tbuckley/cabot-search huggingface dataset:
Antitumor effects of AR-42, a novel histone deacetylase inhibitor, in embryonal carcinoma.
Authors: A. S. Bhinder, V. Varma, B. Abbaoui, J. M. Thomas-Ahner, S. K. Kulp, C. Chen, S. K. Clinton, A. Mortazavi
Journal: Journal of Clinical Oncology (2011)

232 Background: Histone deacetylase inhibitors (HDACIs) modulate gene expression and induce cellular differentiation, growth inhibition and apoptotic cell death by chromatin hyperacetylation. Developmental arrest of germ cell differentiation earlier in the life is responsible for the pathogenesis of germ cell tumors (GCT). With current treatment nearly 95% of patients with GCT can be cured. Yet, effective agents with less toxicity are desired. In addition, those with relapsed/refractory disease have a dismal prognosis, indicating a clear need for new, more effective agents. Here we assess the antitumor effects of AR-42, a novel HDACI in in vitro and in vivo models of embryonal carcinoma. Methods: In vitro effects of AR-42 and suberoylanilide hydroxamic acid (SAHA) were evaluated in NTERA-2, an embryonal carcinoma (EC) cell line derived from a human testicular cancer. Cell viability (MTS assay), apoptosis (caspase 3/7 activity and PARP cleavage), cell cycle analysis (flow cytometry) and HDAC inhibition (immunoblotting) were assessed. The in vivo efficacy of AR-42 was assessed in a NTERA-2 xenograft tumor model in male athymic nude mice. Mice were fed control diet and diet containing AR-42 at an average dose of 25 mg/kg/day. Tumor volumes and weights were used as in vivo endpoints. Results: Treatment of NTERA-2 cells with both agents at 0.1-10 μM concentrations showed a time- and dose-dependent reduction in cell viability. Both agents significantly induced apoptosis, cell cycle inhibition and hyperacetylation of histones H-3 and H-4 in a dose-dependent manner. In vitro studies showed that AR-42 was more potent than SAHA. In our rodent model, AR-42-containing diet resulted in a significant reduction in tumor volumes and weights (50% and 56%, respectively). The results for intratumoral changes of proliferation and apoptosis are pending. There were no significant toxicities associated with AR-42, except for testicular atrophy, known to be reversible. Conclusions: AR-42 appears to be a potent inhibitor of EC through different mechanisms, orally bioavailable and well tolerated in our rodent model. Our data indicates that AR- 42 may have clinical value in the treatment of GCT and requires further investigation in clinical trials. No significant financial relationships to disclose.
Proteins as potential targets of apoptosis induced by chemopreventive isothiocyanates.
Authors: Lixin Mi, Xiantao Wang, Fung-Lung Chung
Journal: Cancer Research (2006)

5598   Dietary isothiocyanates (ITCs) like phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) are anti-carcinogenic agents. It has been shown that both cruciferous vegetable-derived compounds can inhibit lung adenoma and carcinoma formation in mice treated with tobacco carcinogens, possibly by inducing apoptosis (Yang YM  et al. Cancer Res. , 2002 and Conaway CC  et al., Cancer Res ., 2005). Studies by others have shown that oxidative DNA damage caused by ITCs may contribute to the induction of apoptosis. However, mechanisms involving direct protein or DNA binding by ITCs can not be ruled out. Using  14 C-PEITC and  14 C-SFN, we have investigated the material balance of ITCs in human non-small lung cancer cell line A549. Thirty μM of PEITC or SFN were incubated with A549 cells for up to 4 h. The results show that despite their similar initial uptake by cells, PEITC protein binding is more than four-fold that of SFN. More importantly, the amount of PEITC bound to protein increases from 7 nmole/mg protein at 30 min to 15 nmole/mg protein at 4 h, whereas the amounts of SFN bound to protein maintain relatively constant during the 4 h incubation (1.5 nmole/mg protein). Interestingly, no direct binding of ITCs to cellular DNA and RNA was detected. As previously reported the glutathione (GSH) conjugates of both PEITC and SFN as the main intracellular species are exported rapidly. Therefore at 4 h, PEITC-protein binding becomes the dominant (∼ 90%) intracellular reaction. Using bovine serum albumin (BSA) as a model protein, we confirmed that PEITC binds to protein several folds greater than SFN. The extent of protein binding appears to correlate with the potency of apoptosis induction by PEITC and SFN in A549 cells. By altering redox status to deplete glutathione in A549 cells with buthionine sulfoximine (BSO), we show again that the amounts of ITC bound to protein parallel the apoptotic activity of the ITC compounds. Together, these results suggest that proteins are potential targets of ITC, and its binding to proteins may underlie a mechanism for apoptosis. (NCI CA-100853).
Hepcidin Production in Ineffective Erythropoiesis and Chronic Hemolysis: Insights on the Crosstalk Between Erythropoiesis and Iron Metabolism
Authors: Kleber Yotsumoto Fertrin, Carolina Lanaro, Carla Fernanda Franco-Penteado, Dulcinéia Martins Albuquerque, Mariana Rezende Bandeira Mello, Marcos André Cavalcanti Bezerra, Betania Lucena Borges Tavares Domingues, Gordana Olbina, Sara T. Olalla Saad, Aderson S Araujo, Mark Westerman, Fernando Ferreira Costa
Journal: Blood (2011)
Natalizumab Blocks VLA-4 Mediated Red Blood Cell Adhesion and Is a Potential Therapy for Sickle Cell Disease
Authors: Patrick C. Hines, Sriram Krishnamoorthy, Jennell White, Dipti Gupta, Arjan van der Flier, Moira M. Lancelot, Robert T. Peters, Haiyan Jiang, William E Hobbs, David R. Light
Journal: Blood (2014)
The Effects of Secondary Cardiovascular Prevention on Cancer Risk in Patients With Manifest Vascular Disease
Authors: Rob C.M. van Kruijsdijk, Yolanda van der Graaf, Ale Algra, Gert Jan de Borst, Maarten J. Cramer, Peter D. Siersema, Petra H.M. Peeters, Frank L.J. Visseren, P.A. Doevendans, A. Algra, Y. van der Graaf, D.E. Grobbee, G.E.H.M. Rutten, L.J. Kappelle, T. Leiner, F.L. Moll, F.L.J. Visseren
Journal: Journal of the American College of Cardiology (2016)
Cost-effectiveness of three years of adjuvant imatinib in gastrointestinal stromal tumors (GIST).
Authors: Myrlene Sanon, Anju Parthan, Douglas Taylor, John Coombs, Marc Paolantonio, Medha Sasane
Journal: Journal of Clinical Oncology (2012)

137 Background: Recent clinical trial data have demonstrated that 3 years (yr) of adjuvant imatinib therapy for patients with surgically resected GIST leads to a significant improvement in recurrence free survival and overall survival vs. 1 yr of therapy. The objective of this study is to assess cost-effectiveness of treating with 3 yrs vs. 1 yr of adjuvant imatinib in the US from a payer’s perspective. Methods: A Markov model was developed to predict GIST recurrence, treatment (txt) costs, and quality-adjusted survival over a lifetime horizon. Patients transitioned between 3 health states: recurrence free GIST, GIST recurrence, and death. Monthly recurrence and mortality rates for 3 yr and 1 yr imatinib were derived from SSGXVIII/AIO clinical trial. The 5-yr recurrence rate observed in the trial was extrapolated for the remaining duration of the model horizon. First recurrence after active txt was treated with imatinib 400mg daily (800mg daily if recurrence during active txt). For subsequent disease progression, patients were treated with imatinib 800mg, sunitinib or best supportive care. After 5 years, txt specific mortality rate was applied for patients with recurrence. Costs and utilities were derived from published literature. Expected costs and quality-adjusted life years (QALYs) were estimated for each txt strategy. Costs and QALYs were discounted at 3% per yr. Extensive sensitivity analyses were conducted. Results: Total lifetime cost per patient was $302,100 with 3 yrs vs. $217,800 for 1 yr of imatinib therapy. Patients on 3 yrs of imatinib had higher QALYs (8.53 vs 7.18) vs. 1yr of imatinib. Incremental cost effectiveness ratio of 3 yrs of imatinib vs 1 yr of imatinib was $62,600/QALY. Model results were sensitive to rate of GIST recurrence beyond 5 yrs and monthly cost of adjuvant imatinib. At a threshold of $100,000/QALY, 3 yr imatinib therapy was cost-effective in 100% of simulations vs. 1 yr of imatinib. Conclusions: Model results suggest that treating patients with 3 yrs of imatinib is cost-effective vs. 1 yr of imatinib below the widely used $100,000/QALY threshold. Both clinical and economic results suggest treating surgically resected GIST patients with 3 yrs of imatinib would result in improved quality-adjusted and overall survival.
Abstract 5128: Changes in mitochondrial background affect nuclear DNA methylation
Authors: Carolyn J. Vivian, Amanda E. Brinker, Gerald C. Gooden, Christophe Legendre, Bodour Salhia, Danny R. Welch
Journal: Cancer Research (2015)

Abstract There is emerging evidence demonstrating that mitochondrial DNA (mtDNA) contributes to complex genetic diseases such as cancer. To test directly the role of mtDNA in tumorigenicity and metastasis, a new genetically engineered mouse model was created that contains nuclear DNA from one mouse strain and mtDNA contribution from different mouse strain(s). Taking advantage of maternal inheritance, Mitochondrial Nuclear Exchange (MNX) mice can be bred to mice sharing the same nuclear DNA background. As a result, MNX serves as an important tool to determine if and how mitochondrial genetic background contributes to cancer, negating the concern for mixing maternal and paternal nuclear DNA polymorphisms. MNX mice are healthy, breed normally, show no overt differences in cell cycle or apoptosis and are genetically stable for multiple (&amp;gt;10) generations. Nonetheless, they are distinct strains based upon behaviors and gene expression patterns. The mechanisms controlling gene expression in different MNX strains are not yet known; however, retrograde and anterograde cross-talk exists between the nuclear and mitochondrial genomes. Our hypothesis is that important epigenetic changes occur in the nuclear genome depending upon mitochondrial genetics. To test this hypothesis, we performed Meth-Seq using the Agilent Mouse SureSelect platform and Affymetrix gene expression arrays on four mouse brains (8 wk) that were pooled from different litters and cages of wild-type and MNX to minimize age, developmental, inter-individual and generational heterogeneity. Both differential DNA methylation and gene expression patterns were observed but analyses are ongoing to better define the observed differences. Together these observations provide novel insights into how mtDNA could be altering epigenetic regulation and thereby contribute to cancer pathogenesis. Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res., Kansas Bioscience Authority, Steiner Family Fund. Citation Format: Carolyn J. Vivian, Amanda E. Brinker, Gerald C. Gooden, Christophe Legendre, Bodour Salhia, Danny R. Welch. Changes in mitochondrial background affect nuclear DNA methylation. [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 5128. doi:10.1158/1538-7445.AM2015-5128
11 years of tracking aid to reproductive, maternal, newborn, and child health: estimates and analysis for 2003–13 from the Countdown to 2015
Authors: Christopher Grollman, Leonardo Arregoces, Melisa Martínez-Álvarez, Catherine Pitt, Anne Mills, Josephine Borghi
Journal: The Lancet Global Health (2016)

Tracking aid flows helps to hold donors accountable and to compare the allocation of resources in relation to health need. With the use of data reported by donors in 2015, we provided estimates of official development assistance and grants from the Bill & Melinda Gates Foundation (collectively termed ODA+) to reproductive, maternal, newborn, and child health for 2013 and complete trends in reproductive, maternal, newborn, and child health support for the period 2003-13.We coded and analysed financial disbursements to reproductive, maternal, newborn, and child health to all recipient countries from all donors reporting to the creditor reporting system database for the year 2013. We also revisited disbursement records for the years 2003-08 and coded disbursements relating to reproductive and sexual health activities resulting in the Countdown dataset for 2003-13. We matched this dataset to the 2015 creditor reporting system dataset and coded any unmatched creditor reporting system records. We analysed trends in ODA+ to reproductive, maternal, newborn, and child health for the period 2003-13, trends in donor contributions, disbursements to recipient countries, and targeting to need.Total ODA+ to reproductive, maternal, newborn, and child health reached nearly US$14 billion in 2013, of which 48% supported child health ($6·8 billion), 34% supported reproductive and sexual health ($4·7 billion), and 18% maternal and newborn health ($2·5 billion). ODA+ to reproductive, maternal, newborn, and child health increased by 225% in real terms over the period 2003-13. Child health received the most substantial increase in funding since 2003 (286%), followed by reproductive and sexual health (194%), and maternal and newborn health (164%). In 2013, bilateral donors disbursed 59% of all ODA+ to reproductive, maternal, newborn, and child health, followed by global health initiatives (23%), and multilateral agencies (13%). Targeting of ODA+ to reproductive, maternal, newborn, and child health to countries with the greatest health need seems to have improved over time.The increase in reproductive, maternal, newborn, and child health funding over the period 2003-13 is encouraging. Further increases in funding will be needed to accelerate maternal mortality reduction while keeping a high level of investment in sexual and reproductive health and in child health.Subgrant OPP1058954 from the US Fund for UNICEF under their Countdown to 2015 for Maternal, Newborn and Child Survival Grant from the Bill & Melinda Gates Foundation.
Clinical significance of anti-p53 antibody in the sera in patients with breast cancer.
Authors: Y. Yamamoto, S. Yamamoto, M. Ibusuki, M. Hayashi, M. Tomiguchi, K. Murakami, H. Iwase
Journal: Journal of Clinical Oncology (2011)

e11508 Background: Elevation levels of anti-p53 antibody in the sera can reflects intratumoral accumulation of p53 protein and p53 gene mutation. The aim of this study is to clarify the prevalence of serum anti-p53 antibody in patients with breast cancer and to assess its clinical significance in breast cancer. Methods: We examined serum anti-p53 antibody levels in 79 patients with ductal carcinoma in situ (DCIS), 384 patients with primary invasive breast cancer without distant metastasis (PIBC) and 59 patients with distant metastatic breast cancer (MBC), using an ELISA kit. We also studied the correlation between circulating levels of anti-p53 antibody and clinicopathological factors. Results: Median levels of anti-p53 is 0.40 U/ml (range; 0 – 4.3) in 205 healthy controls. Cut-off levels of anti-p53 were previously defined 1.3 U/ml. The elevated levels of anti-p53 were detected in 10 (12.6%) of 79 patients with DCIS, 63 (16.4%) of 384 patients with PIBC, 16 (27.1%) of 59 patients with MBC. Increased levels of anti-p53 were correlated with premenopausal patients (p=0.0003) and triple negative subtype (p=0.0364). Detection rates of breast cancer using CA15-3, CEA and anti-p53 antibody were 9.3%, 20.1% and 17.1%. Serum levels of anti-p53 antibody were not correlated those of CA15-3 and CEA although serum levels of CA15-3 is significantly correlated with those of CEA (p=0.0001). Conclusions: These findings suggest serum anti-p53 antibody may detect breast cancer not detected by CA15-3 and CEA such as triple negative subtype.
Metastatic renal cell carcinoma treated with pazopanib after progression on other targeted agents: A single-institution experience.
Authors: M. R. Matrana, B. J. Atkinson, P. G. Corn, E. Jonasch, N. M. Tannir
Journal: Journal of Clinical Oncology (2011)

351 Background: Pazopanib, a multityrosine kinase inhibitor (TKI), prolongs PFS compared to placebo in treatment-naive and cytokine refractory metastatic renal cell carcinoma (mRCC). No data has been reported about pazopanib salvage therapy after treatment with other targeted agents. Methods: We retrospectively reviewed the records of 88 consecutive patients (pts) with mRCC (median age 62.7, M:F 63/25, 84% clear cell) who received salvage pazopanib between 11/09-8/10. All pts failed previous treatment with one or more targeted agents (median number of prior targeted agents was 2, range 1-5; median time on previous treatments was 632 days). 78% of pts had progressed on sunitinib, 40% on sorafenib, 20% on temsirolimus, 51% on everolimus, and 26% on bevacizumab. 26% received previous chemotherapy and 16% received previous cytokines in addition to targeted therapies. 58% failed both TKI/VEGF inhibitors and mTOR inhibitors. 57% had intermediate-risk disease and 43% had poor-risk disease by MSKCC criteria. All pts had follow-up at least every 3 months after initiating pazopanib. Results: Median time to last follow-up was 114 days (range 30-278 days). 42% continued pazopanib at last follow- up. 25% had partial response (PR) by treating physician assessment. 50% failing 1-2 previous targeted therapies remained on pazopanib at last follow-up, compared to 27% of those failing more than 2 targeted therapies (p=0.04). 56% of pts with intermediate-risk disease by MSKCC criteria continued pazopanib at follow-up compared to 27% with poor-risk disease (p=0.002). 42% of those failing 1 prior targeted therapy achieved PR compared to 18% failing &gt;1 prior targeted therapy (p=0.02). 35% discontinued pazopanib due to progressive disease (PD) (median time to PD 71 days, range 36-198 days), 10% discontinued due to adverse drug events, and 10% died of PD on treatment. There were no treatment related deaths. Conclusions: In this retrospective study, pazopanib demonstrated clinically relevant activity in mRCC following PD with other targeted therapies. Mature survival data will be provided with final presentation. No significant financial relationships to disclose.
Risk factors of brain metastasis in a series of Egyptian breast cancer patients: A single-institution experience.
Authors: H. A. Azim, R. A. Malek, D. Abdelmonem, S. Amin, M. Abdelsalam
Journal: Journal of Clinical Oncology (2011)

50 Background: Incidence of cerebral metastasis is increasing among breast cancer patients. Many factors have been reported associated with increased risk of brain metastasis. The aim of this retrospective analysis is to investigate the predictive factors for the development of brain metastasis in breast cancer patients. Methods: We retrospectively analyzed histologically proven breast cancer patients who presented to Cairo Oncology Center (COC) in the period from 1999 till 2008, with follow up period of 6 months at least for those in adjuvant setting. The following factors were analyzed: age, tumor size and grade, nodal status, ER, PgR and HER2 over-expression status. Results: Our study included 2,338 patients. 96 patients (4.1%) experienced brain metastasis during the course of their disease. 3 patients had brain metastasis among other sites of distant spread at first presentation to COC. 30 out of 96 patients (31.25%) with localized breast cancer had brain metastasis at first relapse with 13 (13.5%) of them had isolated brain metastasis. In a median follow-up of 37.1 months (6-277) the median time to develop brain metastasis was 26.5 months (0-144). Based on univariate analysis, the following variables were associated with shorter time to develop brain metastasis: tumor size more than 5 cm (HR = 2.1, 95% CI 1.14-3.87), lymph node involvement at diagnosis (HR = 1.57, 95%CI 1.17-2.10), ER negativity (HR = 1.58, 95%CI 1.33-1.73), PgR negativity (HR = 1.55, 95%CI 1.29-1.72) and HER2-neu over-expression (HR = 2.68, 95%CI 1.51-4.75). On multivariate analysis, only patients with lymph node involvement at diagnosis and those with HER2-neu positive breast cancer were associated with shorter time to develop brain metastasis. Conclusions: We concluded that HER2 over-expression as well as lymph node involvement are the 2 main factors associated with shorter time to develop brain metastasis. These patients could be good candidates for trials investigating the role of any prophylactic intervention to decrease their risk to develop brain metastases.
DAPK2 and PIM1 Are Myeloma-Associated Antigens That Elicit Coordinated B and T Cell Immunity After Syngeneic HSCT.
Authors: Melinda Biernacki, Anselmo Alonso, Guanglan Zhang, Li Zhang, Wandi Zhang, Yu-Tzu Tai, Nikhil Munshi, Edwin P Alyea, Robert J Soiffer, Vladimir Brusic, Jerome Ritz, Kenneth C. Anderson, Catherine J Wu
Journal: Blood (2009)
Anticancer efficacy of natural withanolides in triple-negative breast cancer through down regulation of BRCA1, cell-cycle arrest, and induction of apoptosis.
Authors: X. Zhang, A. K. Samadi, R. Mukerji, B. N. Timmermann, M. S. Cohen
Journal: Journal of Clinical Oncology (2011)

291 Background: Triple negative breast cancer is often chemoresistant creating the need for novel improved drugs for this disease. Naturally derived withanolides such as withaferin A (WA) have shown potent preclinical efficacy in breast cancers. The purpose of this study is to better define the anticancer activity of WA and novel analogs(X001 and X003) containing a 19-OH substitution, in triple negative MDA-MB-231cells where BRCA1 is important for cell survival. Methods: Cells were treated with increasing doses of WA, X001, or X003 for 24 h. MTS and trypan blue exclusion assays were used to examine cell proliferation and viability. Cell cycle was examined using propidium iodide (PI) staining on flow cytometry (FC). Annexin-V/PI co-staining on FC was used to detect apoptosis. Western analysis was used to evaluate BRCA1 protein levels as well as to confirm apoptosis by PARP cleavage and caspase-3 activation. Results: X003, WA, and X001 inhibited MDA-MB-231 cell viability (IC 50 =125, 500 and 1300nM respectively). IC 50 level of WA induced G2/M phase cell cycle arrest while 2.5μM also induced apoptosis at 24 h as well as a significant decrease in both total and phospho-Akt protein levels. In addition, WA decreased BRCA1, heat shock factor 1, and mutant p53 protein levels in a dose-dependent manner. 2.5 μM of WA decreased BRCA1 protein levels by 75% compared to controls at 24 h (p&lt;0.01) while its natural analogs X003 and X001 induced apoptosis associated with BRCA1 down-regulation at 200nM (1.5xIC 50 ) and 6.5μM (5xIC 50 ) and a G2/M cell cycle arrest at only 50nM (50%IC 50 ) and 2μM (1.5xIC 50 ) respectively after 24 hours. Conclusions: Natural withanolides such as WA and its potent analog X003 demonstrate anticancer effects on triple negative breast cancer cells through cell cycle arrest, apoptosis and down-regulation of BRCA1 protein expression. Targeting BRCA1 in triple negative breast cancer with natural withanolides represents a novel approach for future translational studies in this difficult disease.
Report of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Infection in Four Patients with Hematological Malignancies Treated at King Fahad Medical City, Riyadh, Saudi Arabia
Authors: Ibraheem H Motabi, Syed Ziauddin A. Zaidi, Mamoun Hassan Ibrahim, Imran K Tailor, Nawal Faiez Alshehry, Mubarak S. AlGhamdi, Shahid Iqbal, Samer Mudaibigh, Fouad H Alnajjar
Journal: Blood (2016)