tbuckley/cabot-search huggingface dataset:
Mutant IDH Sensitizes Gliomas to Endoplasmic Reticulum Stress and Triggers Apoptosis via miR-183-Mediated Inhibition of Semaphorin 3E
Authors: Ying Zhang, Stefan Pusch, James Innes, Kastytis Sidlauskas, Matthew Ellis, Joanne Lau, Tedani El-Hassan, Natasha Aley, Francesca Launchbury, Angela Richard-Loendt, Jasper deBoer, Sheng Chen, Lei Wang, Andreas von Deimling, Ningning Li, Sebastian Brandner
Journal: Cancer Research (2019)

Abstract Human astrocytomas and oligodendrogliomas are defined by mutations of the metabolic enzymes isocitrate dehydrogenase (IDH) 1 or 2, resulting in the production of the abnormal metabolite D-2 hydroxyglutarate. Here, we studied the effect of mutant IDH on cell proliferation and apoptosis in a glioma mouse model. Tumors were generated by inactivating Pten and p53 in forebrain progenitors and compared with tumors additionally expressing the Idh1 R132H mutation. Idh-mutant cells proliferated less in vitro and mice with Idh-mutant tumors survived significantly longer compared with Idh-wildtype mice. Comparison of miRNA and RNA expression profiles of Idh-wildtype and Idh-mutant cells and tumors revealed miR-183 was significantly upregulated in IDH-mutant cells. Idh-mutant cells were more sensitive to endoplasmic reticulum (ER) stress, resulting in increased apoptosis and thus reduced cell proliferation and survival. This was mediated by the interaction of miR-183 with the 5′ untranslated region of semaphorin 3E, downregulating its function as an apoptosis suppressor. In conclusion, we show that mutant Idh1 delays tumorigenesis and sensitizes tumor cells to ER stress and apoptosis. This may open opportunities for drug treatments targeting the miR-183–semaphorin axis. Significance: The pathologic metabolite 2-hydroxyglutarate, generated by IDH-mutant astrocytomas, sensitizes tumor cells to ER stress and delays tumorigenesis.
Adherence and patients’ attitude toward oral anticancer drugs: A prospective series of 226 patients focusing onto targeted therapies.
Authors: Philippe Barthelemy, Louis-Marie Dourthe, Sebastian Serra, Irene Asmane-De la Porte, Nathalie Prim, Shanti Ame, Valere Litique, Cathy Giron, Veronica Goldbarg, Luc Fornecker, Brigitte Duclos, Jean Emmanuel Kurtz
Journal: Journal of Clinical Oncology (2013)

e17543 Background: Patients’ adherence has been identified as a challenge in oncology and hematology practice. Hormone therapy data in breast cancer suggest insufficient adherence and poor persistence. Limited data is available for targeted therapies such as tyrosine kinase (TK) and mTOR inhibitors whereas poor adherence to TK treatment was linked to treatment failure in GIST and CML. Methods: We report the result of a prospective survey in 226 patients (pts), with solid tumors and hematologic malignancies receiving oral anticancer therapy including chemotherapy or hormone therapy (CT), and targeted therapies (TT). Treatment duration and setting (adjuvant vs metastatic), cancer type, age, co-medication were analyzed. Patients were given a 15-item questionnaire and asked to anonymously answer questions regarding their attitude towards oral anticancer drugs. To analyze adherence, patients were asked whether they voluntarily or not missed any drug dosing during the last month. Results: 226 patients (median age 65.5 y.o) participated, 115 with TT and 111 with CT, with a median time of drug intake of 10.5 months. Both TT and CT patients stated to be well informed about treatment modalities in (92%), mostly by their oncologist or hematologist (87%). Written information was more frequently given in TT pts (67.0 vs 27.0%, p&lt;0.0001). TT pts declared to be more often fully adherent to therapy (84.3 vs 66.7%, p=0.01) despite experiencing more side-effects (p&lt;0.0001) and taking more concomitant oral medication (p=0.029). The mean treatment duration was 28.0 vs 20.3 months in TT vs CT pts (NS), but in both groups non-adherence was observed at any time since initial prescription. Conclusions: Despite advances in patients’ information leading to better treatment adherence in TT pts, efforts are still warranted such as the onset of dedicated staff for early and prolonged monitoring of outpatient anticancer oral therapy.
A case report of long-term complete remission following cessation of romiplostim dosing in a previously severe ITP patient.
Authors: Allison Ashley Baxley, James N George, Deirdra Terrell, Meredith Moorman, Jennifer L. Holter
Journal: Journal of Clinical Oncology (2012)

e17001 Background: Primary Immune thrombocytopenia(ITP) is a chronic autoimmune disorder characterized by low platelet counts and bleeding complications. Platelet destruction together with insufficient platelet production occur through an antibody-mediated process and early treatment options revolve around targeting antibodies and immunologic pathways. Such therapies may not produce long-term responses and may be accompanied by considerable adverse effects which can lead to complications and/or drug discontinuation. Romiplostim is a thrombopoietic agent that stimulates platelet production and offers an alternative method for treatment of patients with ITP. In clinical trials, patients have achieved durable platelet count responses without clinically important side effects. Methods: We report the case of a 44 year-old female with refractory ITP who has achieved successful remission following treatment with romiplostim. Results: As previously described in Haematologica (2008;93:1445) this patient presented with purpura, menorrhagia, and a platelet count of 7,000. Throughout 2005 she had only transient responses to high dose dexamethasone, intravenous immunoglobulin, rituximab, and splenectomy. She was placed on romiplostim in August 2005 as part of a clinical trial and received a dose of 7 mcg/kg/week for approximately 50 weeks. She was able to tolerate dose reductions and by May 2007 her dose had been de-escalated to 3 mcg/kg/week, which she continued through 2009 as part of an open-label continuation study. In January 2010, after completion of the clinical trial, she began receiving romiplostim by prescription. She was able to gradually tolerate extended dosing intervals due to sustained platelet response. Her last dose was administered on October 27, 2010 and she has maintained a platelet count above 197,000 without further therapy. Conclusions: This case represents, to our knowledge, one of the longest maintained durable responses to romiplostim therapy. Romiplostim provides an alternative approach of treatment for ITP, and as evidenced by this case report, in some patients it may also lead to disease remission and eliminate the need for further treatment.
Socioeconomic status as an independent prognostic factor in node negative, stage I-II breast cancer patients
Authors: I. Zeichner-Gancz, D. E. Munoz-Gonzalez, V. M. Pérez Sánchez, C. Castillero, M. Ramirez-Ugalde
Journal: Journal of Clinical Oncology (2007)

21129 Background: Many prognostic factors for breast cancer are known, of those, clinical , histological, genetical and the socioeconomic status are considered important for the outcome of these patients. The objective of our study vas to evaluate the Socioeconomic status as an independent factor for survival Methods: Clinical records of node negative clinical stage I- II patients treated at the institution from 1980 to 1996 were reviewed . We included those initially treated with surgery, available paraphine blocks, follow up of at five years (the ones that had no recurrence). They were divided in two groups: 1: Lower socioeconomic status, economically deprived and 2: medium low to high status. The slides were reviewed s and the blocks were processed for immuno-histochemistry: steroid receptors, Her-2, p 53 and CD 34. The analysis was performed with X 2 , , t test and log rank for difference in survival Results: A total of 81 patients were studied, 35 in group 1, and 46 in group 2. Mean age for groups 1 and 2 was of 52 (28–74) and 52.9 (28–83) years respectively (p=0.39). Were stage I in group 1 8, II-28. In Group 2 were stage I, 12, II-34 (p=0.87). Patients in both groups were treated with surgery alone, with radiotherapy, chemotherapy and/or hormone therapy, without statistical significance for treatment.Vascular or lymphatic permeation was observed in 20 and 22 patients from groups 1 and 2 respectively (p=0.40). Mean SBR was of 7.2 and 7.1 respectively for groups 1 and 2 (p=0.54) Estrogen receptor was present in 10 and 11 patients (p=0.63) and progesterone receptor in 8 and 6 (p0.25) for each group. Her-2 was over expressed in 12 and 17 patients from group 1 and 2, p53 in 6 and 14 respectively (p=0.17)and CD34 in 7 and 6 for both groups respectively ( p=0.40). Median survival was of 225 months for group 1 and not reached at 243 months for group 2, with 90.22% alive, p= 0.005 Conclusions: According to our results, in this group of well studied patients, the only significant factor observed that had an impact over survival was the socioeconomic status. None of the clinical, histological or genetical variables showed significance. We think that prospective studies with special emphasis on the socioeconomic status have to be carried out in order to try to explain the differences that we observed. No significant financial relationships to disclose.
Analysis of nerve growth factor (NGF) blood levels in patients with advanced non-small cell lung cancer patients (NSCLC): Its correlation with clinical outcome
Authors: A. Blasco, R. Sirera, C. Camps, V. Giner, L. Llobat, M. J. Safont, A. Berrocal, M. Taron, J. J. Sanchez, R. Rosell
Journal: Journal of Clinical Oncology (2006)

17025 Background: Platinum compounds and taxanes have severe side effects in a dose and time-dependent manner, especially neurotoxicity. NGF plays an important role in growth and differentiation of neuronal components. Our goal was to study NGF levels in plasma and correlate it with patient’s clinico-pathologic characteristics. Methods: The study was performed with 451 patients with advanced NSCLC, stages IIIB-IV and treated with cisplatin and docetaxel. Peripheral blood was collected before therapy. NGF were assessed by commercial ELISA (detection limit, 5 pg/ml). Plasma from 32 age and gender-matched controls was used. Results: 91% of males, mean age 61 y [35–82]. 86 patients in ECOG PS 0–1 and 14 PS2. 71% in stage IV and 29% in IIIB. The histological subtypes were 38% squamous cell, 37% adenocarcinoma, 5% anaplasic large cell and 20% undifferentiated. 77.5% of the metastasis was out of the lung. Patients received a median of 6 cycles of chemotherapy [1–7]. 4% presented complete response (CR), 38% partial response (PR), 25% stable disease (SD) and 30% progressive disease (PD). Patient’s median plasma levels of NGF did not differ significantly from controls: 44 pg/ml [6–176] vs 31 pg/ml [14–144] respectively. There were not differences according to histology, site of metastasis and ECOG; however we could observe significant differences with stage: 25 pg/ml [10–70] in stage IIIB vs 47 pg/ml [6–176] in stage IV (p = 0.008). We could not observe any differences in response to therapy: CR+PR patients presented median NGF of 35 pg/ml [6–92] vs 39 pg/ml [10–165] in the SD+PD group. Splitting the cohort according to NGF median we found two significantly different groups in terms of Overall Survival (OS): patients with NGF &lt;44 pg/ml had a median OS of 10.9 months (m) [7.9–13.9] vs 7.3 m [3–11.5] for patients with NGF &gt;44 pg/ml (p = 0.03). In the multivariate analysis, NGF levels was not predictor for time to progression (TTP) and OS. Conclusions: NGF plasma levels did not differ in patients and controls. In our cohort with advanced NSCLC we have not found any relationship between NGF levels with histology, response, site of metastasis and TTP. By contrast NGF levels are higher in those patients in stage IV and in those presenting poorer OS. No significant financial relationships to disclose.
Outpatient chemotherapy supportive care: Trial of an IT-integrated, NP-delivered system for unrelieved symptoms.
Authors: Kathi Mooney, Susan L. Beck, Bob Wong, William A. Dunson, Debra Wujcik
Journal: Journal of Clinical Oncology (2012)

9137 Background: We tested an automated computer based remote monitoring system paired with nurse practitioner (NP) follow up using a case management system to address unrelieved symptoms. Methods: Prospectively 336 patients beginning a course of chemotherapy were randomized to the Telephone Care NP (TC) intervention (n 174) or usual care (UC) (n 162). All called daily reporting presence, severity, and distress (0-10 scale) for 11 common symptoms. Those in the TC intervention also received automated tailored symptom self-care messages and, based on automated alerts for unrelieved symptoms at moderate or higher levels, NP calls to further treat symptoms utilizing national guidelines. Results: There were no differences between groups on any demographics: 84% White, 56 years old, female (77%), breast (45%) or lung (17%) cancer. Average study days were 73 with 87% call completion. Prevalence of participants reporting moderate to severe symptoms were fatigue (86%), pain (80%), sleep (78%), nausea (60%), depressed mood (52%), anxious (49%), trouble thinking (48%), numbness (43%), sore mouth (38%), diarrhea (38%), and appearance concerns (35%). Mixed modeling with intention to treat was used to compare overall symptom scores by treatment condition (TC/UC) while accounting for individuals. Results indicate the TC group mean symptom score was significantly lower than UC (mean difference = .30, p &lt; .001). Also, each symptom was significantly lower for the TC group except for diarrhea. Poisson regression showed TC had lower Severe days than UC (est. means and SE) 3.16 (0.44) vs 10.24 (1.84), p &lt; .001; and lower Moderate days 8.91 (1.04) vs 19.06 (2.22), p &lt; .001. TC had somewhat higher Mild days than UC 19.85 (2.81) vs 13.75 (1.85), p = .06; and more No symptom days 66.06 (3.82) vs 52.02 (4.15), p = .01. Mixed modeling was used to explore TC intervention impact following NP calls for alerts. TC reduced symptom scores compared to UC over a 4 day period (mean difference = 1.28, p&lt; .001). Conclusions: Remote telephone monitoring of symptoms after chemotherapy with nurse practitioner follow up on moderate and severe symptoms results in decreased symptom severity, distress, fewer severe and moderate days and more no symptom days.
Randomized phase II trial of erlotinib (E) plus high-dose celecoxib (HD-C) or placebo (P) in advanced non-small cell lung cancer.
Authors: Karen L. Reckamp, Marianna Koczywas, Mihaela C. Cristea, Jonathan Dowell, Brian Gardner, Ginger L Milne, Robert A. Figlin, Robert M. Elashoff, Steven M. Dubinett
Journal: Journal of Clinical Oncology (2012)

7518 Background: Cyclooxygenase-2 (COX-2)-dependent signalling represents a potential mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in NSCLC. This is mediated in part through an EGFR-independent activation of MAPK/Erk by the COX-2 metabolite PGE2. In addition, PGE2 promotes downregulation of E-cadherin and epithelial to mesenchymal transition. We hypothesize that EGFR and COX-2 inhibition with E and HD-C will augment EGFR TKI efficacy by increasing tumor E-cadherin expression and blocking PGE2-mediated resistance to EGFR inhibition. Methods: Pts with stage IIIB/IV NSCLC who progressed following at least one line of therapy or refused standard chemotherapy were randomized to E (150mg/day)/HD-C (600mg/2x day) vs E/P in a 28-day cycle. Pts were stratified by smoking status and ECOG PS. The primary endpoint was PFS with 80% power to detect a 50% improvement; assessments were performed every 2 cycles. Secondary endpoints included response rate, OS and evaluation of molecular markers in tissue and serum to assess targeting COX-2-related pathways and evaluate EGFR TKI-resistance. All pts were required to have pre-treatment tissue available. Results: 107 pts were enrolled with comparable baseline characteristics in both arms. Disease control rate (DCR) was similar in both arms, and a trend toward improved PFS was seen in the E/HD-C arm with HR 0.81 (see Table). Analysis of those with EGFR wild type revealed a significantly increased PFS while those with EGFR mutation had similar PFS in both groups. Safety analysis showed similar toxicity in both arms. Additional biomarker correlations will be presented. Conclusions: The combination of E/C in metastatic NSCLC with HD-C is well tolerated and demonstrates significantly improved efficacy in EGFR wt population. This warrants further study into the COX-2-dependent mechanisms of primary resistance to EGFR TKI therapy. Supported by NIH 1P50 CA90388, K12 CA01727 and medical research funds from the Dept of Veterans’ Affairs. [Table: see text]
Clinical and virological characteristics of human infections with H7N9 avian influenza virus in Shenzhen, China, 2013–2017
Authors: Yang Yang, Chenguang Shen, Jin Li, Rongrong Zou, Gary Wong, Ling Peng, Liuqing Yang, Shisong Fang, Jianming Li, Xiaohe Li, Weibo Wu, Xiao Jiang, Lijiao Zeng, Jianfeng Lan, Yuhai Bi, George F. Gao, Jing Yuan, Yingxia Liu
Journal: Journal of Infection (2019)
Genetic determinants of VWF clearance and FVIII binding modify FVIII pharmacokinetics in pediatric hemophilia A patients
Authors: Laura L. Swystun, Kenichi Ogiwara, Orla Rawley, Christine Brown, Ilinca Georgescu, Wilma Hopman, Veerle Labarque, Christoph Male, Katharina Thom, Victor S. Blanchette, Manuel D. Carcao, David Lillicrap
Journal: Blood (2019)
Abstract 5294: The PanNET-related histone H3.3 chaperone Daxx regulates lineage specification and tissue homeostasis in the pancreas
Authors: Teresa Sposito, Marie-Sophie Nguyen Tu, Guy A. Rutter, Marco Novelli, Chrissie Thirlwell, Paolo Salomoni
Journal: Cancer Research (2019)

Abstract Progressive age-dependent replacement of canonical H3.1/2 with H3.3 in post-mitotic cells is a crucial mechanism for maintaining genome integrity at heterochromatic sites. The histone chaperone DAXX cooperates with the chromatin remodeller ATRX for the deposition of the non-canonical histone H3.3 at heterochromatin, while it prevents the expression of endogenous retroviral elements in another complex involving the SETDB1 methyltransferases. Loss of function mutations affecting ATRX/DAXX and MEN-1 have been recently identified as a subgroup of pancreatic neuroendocrine tumours (PanNETs) leading to poor prognosis and more aggressive phenotype compared to the ATRX/DAXX and MEN-1 wild-type counterparts. We developed a mouse model for conditional Daxx inactivation in mouse islets to understand the impact of DAXX loss on pancreas homeostasis and PanNETs development. We found that loss of Daxx in the endocrine pancreas, using the Insulin-1Cre driver, leads to aberrant glucose metabolism with the development of hyperglycemia and consequently insulin resistance in mice. We have also shown that loss of DAXX is linked to increased expression of α-cell lineage genes upon glucose stimulation of isolated islets in vitro, resembling the recently reported phenotype of PanNETs harboring ATRX/DAXX or MEN1 mutations. Nonetheless, loss of Daxx was not sufficient to lead to PanNET development. We are currently investigating the chromatin and transcriptional perturbations caused by Daxx loss and how these could be linked to the aberration of cell lineage specification and tissue dysfunction in the pancreas. More generally, this work will provide new insight into how epigenetic alterations contribute to misregulation of developmental programmes and cancer development in the pancreas. Citation Format: Teresa Sposito, Marie-Sophie Nguyen Tu, Guy A. Rutter, Marco Novelli, Chrissie Thirlwell, Paolo Salomoni. The PanNET-related histone H3.3 chaperone Daxx regulates lineage specification and tissue homeostasis in the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5294.
Detection of Novel NRG1, EGFR, and MET Fusions in Lung Adenocarcinomas in the Chinese Population
Authors: Yunjian Pan, Yang Zhang, Ting Ye, Yue Zhao, Zhendong Gao, Hui Yuan, Difan Zheng, Shanbo Zheng, Hang Li, Yuan Li, Yan Jin, Yihua Sun, Haiquan Chen
Journal: Journal of Thoracic Oncology (2019)
Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses
Authors: P. Kent Langston, Aya Nambu, Jonathan Jung, Munehiko Shibata, H. Ibrahim Aksoylar, Jiahui Lei, Peining Xu, Mary T. Doan, Helen Jiang, Michael R. MacArthur, Xia Gao, Yong Kong, Edward T. Chouchani, Jason W. Locasale, Nathaniel W. Snyder, Tiffany Horng
Journal: Nature Immunology (2019)
Abstract 18349: A Pilot Study to Evaluate the Feasibility and Safety of Transendocardial CD34+ Cell Therapy in Heart Failure With Preserved Ejection Fraction
Authors: Bojan Vrtovec, Gregor Poglajen, Gregor Zemljic, Matjaz Sever, Marko Cukjati, Sabina Frljak, Andraz Cerar, Renata Okrajsek, Peter Cernelc, Francois Haddad, Joseph C Wu
Journal: Circulation (2016)

Introduction: To date, no clinical trials of cell therapy in heart failure with preserved ejection fraction (HFpEF) have been performed. Hypothesis: We sought to investigate the safety and feasibil...
Theraputic Approaches to High Grade B-Cell Lymphoma Double-Hit and Follicular Lymphoma with C -MYC, BCL2 and/or BCL6 rearrangements. Single Center Expirience
Authors: Anna E. Misyurina, Sergey K. Kravchenko, Alla M. Kovrigina, Elena A. Baryakh, Lubov V. Plastinina, Aminat U. Magomedova, Tatiana N. Obukhova, Ekaterina S. Nesterova, Vsevolod A. Misyurin, Andrey V. Misyurin, Andrey I. Vorobiev, Fatima E. Babaeva, Valery Savchenko
Journal: Blood (2017)
Yttrium-90-labeled ibritumomab tiuxetan for primary CNS lymphoma
Authors: P. Kiewe, K. Jahnke, S. Maza, A. Korfel, D. L. Munz, E. Thiel
Journal: Journal of Clinical Oncology (2006)

11512 Background: Salvage treatment has not yet been established in primary CNS lymphoma (PCNSL). Here we report first results of an ongoing phase II study with a single treatment course of Y-90 anti-CD20 antibody ibritumomab tiuxetan in relapsed/resistant PCNSL. Methods: Eligibility criteria include histologically confirmed, recurrent PCNSL after at least one prior treatment, HIV negativity and adequate bone marrow and cardiac function. Primary endpoint is overall response, secondary endpoints are response duration, survival, and toxicity including late neurotoxicity. Treatment includes rituximab 250 mg/m 2 on day -7 and day 0, followed by Y-90-ibritumomab tiuxetan 15 MBq/kg IV. Response evaluation by contrast-enhanced magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) is scheduled before, one month and two months after treatment as well as every three months thereafter in responders. In two patients single photon emission computed tomography (SPECT) target imaging with gamma-emitting 111-Indium-ibritumomab tiuxetan was performed repeatedly. Results: To date, four patients have been enrolled. Complete response on MRI and decreased but still detectable FDG-uptake in PET was seen in one patient; the response duration was one month. In another patient uncertain complete response with minimal residual contrast enhancement lasting 12+ months was observed. Two patients had disease progression. One patient developed CTC grade 3 pneumonia during CTC grade 2 leukopenia, two patients had CTC grade 3 thrombocytopenia lasting up to 6 weeks. SPECT indicated target accumulation in the tumor starting 48 hours and still ongoing 7 days after injection of 111-Indium-ibritumomab tiuxetan. Conclusions: This is the first report on a successful treatment of PCNSL with Y-90-ibritumomab tiuxetan and penetration of a therapeutic antibody into PCNSL, warranting further investigation. No significant financial relationships to disclose.