tbuckley/cabot-search huggingface dataset:
Abstract 5365: Alternating electric fields (TTFields) in combination with paclitaxel are therapeutically effective against ovarian cancer cells <i>in vitro</i> and <i>in vivo</i>
Authors: Mijal Munster, Christopher P. Roberts, Eva M. Schmelz, Moshe Giladi, Roni Blat, Rosa S. Schneiderman, Yaara Porat, Zeev Bomzon, Noa Urman, Aviran Itzhaki, Tali Voloshin Sela, Shay Cahal, Eilon D. Kirson, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2015)

Abstract Tumor Treating Fields (TTFields) are low intensity intermediate frequency alternating electric fields that disrupt mitosis. Our previous in vitro studies suggest that ovarian cancer cells are highly sensitive to TTFields treatment. The goal of the present study was to evaluate the efficacy of the combined treatment of TTFields and paclitaxel against ovarian cancer cells in vitro and in vivo. For in vitro studies, TTFields (1.75 V/cm) were applied for 72 hours using the inovitro system. The in vivo efficacy of the combined treatment was tested in C57Bl/6 mice, orthotopically injected with MOSE-L FFL luciferase positive cells. Finite Element Mesh (FEM) simulations were performed using the Sim4life software package (ZMT, Zurich, Switzerland) for the calculations of the electric fields intensities around the ovaries. Our results demonstrate that in vitro application of 200 kHz TTFields led to a significant reduction in both the number of viable cells (44.6%) and the clonogenic potential (23.8%) as compared to untreated cells (p&amp;lt;0.001). Further reduction in the number of viable cells was achieved when TTFields were combined with paclitaxel. In vivo, the combined treatment of TTFields and Paclitaxel led to a significant reduction in tumor luminescence (40%, p&amp;lt;0.01) and in the tumor weight (55%, p&amp;lt;0.05) as compared to untreated tumor bearing mice. FEM simulations demonstrated that electric fields intensities inside and in the vicinity of the ovaries of a real human anatomy model are about 1 and 2 V/cm RMS which is above the minimal threshold required for TTFields response. Taken together these results demonstrate that the combined treatment of TTFields and paclitaxel could serve as an effective treatment against ovarian cancer. A clinical trial testing the efficacy of the combined modalities is now underway. Citation Format: Mijal Munster, Christopher P. Roberts, Eva M. Schmelz, Moshe Giladi, Roni Blat, Rosa S. Schneiderman, Yaara Porat, Zeev Bomzon, Noa Urman, Aviran Itzhaki, Tali Voloshin Sela, Shay Cahal, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Alternating electric fields (TTFields) in combination with paclitaxel are therapeutically effective against ovarian cancer cells in vitro and in vivo. [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 5365. doi:10.1158/1538-7445.AM2015-5365
Sorafenib Combined with Non-Conventional Chemotherapy Produces Deep Remissions in FMS-like Tyrosine Kinase-3 Gene / Internal Tandem Duplication Positive (FLT-3 / ITD+) Acute Myeloid Leukemia (AML) Patients
Authors: Shripad Banavali, Nirav Thacker, Brijesh Arora, Gaurav Narula, Maya Prasad, Nirmalya Pradhan, Saroj Panda, Nikhil Patkar, Prashant Tembhare, Papagudi Ganesan Subramanian
Journal: Blood (2015)
Abstract 3613: P300 inhibition enhances cytotoxic effect of Gemcitabine through E2F1 activation in pancreatic cancer
Authors: Hiroaki Ono, Marc D. Basson, Hiromichi Ito
Journal: Cancer Research (2015)

Abstract Background: Transcriptional cofactor, P300 has been reported to regulate cell cycle on G1/S transition. Previously, we shown that prolonged S-phase is associated with increased apoptosis induced by Gemcitabine (GEM) in pancreatic cancer cells. Thus, we hypothesized that targeting P300 enhances the cytotoxic effect of GEM on pancreatic cancer. Methods: We studied 2 human pancreatic cancer cell lines, Panc1 and MIAPaCa2. P300 was gene-silenced using siRNA, and P300 histone acetyltransferase (HAT) activity was inhibited by specific inhibitor C646. Cell viability was measured by WST-8 assay and GEM-induced apoptosis was measured using Caspase3 and PARP by Western blotting, Tunel assay by immunofluorescence staining, and Annexin V-PI staining by flow cytometry. CDK4/6 inhibitor Palbociclib was used to block S-phase entry. Results: Robust P300 expression was observed in pancreatic cancer cell lines and human pancreatic adenocarcinoma tissues. When P300 expression was depleted by specific P300 siRNA, cell viability after GEM treatment was decreased significantly compared with the control pancreatic cancer cells (43% decrease in MIAPaCa2 and 39% decrease in Panc1, respectively, p&amp;lt;0.05). Increased GEM-induced apoptosis was confirmed by increased cleaved forms of Caspase3 and PARP, increased tunel positive cells, and increased Annexin positive cells in P300-depleted cells compared to the control cells. When S phase entry was blocked by Palbociclib, the effect of gene silencing of P300 on GEM-induced apoptosis was abolished. As Rb-E2F1 complex is known as the key regulator of the S phase specific gene transcriptions, we evaluated the effect of P300 gene silencing on Rb and E2F1. While P300 gene-silencing did not affect Rb phosphorylation after GEM treatment, it increased E2F1 expression significantly (56% increase in MIAPaCa2 and 119% increase in Panc1, respectively, p&amp;lt;0.05). When pancreatic cancer cells were treated with combination of GEM and C646, P300 specific HAT inhibitor, the cell viability was reduced significantly compared with when treated with GEM alone (48% decrease for Panc1, and 58% for MIAPaCa2, respectively, p&amp;lt;0.05). Conclusion: Targeting P300 by siRNA or HAT inhibitor enhances the efficacy of GEM on pancreatic cancer cells. Our observation suggests the presence of Rb-independent E2F1 regulatory mechanism in pancreatic cancer cells. This pathway may be an important therapeutic target to potentiate GEM chemotherapy in the treatment of pancreatic cancer. Citation Format: Hiroaki Ono, Marc D. Basson, Hiromichi Ito. P300 inhibition enhances cytotoxic effect of Gemcitabine through E2F1 activation in pancreatic 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 3613. doi:10.1158/1538-7445.AM2015-3613
Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study
Authors: Jürgen Braun, Xenofon Baraliakos, Atul Deodhar, Dominique Baeten, Joachim Sieper, Paul Emery, Aimee Readie, Ruvie Martin, Shephard Mpofu, Hanno B Richards
Journal: Annals of the Rheumatic Diseases (2016)

Objective To evaluate the effect of secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic changes through 2 years in patients with ankylosing spondylitis (AS). Methods In the phase III MEASURE 1 study, patients were randomised to receive intravenous secukinumab 10 mg/kg (at baseline, week 2 and week 4) followed by subcutaneous secukinumab 150 mg (intravenous 150 mg; n=125) or 75 mg (intravenous 75 mg; n=124) every four weeks, or matched placebo (n=122). Placebo-treated patients were re-randomised to subcutaneous secukinumab 150 or 75 mg from week 16. Clinical efficacy assessments included Assessment of SpondyloArthritis international Society 20 (ASAS20) response rates through week 104. Radiographic changes at week 104 were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Results 97 (77.6%) and 103 (83.1%) patients in the intravenous 150 mg and intravenous 75 mg groups, respectively, completed week 104. In the full analysis set (intent-to-treat), ASAS20 response rates at week 104 were 73.7% and 68.0% in the intravenous 150 mg and intravenous 75 mg groups, respectively. Among patients with evaluable X-rays who were originally randomised to secukinumab (n=168), mean change in mSASSS from baseline to week 104 was 0.30±2.53. Serious adverse events were reported in 12.2% and 13.4% of patients in the 150 mg and 75 mg groups, respectively. Conclusions Secukinumab improved AS signs and symptoms through 2 years of therapy, with no unexpected safety findings. Data from this study suggest a low mean progression of spinal radiographic changes, which will need to be confirmed in longer-term controlled studies. Trial registration number NCT01358175.
Abstract 502: Copy number alterations identify targeted therapies in preclinical models of osteosarcoma
Authors: Leanne C. Sayles, Marcus Breese, Alejandro Sweet-Cordero
Journal: Cancer Research (2015)

Abstract Osteosarcoma (OS) is an aggressive pediatric bone malignancy that affects 400 children per year in the United States. It has one of the lowest 5 yr. survival rates of any pediatric cancer. OS is characterized by genomic instability and numerous copy number alterations (CNA). We hypothesized that CNA may be drivers of OS and that targeting cancer genes with CNAs may be a novel approach for treatment of OS. We have established a robust approach for generation of patient-derived xenografts (PDX) from patients with OS. To date, 12 PDX have been established from OS patients. Using whole-genome sequencing (WGS), we have identified possible target CNAs for individual patients and are currently testing them in their corresponding PDX. In one patient, an amplification in c-myc suggested possible susceptibility to the bromodomain inhibitor JQ1. In a second patient sample, amplification of Cyclin D1 in the setting of p16 loss and wild-type Rb suggested responsiveness to a CDK4/6 specific inhibitor. This patient sample also has an Aurora kinase B amplification, suggesting susceptibility to inhibition of this kinase as a therapeutic approach. We treated the corresponding PDX with the drug predicted to target the patient sample based on CNA. In one case, JQ1 treatment inhibited tumor growth in the PDX generated from the patient sample with c-myc amplification. In the second case, Aurora kinase B inhibition arrested tumor growth in the PDX harboring the Aurora kinase B amplification. We are currently testing whether CDK4/6 inhibition is sufficient to inhibit tumor growth as predicted by WGS. As a follow up we are currently submitting several more patient samples and paired PDX for WGS as well as RNAseq to determine other potential targeted therapeutics based on CNA. In summary, our work suggests that WGS can be used to identify potential novel therapies for patients with OS. Further work will be needed to determine whether response in PDX models correlates with clinical response in patients. Citation Format: Leanne C. Sayles, Marcus Breese, Alejandro Sweet-Cordero. Copy number alterations identify targeted therapies in preclinical models of osteosarcoma. [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 502. doi:10.1158/1538-7445.AM2015-502
Reply:
Authors: Gonzalo Sapisochin, Jordi Bruix
Journal: Hepatology (2016)

Potential conflict of interest: Dr. Bruix consults, advises, and received grants from Bayer. He consults and advises Biocompatibles and Novartis. He consults and received grants from Daichi and Arqule. He consults for Abbott, Bristol‐Myers Squibb, GlaxoSmithKline, Kowa, Lilly, and Roche. We appreciate the interest of Dr. Gupta in our study. As mentioned in their letter, there are several aspects that need further research in the field of intrahepatic cholangiocarcinoma. Certainly one of these aspects is the issue of neoadjuvant treatments,1 as the authors raise in their letter; but our data set would not be robust enough to assess its role. In our study we offered the background to challenge the current exclusion of such patients, even if diagnosed at a very early stage, from transplant programs. Indeed, we are currently in the process of launching an international prospective trial testing the efficacy of transplantation for such patients. It is important to note that in most programs the diagnosis of cholangiocarcinoma is an exclusion criterion for such an option2 and, hence, there would be no added information from this effort.
Disabled Gene Is Involved in CML Progression and Its Expression Level at Diagnosis Can Predict Major Molecular Response (MMR) to Imatinib Therapy.
Authors: Daniela Cilloni, Francesca Arruga, Francesca Messa, Monica Pradotto, Enrico Bracco, Sonia Carturan, Chiara Maffè, Emanuela Messa, Antonia Rotolo, Elisabetta Greco, Ilaria Iacobucci, Roberto Bernardoni, Fabrizio Pane, Thea Kalebic, Giovanni Martinelli, Michele Baccarani, Giuseppe Saglio
Journal: Blood (2009)
Higher Rate of Thrombotic Thrombocytopenic Pupura (TTP) Associated with Graft Versus Host Disease (GVHD) and Unrelated Donor Bone Marrow Transplantation (BMT).
Authors: B. Oran, A. Aleman, E. J. Shpall, C. Hosing, M. Korbling, P. Anderlini, R. Champlin, M. Donato
Journal: Blood (2005)
Monitoring of Persons with Risk for Exposure to Ebola Virus — United States, November 3, 2014–December 27, 2015
Authors: Hyacinte Julien Kabore, Rodel Desamu-Thorpe, Lisa Jean-Charles, Karrie-Ann Toews, Rachel Nonkin Avchen
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

During November 3, 2014-December 27, 2015, CDC implemented guidance on movement and monitoring of persons in the United States with potential exposure to Ebola virus (Ebola) (1). Monitoring was concluded in December 2015. After CDC modified the guidance for monitoring travelers from Guinea (the last country for which monitoring of travelers was recommended) in late December 2015, jurisdictional reports were no longer collected by CDC. This report documents the number of persons monitored as part of the effort to isolate, test, and, if necessary, treat symptomatic travelers and other persons in the United States who had risk for exposure to Ebola during the period the guidance was in effect. Sixty jurisdictions, including all 50 states, two local jurisdictions, and eight territories and freely associated states, reported a total of 29,789 persons monitored, with >99% completing 21-day monitoring with no loss to follow-up exceeding 48 hours. No confirmed cases of imported Ebola were reported once monitoring was initiated. This landmark public health response demonstrates the robust infrastructure and sustained monitoring capacity of local, state, and territorial health authorities in the United States as a part of a response to an international public health emergency.
Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐<scp>5A</scp> inhibitor vardenafil in rats with type 2 diabetes
Authors: Csaba Mátyás, Balázs T. Németh, Attila Oláh, Marianna Török, Mihály Ruppert, Dalma Kellermayer, Bálint A. Barta, Gábor Szabó, Gábor Kökény, Eszter M. Horváth, Beáta Bódi, Zoltán Papp, Béla Merkely, Tamás Radovits
Journal: European Journal of Heart Failure (2016)

Abstract Aims Heart failure with preserved ejection fraction ( HFpEF ) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate ( cGMP ) signalling has been intensively investigated in HFpEF . Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long‐term preventive application of the phosphodiesterase‐ 5A ( PDE5A ) inhibitor vardenafil in diabetic cardiomyopathy‐associated HFpEF . Methods and results Zucker diabetic fatty ( ZDF ) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular ( LV ) pressure–volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro‐oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV /cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G ( PKG ) activity, increased nitro‐oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV /cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro‐oxidative stress, myocardial hypertrophy and fibrotic remodelling. Conclusions We report that vardenafil successfully prevented the development of diabetes mellitus‐associated HFpEF . Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus.
Combining different types of multifunctional liposomes loaded with ammonium bicarbonate to fabricate microneedle arrays as a vaginal mucosal vaccine adjuvant-dual delivery system (VADDS)
Authors: Ning Wang, Yuanyuan Zhen, Yiguang Jin, Xueting Wang, Ning Li, Shaohong Jiang, Ting Wang
Journal: Journal of Controlled Release (2016)
19. Using a Novel Combinatorial Non-Viral Vector and Small Molecules to Treat Familial Hypercholesterolaemia (FH)
Authors: Alastair G. Kerr, Lawrence Tam, Milena Cioroch, Ashley Hale, Gillian Douglas, Joe Mason, Carole Bataille, Graham Wynne, Angela Russell, Keith Channon, Richard Wade-Martins
Journal: Molecular Therapy (2016)

Familial hypercholesterolaemia (FH) is a life-threatening genetic disorder characterised by elevated levels of plasma low density lipoprotein cholesterol (LDL-C). Loss-of-function mutations in the gene encoding the low density lipoprotein receptor (LDLR) are responsible for ~85% of all FH cases. We have previously generated mini-gene vectors carrying the human LDLR cDNA, driven by 10 kb of genomic DNA from the native human LDLR locus, encompassing a promoter region with all essential elements required for physiologically regulated expression (pLDLR-LDLR). We demonstrated that incorporation of the genomic DNA promoter elements resulted in long-term physiologically-regulated LDLR transgene expression that complemented Ldlr deficiency. Here we further enhance LDLR transgene expression by characterising and cloning in a miRNA, targeting Hmgcr (miR82) generating a combinatorial RNAi-LDLR vector (pLDLR-LDLR-miR82). We show in vivo that the combinatorial vector efficiently suppresses endogenous Hmgcr transcripts, which leads to an increase in LDLR transgene expression through induction of the LDLR promoter. In a preliminary study the pLDLR-LDLR-miR82 vector was able to significantly reduce total and LDL-C, in Ldlr−/− mice fed a 1% cholesterol diet at two and four weeks post vector delivery. We then carried out a longer term study in Ldlr−/− mice fed a 0.25% cholesterol diet, LDLR expression could be detected 12-weeks post-delivery with the plasmid able to be rescued as a functioning episome. LDL-C was significantly lowered throughout the study and this resulted in reduced atherosclerosis in the pLDLR-LDLR-miR82 vector treated mice. Here we demonstrate for the first time, that an episomal non-viral vector is able to significantly reduce LDL-C and the progression of atherosclerosis in a mouse model of FH. Based on the success of the miRNA to further enhance the lipid lowering of our non-viral vector, we went on to screen small molecules which can drive the expression of the human LDLR promoter. 216 molecules were screened, where we identified a novel series of small molecules that increased the LDLR in human and mouse cell lines at nano molar potencies. We then went on to elucidate the mechanism of action as squalene synthase inhibitors and demonstrated, that when used in combination with statins, these compounds give a much greater increase in LDLR expression than statins alone. These small molecules could be used in conjunction with low dose statins, alongside our non-viral vector to further enhance expression of the LDLR and provide greater therapeutic outcome for patients of FH.
Abstract 3032: Genomic deregulation and therapeutic role of the cell-cycle kinase TLK2 in more aggressive breast cancers
Authors: Jin-Ah KIM, Ying Tan, Xian Wang, Xixi Cao, Jamunarani Veeraraghavan, Yulong Liang, Dean P. Edwards, Xuewen Pan, Kaiyi Li, Rachel Schiff, Xiaosong Wang
Journal: Cancer Research (2015)

Abstract More aggressive breast cancers often coincide with enhanced chromosomal instability (CIN), which poses a great challenge to clinical management. By integrative analysis of genomic data, we observed the amplification of tousled-like kinase 2 (TLK2), a cell cycle serine-threonine kinase, in approximately 9% of breast cancer, which is more frequent in the luminal B and late-stage breast tumors. The resulting TLK2 upregulation correlates with the level of CIN in breast tumors, and predicts worse outcome regardless of endocrine therapy. Further studies suggest that TLK2 overexpression leads to a G2/M checkpoint defect, delayed DNA repair, and enhanced invasiveness. TLK2 silencing selectively inhibits the growth of TLK2-high breast cancer cells, and induces apoptosis. This response is retained in the breast cancer cells with acquired endocrine resistance. TLK2 inhibition in a preclinical tumor model significantly improved progression-free survival. Together, targeting TLK2 presents an attractive therapeutic strategy on TLK2-amplified breast cancers. Citation Format: Jin-Ah KIM, Ying Tan, Xian Wang, Xixi Cao, Jamunarani Veeraraghavan, Yulong Liang, Dean P. Edwards, Xuewen Pan, Kaiyi Li, Rachel Schiff, Xiaosong Wang. Genomic deregulation and therapeutic role of the cell-cycle kinase TLK2 in more aggressive breast cancers. [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 3032. doi:10.1158/1538-7445.AM2015-3032
Evaluation of Cytokines Mobilizing Hematopoietic Progenitor Cells in Patients with Myelofibrosis with Myeloid Metaplasia (MMM).
Authors: Rita Campanelli, Margherita Massa, Valentina Meli, Vittorio Rosti, Isabella Ramajoli, Alessandro Pecci, Gian Luca Viarengo, Monia Marchetti
Journal: Blood (2004)