tbuckley/cabot-search huggingface dataset:
PO42A NOVEL POLYCOMB FEED FORWARD LOOP IN GLIOBLASTOMA
Authors: Barbara Ricci, Michael Barnes, Silvia Marino
Journal: Neuro-Oncology (2015)

INTRODUCTION: Glioblastoma (GBM) is the most common malignant adult brain tumour.Polycomb group proteins (PcG) are chromatin modifiers that maintain heritable gene repression.We recently showed that overexpression of the PcG gene Bmi1 (Bmi1Over) in murine neural stem cells (NSC) increased their proliferation and self-renewal without inducing glioma formation.However, downregulation of Bmi1 expression in GBM initiating cells (GBM-IC) severely impairs their proliferation, raising the possibility that Bmi1 plays a role in tumour maintenance rather than initiation.At the mechanistic level, we observed accumulation of H3K27me3 at the promoter region of selected functionally relevant target genes in both non-neoplastic and neoplastic context.METHOD: H3K27me3 ChIPSeq and RNASeq were performed on GBM-IC as compared to Bmi1Over NSC and controls.System biology analysis (IPA) and functional validation with qRT-PCR were carried out.RESULTS: 180 genes were uniquely marked for H3K27me3 in GBM-IC and their expression was downregulated as compared to both Bmi1Over and wild type NSC.121 of these genes had the peak in the extended promoter region.IPA analysis revealed significant enrichment in canonical pathways such as axonal guidance signalling, basal cell carcinoma signalling and Wnt signalling.Metaanalysis of a publicly available human GBM-IC ChIPSeq dataset confirmed similar deregulation of a proportion of the genes and pathways identified.CONCLUSION: Elucidating the molecular mechanisms of the epigenetic dysregulation observed in GBM is essential for the identification of novel biomarkers and also offers an opportunity to identify novel druggable targets or drug repositioning opportunities for more effective therapies.
Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells
Authors: Elena Binda, Alberto Visioli, Fabrizio Giani, Nadia Trivieri, Orazio Palumbo, Silvia Restelli, Fabio Dezi, Tommaso Mazza, Caterina Fusilli, Federico Legnani, Massimo Carella, Francesco Di Meco, Rohit Duggal, Angelo L. Vescovi
Journal: Cancer Research (2016)

Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical glioblastoma. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly infiltrating mesenchymal glioblastoma cells (Wnt5aHigh). Inhibiting Wnt5a in mesenchymal glioblastoma TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical glioblastoma TPC and Wnt5aLow mesenchymal TPC. In intracranial mouse xenograft models of glioblastoma, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in patients with glioblastoma. Cancer Res; 77(4); 996-1007. ©2016 AACR.
Delivering a Hemophilic Newborn with No Intracranial Hemorrhage: Is Caesarian Section the Answer?
Authors: Hanan Nazir, Tuqa Allawati, Ismail Elbeshlawi, Murtadha K. Al-Khabori, Sara Alkindi, Wafa Alriyami, Prof. Yasser Wali
Journal: Blood (2014)
Abstract 2542: Lurbinectedin (PM01183) synergizes in vivo the antitumor activity of doxorubicin in SCLC tumor xenografts
Authors: Maria Jose Guillen, Oscar Cataluña, Mandy Palomares, Raquel Lopez, Praxedes Nuñez, Carmen Cuevas, Pablo M. Aviles
Journal: Cancer Research (2015)

Abstract Background: Lurbinectedin (PM01183) is a synthetic tetrahydroisoquinoline alkaloid currently evaluated as single agent and in combination in phase I and II clinical trials for solid tumors and hematological malignancies. In living cells, PM01183-DNA adducts stall replication and transcription giving rise to double strand breaks, inducing accumulation of cells in the S-phase of the cell cycle and triggering apoptosis. Studies aimed at defining the in vivo synergism of PM01183 and doxorubicin in the treatment of Small Cell Lung Cancer (SCLC) xenografted tumors are presented here. Material and Methods: Athymic nude mice were implanted with SCLC cells (NCI-H82 or NCI-H526). Mice bearing tumors (ca. 150 mm3) were allocated (N = 6-8/group) to experimental groups, namely: placebo; PM01183 at MTD (0.18 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; doxorubicin at their MTD (8.0 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; and, PM01183 combined with doxorubicin at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) MTDs. All treatments were given intravenously once per week during the placebo-treated survival time. The antitumor effect induced by the treatments was analyzed using two-tailed Mann-Whitney U test. Also, the synergism was defined by the combination index (CI) determined by the CI-isobol method. Results: In both experiments, the combination of PM01183 and doxorubicin resulted in stronger antitumor effect (P&amp;lt;0.05) than that obtained with the more active single agent at the highest dose (MTD level). Analyses of the results by the CI-isobol method indicated that, after the treatment with PM01183 plus doxorubicin in the SCLC models resulted in an additive (at Fa = 0.97, CI = 1.05) or synergistic (at Fa = 0.97, CI = 0.66) effect. Conclusion: An improved (additive or synergism) in vivo antitumor activity was recorded after the treatment with PM01183 plus doxorubicin of mice bearing SCLC xenografted tumors. Citation Format: Maria Jose Guillen, Oscar Cataluña, Mandy Palomares, Raquel Lopez, Praxedes Nuñez, Carmen Cuevas, Pablo M. Aviles. Lurbinectedin (PM01183) synergizes in vivo the antitumor activity of doxorubicin in SCLC tumor xenografts. [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 2542. doi:10.1158/1538-7445.AM2015-2542
Left Ventricular Dysfunction With Trastuzumab Therapy: Is Primary Prevention the Best Option?
Authors: Paaladinesh Thavendiranathan, Eitan Amir
Journal: Journal of Clinical Oncology (2017)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 51-year-old women with left-sided, T2N1, grade 3, estrogen receptor- and progesterone receptor-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer was referred to a cardio-oncology clinic for pre-cancer treatment cardiovascular risk assessment. The planned cancer treatment was 3 cycles of FEC (fluorouracil, epirubicin [100 mg/m2 per dose], and cyclophosphamide), followed by 3 cycles of concurrent docetaxel and trastuzumab, followed by maintenance trastuzumab to complete a 1-year course. Other than a prior history of hysterectomy, there was no relevant medical history. Her cardiac history was notable for the absence of prior cardiovascular disease, hypertension, diabetes, or hypercholesterolemia. She was a nonsmoker. At initial clinic visit, her blood pressure was 138/84 with an unremarkable cardiovascular examination. Her echocardiography demonstrated normal sinus rhythm at 73 beats per minute. During cancer treatment, she was observed with echocardiography (baseline left ventricular ejection fraction [LVEF], 61%; global longitudinal strain, -21.5%), cardiac magnetic resonance imaging (CMR, as part of an ongoing study), high-sensitivity troponin I, and B-type natriuretic peptide ( Table 1 ). Given that her baseline evaluations were negative at her initial visit, we discussed whether there were agents to prevent the rare, but serious, complication of congestive heart failure (HF) associated with anthracycline- and trastuzumab-based therapy.
Abstract 682: Targeting heat shock protein 90 with ganetespib for molecularly targeted therapy of gastric cancer
Authors: Hanqing Liu, Jian Lu, Ye Hua, Peishan Zhang, Zhiquan Liang, Lingling Ruan, Caixia Lian, Haifeng Shi, Keping Chen, Zhigang Tu
Journal: Cancer Research (2015)

Abstract Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, due to its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib dramatically reduced growth of MGC-803 and also significantly inhibited growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected EGFR signaling cascades by dramatically decreasing levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, while SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Though SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of H&amp;E staining, TUNEL assays, and immunohistochemistry staining of pCDK1, EGFR, and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR. Note: This abstract was not presented at the meeting. Citation Format: Hanqing Liu, Jian Lu, Ye Hua, Peishan Zhang, Zhiquan Liang, Lingling Ruan, Caixia Lian, Haifeng Shi, Keping Chen, Zhigang Tu. Targeting heat shock protein 90 with ganetespib for molecularly targeted therapy of gastric 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 682. doi:10.1158/1538-7445.AM2015-682
Hypoxia and sterile inflammation in cystic fibrosis airways: mechanisms and potential therapies
Authors: Samuel T. Montgomery, Marcus A. Mall, Anthony Kicic, Stephen M. Stick
Journal: European Respiratory Journal (2016)

Cystic fibrosis is one of the most common autosomal recessive genetic diseases in Caucasian populations. Diagnosis via newborn screening and targeted nutritional and antibiotic therapy have improved outcomes, however respiratory failure remains the key cause of morbidity and mortality. Progressive respiratory disease in cystic fibrosis is characterised by chronic neutrophilic airway inflammation associated with structural airway damage leading to bronchiectasis and decreased lung function. Mucus obstruction is a characteristic early abnormality in the cystic fibrosis airway, associated with neutrophilic inflammation often in the absence of detectable infection. Recent studies have suggested a link between hypoxic cell death and sterile neutrophilic inflammation in cystic fibrosis and other diseases via the IL-1 signalling pathway. In this review, we consider recent evidence regarding the cellular responses to respiratory hypoxia as a potential driver of sterile neutrophilic inflammation in the lung, current knowledge on hypoxia as a pathogenic mechanism in cystic fibrosis and the potential for current and future therapies to alleviate hypoxia-driven sterile inflammation.
Improved Suicide Gene Therapy: Lentiviral Gene Transfer of Equine Herpes Virus Type 4 Thymidine Kinase into Target Cells.
Authors: Takeya Sato, Anton Neschadim, Vanessa I. Rasaiah, Manfred Konrad, Daniel H. Fowler, Arnon Lavie, Jeffrey A. Medin
Journal: Blood (2005)
Recombinant FIX/X-Bp from the Japanese Habu Snake Is a Universal Ligand for Purification of Highly Carboxylated Factor IX Variants and Factor X
Authors: Oblaise Mercury, Lucy Liu, Ayman Ismail, Ming Zhang, Qi Lu, Tom O Cameron, Allison Goodman, Liz Culyba, Rahul Ravindran Nair, Amy M Holthaus, John Kulman, Robert Peters
Journal: Blood (2015)
Plasma TS mRNA expression as a potential predictive biomarker for pemetrexed and raltitrexed in gastric cancer.
Authors: Baorui Liu, Jie Shen, Hao Wang, Jia Wei, Lixia Yu, Li Xie, Xiaoping Qian, Zhengyun Zou, Wen xian Guan
Journal: Journal of Clinical Oncology (2012)

e21034 Background: Plasma mRNA opens up new investigational opportunities and has great potential for use in disease and treatment assessment. Pemetrexed and raltitrexed are novel water-soluble quinazoline folate analogues and act as direct and specific TS inhibitors. Although TS expression levels detected in tumor have shown potential in predicting sensitivity to those two chemotherapeutic agents, current knowledge is limited on the role of plasma TS mRNA as a predictive biomarker. The aim of this study was to investigate the association between plasma TS mRNA expression and in vitro chemosensitivity to pemetrexed and raltitrexed in gastric cancer. Methods: 150 freshly-removed gastric tumor specimens and corresponding blood samples before surgery were collected. Pemetrexed and raltitrexed sensitivity was determined by histoculture drug response assay (HDRA) procedures. Plasma and tumor TS mRNA expression level were determined by quantitative RT-PCR. Results: A significant correlation was observed between plasma and tumor TS mRNA expression levels (rho=0.665, P&lt;0.001). Plasma TS expression level was negatively correlated with in vitro sensitivity to pemetrexed and raltitrexed in gastric cancer (pemetrexed-sensitive sub-group: 0.90, 95% CI: 0.66-1.16; pemetrexed-resistant sub-group: 1.82, 95% CI: 1.38-2.26, P&lt;0.001; raltitrexed-sensitive sub-group: 0.91, 95% CI: 0.64-1.22; raltitrexed-resistant sub-group: 1.62, 95% CI: 1.06-2.17, P=0.013). There was no significant association between clinical characteristics and plasma TS mRNA levels or in vitro chemosensitivity. Conclusions: Our results indicated that plasma TS mRNA expression could be a prominent predictive biomarker for raltitrexed in gastric cancer, enabling the development of ‘‘real-time’’ individualized chemotherapy while tumor progression.
Single Cell Microgel Based Modular Bioinks for Uncoupled Cellular Micro‐ and Macroenvironments
Authors: Tom Kamperman, Sieger Henke, Albert van den Berg, Su Ryon Shin, Ali Tamayol, Ali Khademhosseini, Marcel Karperien, Jeroen Leijten
Journal: Advanced Healthcare Materials (2016)

Modular bioinks based on single cell microgels within distinct injectable prepolymers enable uncoupling of biomaterials' micro- and macroenvironments. These inks allow biofabrication of 3D constructs that recapitulate the multiscale modular design of native tissues with a single cell resolution. This approach represents a major step forward in endowing engineered constructs with the multifunctionality that underlies the behavior of native tissues.
Antitumor Activity of RXDX-105 in Multiple Cancer Types with <i>RET</i> Rearrangements or Mutations
Authors: Gang G. Li, Romel Somwar, James Joseph, Roger S. Smith, Takuo Hayashi, Leenus Martin, Aleksandra Franovic, Anni Schairer, Eric Martin, Gregory J. Riely, Jason Harris, Shunqi Yan, Ge Wei, Jennifer W. Oliver, Rupal Patel, Pratik Multani, Marc Ladanyi, Alexander Drilon
Journal: Clinical Cancer Research (2016)

Purpose: While multikinase inhibitors with RET activity are active in RET-rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by RET alterations.Experimental design: The RET-inhibitory activity of RXDX-105 was assessed by biochemical and cellular assays, followed by in vivo tumor growth inhibition studies in cell line- and patient-derived xenograft models. Antitumor activity in patients was assessed by imaging and Response Evaluation Criteria in Solid Tumors (RECIST).Results: Biochemically, RXDX-105 inhibited wild-type RET, CCDC6-RET, NCOA4-RET, PRKAR1A-RET, and RET M918T with low to subnanomolar activity while sparing VEGFR2/KDR and VEGFR1/FLT. RXDX-105 treatment resulted in dose-dependent inhibition of proliferation of CCDC6-RET-rearranged and RET C634W-mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition in CCDC6-RET, NCOA4-RET, and KIF5B-RET-containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLCγ. Additionally, a patient with advanced RET-rearranged lung cancer had a rapid and sustained response to RXDX-105 in both intracranial and extracranial disease.Conclusions: These data support the inclusion of patients bearing RET alterations in ongoing and future molecularly enriched clinical trials to explore RXDX-105 efficacy across a variety of tumor types. Clin Cancer Res; 23(12); 2981-90. ©2016 AACR.
Abstract 11545: Moving to a Highly Walkable Neighborhood and Incidence of Hypertension: A Propensity-score Matched Cohort Study
Authors: Maria Chiu, Mohammad-Reza Rezai, Laura C Maclagan, Peter C Austin, Baiju R Shah, Donald A Redelmeier, Jack V Tu
Journal: Circulation (2015)

Introduction: Despite growing interest in the built environment and its impact on cardiovascular health, little is known about whether moving to a neighborhood more conducive to walking influences one’s risk of hypertension, a key risk factor of cardiovascular diseases. Objective: To conduct the first cohort study examining the association between moving to a highly walkable neighborhood and the risk of incident hypertension among a population-based sample of adults in Ontario, Canada. Methods: From the Canadian Community Health Survey (2001-2010), we identified a propensity-score matched cohort of 1057 pairs of Canadian adults who moved from a low (Walk Score&lt;90) walkability neighborhood to either a high (Walk Score≥90) or another low walkability neighborhood. The Walk Score (www.walkscore.com) is a walkability index shown to be valid in multiple geographic locations and at multiple spatial scales. The matched groups were well balanced on 16 important factors, including age, income, marital status and body-mass index. Incident hypertension was ascertained by linking the cohort to administrative health databases using a validated algorithm. Thyroid stimulating hormone testing and annual health examinations were used as the control events. Results: We observed a 42% lower risk of incident hypertension among those who moved from a low to high walkability neighborhood vs. those who moved from a low to another low walkability neighborhood (p=0.03) (Figure below). The incidence rate of hypertension was 8.6 per 1,000 person-years among the low to high walkability movers compared to 14.9 per 1,000 person-years among the low to low walkability movers. There were no significant differences in the control event rates between the two mover groups. Conclusions: Moving to a highly walkable neighborhood was associated with a significant protective effect on hypertension incidence, suggesting that the built environment can positively influence cardiovascular health.
ATIM-29. FIRST CLINICAL OBSERVATION OF IMPROVED ANTI-TUMOR EFFECTS OF VIRO-IMMUNOTHERAPY WITH ONCOLYTIC PARVOVIRUS H-1 IN COMBINATION WITH PD-1 CHECKPOINT BLOCKADE AND BEVACICUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Karsten Geletneky, Christian Weiss, Helga Bernhard, David Capper, Barbara Leuchs, Antonio Marchini, Jean Rommelaere
Journal: Neuro-Oncology (2016)

One emerging alternative concept for glioblastoma therapy is the use of oncolytic viruses that specifically target and destroy cancer cells. Parvovirus H-1 (H-1PV), an apathogenic oncolytic rodent DNA virus, was until recently tested as single agent in a phase 1/2a trial in patients with recurrent glioblastoma (ParvOryx01). One important finding was the capacity of H-1PV to induce a cellular anti-virus and anti-tumor immune response. A next step would therefore be to combine parvovirus treatment with immune therapy, in particular checkpoint blockade. Here we report on a series of 3 patients with recurrent glioblastoma who received H-1PV viro-immunotherapy based on a compassionate use (CU) agreement. Three patients (two male, one female, age 41, 47 and 49 years) with rapidly progressing recurrent tumors were treated by intratumoral and intravenous (n=2) or only intravenous (n=1) injection of H-1PV (cumulative dose 3,6E9 PFU) followed by bevacicumab (10mg/kg) and nivolumab (3mg/kg) every two weeks. In addition, two patients were re-irradiated (20Gy) prior to virus injection and all patients received valproic acid. H-1 virus was provided by the sponsor of the ParvOryx trial (Oryx GmbH&Co KG, Baldham, Germany) on a humanitarian basis. In all three patients this multi-modal combination treatment did not show any cerebral side effects. In contrast to previous experience all patients reported flu-like symptoms and mild fever after H-1PV infection. Temporarily, serum markers of inflammation were slightly elevated. MRI showed tumor regression in all three patients within four to eight weeks after virus injection. The radiological response was accompanied by clinical improvement in all three patients. Viro-immunotherapy based on H-1PV showed previously not reported induction of clinical and radiological responses in all treated patients. Even though the number of cases is small, this observation gives first clinical support for this novel concept in malignant glioma therapy.
Serum Neutrophil Extracellular Traps (NETs) Are a Potential Predictive Marker for Thrombotic Microangiopathy (TMA) After Allogeneic Stem Cell Transplantation
Authors: Yasuyuki Arai, Soichiro Sakamoto, Kouhei Yamashita, Kiyomi Mizugishi, Toshiyuki Kitano, Tadakazu Kondo, Hiroshi Kawabata, Norimitsu Kadowaki, Akifumi Takaori-Kondo
Journal: Blood (2012)
JAK2 (V617F)-Positive Essential Thrombocythemia and Polycythemia Vera Are Different Expressions Of a Genotypic/Phenotypic Continuum
Authors: Elisa Rumi, Daniela Pietra, Chiara Elena, Ilaria Casetti, Emanuela Sant 'Antonio, Cesare Astori, Chiara Milanesi, Marta Bellini, Emanuela Boveri, Virginia Ferretti, Cristiana Pascutto, Mario Cazzola
Journal: Blood (2013)