: A total of 511 patients who underwent TAVR were included in the analysis. Patients undergoing TA-TAVR had higher rates of peripheral vascular disease compared with TF-TAVR (56% vs 29%, p&lt;0.001) and Society of Thoracic Surgeons Score (10.9 ± 4 vs 9.2 ± 4, p&lt;0.001). TA-TAVR was associated with higher mortality at 1 year (32% vs 21%, p=0.01). However, there was no significant difference in very-long term mortality of patients undergoing TA-TAVR vs TF-TAVR (Figure). Conclusions: Long-term mortality following TAVR surpasses 50%. While in the first 2 years TA-TAVR is associated with higher mortality rates after three years the survival rates are similar in both approaches.
Lack of Evidence for Human Lymphokines with Thrombocyte Aggregating Activity
Authors: P. Oxholm, K. Winther, K. Bendtzen, G. Bendixen
Journal: Allergy (1984)

The ability of human lymphocytes to produce soluble mediator(s) with thrombocyte aggregating activity (TAA) was investigated in an in vitro technique. Isolated human mononuclear cells were stimulated with phytohaemagglutinin or purified protein derivative of tuberculin. The supernatants were investigated for lymphokine activity in a leucocyte migration inhibitory factor assay. Supernatants were then tested for their ability to aggregate human thrombocytes, and in contrast to the results of previous studies, we were not able to demonstrate any TAA. Most likely, lymphokines with TAA are not involved in the thrombotic processes seen in human cell‐mediated immune inflammatory reactions.
Abstract 3478: Differential level of L-homocysteic acid and lysophosphatidylcholine (16:0) in sera of patients with ovarian cancer
Authors: Yun Hwan Kim, Woong Ju, Seung Cheol Kim, Byong Chul Yoo
Journal: Cancer Research (2014)

Abstract Ovarian cancer (OVC) is one of the most difficult cancers to detection in the early periods of its development. Therefore there have been numerous attempts to find a biomarker for OVC, but an accurate diagnostic marker is yet to be discovered. In this study, we profiled OVC candidate metabolites from serum to find potential diagnostic marker for OVC. Information of low-mass-ions (LMIs) in serum was obtained by using MALDI-TOF. MALDI-MS analysis of each serum sample was repeated six times in order to reduce experimental errors. Intensity of LMI mass peak was normalized using total peak area sums. Normalized intensity of LMI was used in principal component analysis-discriminant analysis (PCA-DA) to discriminate 142 OVC from 100 controls. LC-MS/MS was used to identify the selected LMIs. Extracted ion chromatogram (EIC) analysis was used to measure the relative quantity of candidate metabolite from the LMI mass peak areas. The concentration of common metabolite in serum was determined by ELISA. Top 20 LMI mass peaks with weigh factor over 0.05 were selected to separate OVC from controls. Among them two LMIs with 184.05 m/z and 496.30 m/z were identified as L-homocysteic acid (HCA) and lysophosphatidylcholine (LPC) (16:0), respectively. Relative quantity of LPC (16:0) was decreased in OVC serum (P=0.05), whereas the amount of HCA was significantly higher in OVC serum (P&amp;lt;0.001). HCA was not detected in 59 cases out of 63 controls, but most cases of OVC (16 out of 25) showed significantly higher amount of HCA. When the cutoff was 10 nmol/ml, sensitivity and specificity of HCA were 64.0% and 96.9%, respectively. Level of LPC (16:0) was significantly correlated with tumor grade (P=0.045). Both HCA and LPC (16:0) showed correlation with stage and tumor histology, but limited sample number could not assign the statistical significance. HCA alone showed a potential power of biomarker for OVC. Even the stratified screening including LPC (16:0) did not significantly increase the power for OVC screening, our present study showed that a good example of profiling of LMIs in serum can be useful to select and identify candidate metabolites for OVC screening. Citation Format: Yun Hwan Kim, Woong Ju, Seung Cheol Kim, Byong Chul Yoo. Differential level of L-homocysteic acid and lysophosphatidylcholine (16:0) in sera of patients with ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3478. doi:10.1158/1538-7445.AM2014-3478
Growing Role for Umbilical Cord Blood
Authors: M J Friedrich
Journal: JAMA (2004)

BOSTON—Sixteen years after the first successful stem cells transplant using umbilical cord blood, cord blood has proved to be a viable alternative to bone marrow as a source of these lifesaving cells to treat a variety of diseases, according to clinicians and researchers who gathered here last month at the Sixth International Cord Blood Society Congress. Since that landmark effort in 1988, when cord blood donated by a sibling infused into a 5-year-old boy with Fanconi anemia resulted in a durable and functional graft (the former patient is now a healthy 21-year-old man), use of this type of transplant has grown dramatically, especially in children. Today, said experts presenting findings from clinical and laboratory studies, cord blood–derived stem cells are currently being used to treat a variety of malignancies (such as blood cancers and brain tumors) and rare genetic diseases and are showing some therapeutic potential for other conditions.
Abstract 4021: A kinome screen identifies SRPK1 to mediate breast cancer metastasis
Authors: Bob van de Water, Wies van Roosmalen, Sylvia L. Devedec, John Meerman, John Foekens, John Martens, Benny Geiger
Journal: Cancer Research (2014)

Abstract Tumor cell migration plays key role in cancer cell dissemination and metastasis and is controlled by signaling-mediated cytoskeletal and cell-matrix adhesion remodeling. Using a phagokinetic track (PKT) assay with migratory H1299 cells, we performed a siRNA screen of almost 1,500 genes encoding kinases/phosphatases, adhesome-related and migration-related proteins, with the aim of identifying genes that determine tumor cell migration speed, and persistence. Thirty candidate genes, showing significant effect were validated in live tumor cell migration assays, and eight of those had a significant association with metastasis free survival in breast cancer patients, ITGB3BP, MAP3K8, NEK2, SHC1 and SRPK1 being most significant . Further examination indicated that the expression of SRPK1, the most interesting gene identified in this screen , was highest in basal-like breast cancer and its expression level was correlated with poor disease outcome and preferred metastasis to the lungs and brain. In two independent breast tumor metastasis models, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver and spleen and inhibited focal adhesion reorganization. We provide here a comprehensive information resource on the molecular determinants of tumor cell migration and identify SRPK1 as a potential candidate drug target associated with breast cancer metastasis. Citation Format: Bob van de Water, Wies van Roosmalen, Sylvia Le Devedec, John Meerman, John Foekens, John Martens, Benny Geiger. A kinome screen identifies SRPK1 to mediate breast cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4021. doi:10.1158/1538-7445.AM2014-4021
Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy
Authors: Michael R. Zile, William T. Abraham, Fred A. Weaver, Christian Butter, Anique Ducharme, Marcel Halbach, Didier Klug, Eric G. Lovett, Jochen Müller‐Ehmsen, Jill E. Schafer, Michele Senni, Vijay Swarup, Rolf Wachter, William C. Little
Journal: European Journal of Heart Failure (2015)

Aims Increased sympathetic and decreased parasympathetic activity contribute to heart failure ( HF ) symptoms and disease progression. Carotid baroreceptor stimulation (baroreflex activation therapy, BAT ) results in centrally mediated reduction of sympathetic and increase in parasympathetic activity. Because patients treated with cardiac resynchronization therapy ( CRT ) may have less sympathetic/parasympathetic imbalance, we hypothesized that there would be differences in the response to BAT in patients with CRT vs. those without CRT . Methods and results New York Heart Association ( NYHA ) Class III patients with an ejection fraction ( EF ) ≤35% were randomized (1 : 1) to ongoing guideline‐directed medical and device therapy ( GDMT , control) or ongoing GDMT plus BAT . Safety endpoint was system‐/procedure‐related major adverse neurological and cardiovascular events ( MANCE ). Efficacy endpoints were Minnesota Living with Heart Failure Quality of Life ( QoL ), 6‐min hall walk distance ( 6MHWD ), N ‐terminal pro‐brain natriuretic peptide ( NT‐proBNP ), left ventricular ejection fraction ( LVEF ), and HF hospitalization rate. In this sample, 146 patients were randomized (70 control; 76 BAT ) and were 140 activated (45 with CRT and 95 without CRT ). MANCE ‐free rate at 6 months was 100% in CRT and 96% in no‐ CRT group. At 6 months, in the no‐ CRT group, QoL score, 6MHWD , LVEF , NT‐proBNP and HF hospitalizations were significantly improved in BAT patients compared with controls. Changes in efficacy endpoints in the CRT group favoured BAT ; however, the improvements were less than in the no‐ CRT group and were not statistically different from control. Conclusions BAT is safe and significantly improved QoL , exercise capacity, NTpro‐BNP , EF , and rate of HF hospitalizations in GDMT ‐treated NYHA Class III HF patients. These effects were most pronounced in patients not treated with CRT .
CD4 Cell Count and the Risk of AIDS or Death in HIV-Infected Adults on Combination Antiretroviral Therapy with a Suppressed Viral Load: A Longitudinal Cohort Study from COHERE
Journal: PLoS Medicine (2012)

Background Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. Methods and Findings Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements <50 copies/µl and ending with either a measurement >500 copies/µl, the first of two consecutive measurements between 50–500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30–0.40) for counts <200 cells/µl, 0.81 (0.71–0.92) for counts 200 to <350 cells/µl, 0.74 (0.66–0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92–0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. Conclusions Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl. Please see later in the article for the Editors' Summary
Abstract 1750: Combined blockade of Aurora A and JAK2 kinase is highly effective at inhibiting malignant transformation
Authors: Said M. Sebti, Hua Yang, Harshani Lawrence, Aslamuzzaman Kazi, Harsukh Gervaria, Ronil Patel, Yunting Luo, Uwe Rix, Ernst Schonbrunn, Nicholas Lawrence
Journal: Cancer Research (2014)

Abstract Our ongoing efforts to validate kinases for cancer therapy led to the novel finding that ectopic expression of JAK2 and Aurora A together is more effective than each alone at inducing normal cells to grow in an anchorage-independent manner and to invade. In addition, siRNA silencing or pharmacological inhibition of JAK2 and Aurora A with Ruxolitinib and Alisertib, respectively, is more effective than blocking each kinase alone at suppressing anchorage-dependent and -independent growth and invasion as well as at inducing apoptosis. This led us to develop dual Aurora and JAK inhibitors, AJI-214 and AJI-100, which potently inhibit the activities of Aurora A, Aurora B and JAK2 in vitro. In human cancer cells, these dual inhibitors block the auto-phosphorylation of Aurora A (Thr-288) and the phosphorylation of the Aurora B substrate histone H3 (Ser-10) and the JAK2 substrate STAT3 (Tyr-705). Furthermore, AJI-214 and AJI-100 inhibit anchorage dependent and independent cell growth and invasion and induce G2/M cell cycle accumulation and apoptosis. Finally, the more soluble AJI-100 was effective at inducing tumor regression of human xenografts in mice. Taken together, our genetic and pharmacological studies indicate that targeting Aurora A and JAK2 together is a more effective approach than each alone at inhibiting malignant transformation and warrant further advanced pre clinical investigations of dual Aurora A/JAK2 inhibitors as potential anti tumor agents. Citation Format: Said M. Sebti, Hua Yang, Harshani Lawrence, Aslamuzzaman Kazi, Harsukh Gervaria, Ronil Patel, Yunting Luo, Uwe Rix, Ernst Schonbrunn, Nicholas Lawrence. Combined blockade of Aurora A and JAK2 kinase is highly effective at inhibiting malignant transformation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1750. doi:10.1158/1538-7445.AM2014-1750
Plasma galectin 3 and heart failure risk in the <scp>P</scp>hysicians' <scp>H</scp>ealth <scp>S</scp>tudy
Authors: Luc Djoussé, Chisa Matsumoto, Andrew Petrone, Natalie L. Weir, Michael Y. Tsai, J. Michael Gaziano
Journal: European Journal of Heart Failure (2013)