tbuckley/cabot-search huggingface dataset:
Abstract 1679: Immunotherapeutic strategies targeting CXCR4 axis plus γ/δ T cells in treating ovarian cancer
Authors: Chao Lien Liu, Tsui Lien Mao
Journal: Cancer Research (2015)

Abstract Ovarian carcinoma is the most crucial and difficult problem for therapeutic treatment in gynecological malignancies, which requires great efforts for an effective solution. Molecular studies have shown that chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 and its receptor CXCR4 are the key determinants of tumor initiation, progression and metastasis in ovarian carcinoma. It is also believed that blocking CXCR4-CXCL12 pathway plays potential roles in treating ovarian cancer patients. Recent studies also showed that the cytotoxic function of gamma delta (γ/δ) T lymphocytes could efficiently kill ovarian CSCs (cancer stem cells) and present a promising immunotherapy for ovarian cancer. To investigate how the CXCL12/CXCR4 pathway is involved in the regulation of ovarian cancer. We eliminated the expression of CXCR4 in different ovarian cancer cell lines using CXCR4 antagonist (e.g., AMD3100) and CXCR4 shRNA silencing to prevent the CXCR4/CXCL12 axis interaction. Besides, up to 78% of γ/δ T cells was expanded in-vitro using aminobisphosphonates plus low-dose interleukin-2 for the therapeutic investigating. The therapeutic effects following different treatments were measured. First, our results showed that blocking of Cxcr4/Cxcl12 axis by AMD3100 reduced around 37% on cell survival rate. Similar results were also observed in the CXCR4-shRNA silencing ovarian cancer cells. Additionally, the higher CXCR4-expressed cells were highly proliferation after CXCL12 stimulating compared to the CXCR4 non-expressed cells. Next, cancer cells treated with the exogenous activated γ/δ T cells showed a reduction of 35% on cell survival rate. Finally, the combined treatment strategy using AMD3100 plus γ/δ-T cells showed the most significant therapeutic effects in the high-grade ovarian cancer cells, and the cell survival rate was reduced almost to 50% after the cell cytotoxic assay. We therefore conclude that the limitation of CXCL12/CXCR4 activities combined with the γ/δ T cell cytotoxicity is a potent immunotherapy for treating ovarian cancer and would served as a promising new strategies for clinical translation. Citation Format: Chao Lien Liu, Tsui Lien Mao. Immunotherapeutic strategies targeting CXCR4 axis plus γ/δ T cells in treating ovarian 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 1679. doi:10.1158/1538-7445.AM2015-1679
Dissémination délibérée d’agents biologiques : premières leçons pour l’Europe des évènements survenus aux Etats-Unis
Authors: R Harling, B Twisselmann, N Asgari, D Morgan, N Lightfoot, M Reacher, A Nicoll
Journal: Eurosurveillance (2001)

L'experience vecue a l'automne 2001 d'envois de lettres contenants des spores de charbon a eu des consequences considerables aussi bien aux Etats-Unis qu'en Europe. La menace d'attentats non revendiques diriges contre des civils est devenue une realite. En Europe, bien que les canulars de mauvais gout se soient multiplies, aucun cas de charbon du a une action malveillante n'est a deplorer, les seules lettres effectivement contaminees etant destinees a des ambassades americaines a l'etranger. Il reste neanmoins que l'Europe doit preparer des plans de lutte efficaces et reactifs en coordination avec la Commission europeenne.
P3-059: Cryoablation against primary lung cancer in postpneumonectomy patients-preliminary experience
Authors: Norimasa Tsukada, Keisuke Asakura, Yotaro Izumi, Masafumi Kawamura, Koichi Kobayashi, Hideki Yashiro, Seishi Nakatsuka, Sachio Kuribayashi
Journal: Journal of Thoracic Oncology (2007)
C6-03: Involvement of a Tumor Suppressor TSLC1/CADM1 in Lung Tumorigenesis in Human and the Gene-deficient Mice
Authors: Yoshinori Murakami, Shinji Kikuchi, Daisuke Yamada, Masayoshi Nagata, Takashi Obana, Mari Masuda, Yumi Tsuboi, Shingo Usui, Hiromi Ichihara, Tomoko Maruyama
Journal: Journal of Thoracic Oncology (2007)
ATNT-13A PHASE I DOSE ESCALATION AND CENTRAL NERVOUS SYSTEM (CNS) PHARMACOKINETIC STUDY OF DEXANABINOL IN PATIENTS WITH BRAIN CANCER
Authors: Tiffany Juarez, David Piccioni, Angel Nguyen, Bradley Brown, Lara Rose, Minya Pu, Karen Messer, Santosh Kesari
Journal: Neuro-Oncology (2015)

BACKGROUND: Dexanabinol is a synthetic analogue of tetrahydrocannabinol previously developed as a neuroprotector and subsequently identified through a network pharmacology platform as a potential anti-cancer therapeutic by e-Therapeutics PLC. Dexanabinol was selected for further investigation based on its tumoricidal activity observed in vitro and in vivo, presumably due to inhibitory activity against NFκB, COX-2, and TNFα. This phase I dose-escalation trial examines the safety of multiple dosing of dexanabinol and drug penetration into the central nervous system in patients with brain cancer. METHODS: Patients having failed prior therapy or having no further available standard therapies and Karnofsky Performance Score of ≥ 60% were included. Dose escalation was performed using a‘3 + 3’ design. Patients received weekly dexanabinol via an intravenous infusion. The objectives were to determine the safety, tolerability, recommended phase 2 dose, pharmacokinetics, and antitumor activity. RESULTS: 26 patients have been enrolled at escalating doses of dexanabinol (range 2 to 36 mg/kg). Two patients at the highest dose level were non-evaluable for dose tolerability and no dose limiting toxicities occurred in this study. Dose escalation was stopped due to emerging data in another clinical study (ETS2101-001). To date, adverse events attributed to dexanabinol were grades 1 or 2 and consisted of a depressed level of consciousness and lightheadedness in 3/26 pts; diarrhea and itching in 2/26 pts; fatigue, chest discomfort and tingling in mouth in 1/26 pts. From 2 to 36 mg/kg, systemic exposure to dexanabinol (AUC0-∞ and Cmax) increased greater than dose proportionately; dexanabinol was present in appreciable levels in the CSF, which implies the possibility of exposure of intracranial tumors to drug. Four of 24 efficacy-evaluable patients (17%) experienced stable disease with median duration of two cycles (28-day cycle) as best response. CONCLUSIONS: Dexanabinol was safe and well-tolerated warranting continued investigation. A Phase 1b program with dexanabinol is planned.
C6-07: Mutations in the LKB1 tumor suppressor are frequently found in tumors from Caucasian NSCLC patients
Authors: Jussi P. Koivunen, Jhingook Kim, Jinseon Lee, Matthew L. Meyerson, Kwok-Kin Wong, William G. Richards, David J. Sugarbaker, Bruce E. Johnson, Pasi A. Jänne
Journal: Journal of Thoracic Oncology (2007)
A randomized phase II trial of chemoradiotherapy with oral fluoropyrimidine inhibitory for dihydropyrimidine dehydrogenase for low rectal cancer: An interim report.
Authors: M. Nishioka, M. Shimada, N. Kurita, T. Iwata, S. Morimoto, K. Yoshikawa, J. Higashijima, T. Miyatani, H. Kashihara, C. Mikami
Journal: Journal of Clinical Oncology (2011)

524 Background: Preoperative chemoradiotherapy (CRT) has been widely used to improve local control of disease and to preserve anal sphincter in the treatment of rectal cancer. However, the response to CRT differs among individual tumors. In ASCO 2008 Gastrointestinal Cancers Symposium, we reported that the patients with up-regulation of 17 genes were suggested to be good responder of CRT. Our purpose of this study was to evaluate the toxicity and efficacy of CRT using UFT versus S-1 and explore biomarkers for response in patients with locally advanced rectal cancer. Methods: Fifty patients who received preoperative CRT (40Gy radiotherapy) were randomly assigned to either UFT or S-1. UFT and S-1 were administered during the radiotherapy course. S-1 was a novel oral fluoropyrimidine inhibitory for dihydropyrimidine dehydrogenase and had potent radiosensitizing property. Biopsy specimens were obtained from rectal cancer before preoperative CRT and were analyzed by focused DNA microarray (132 genes). To pick up the predictive factors, the 132 genes were selected in the view of sensitivity of 5FU. Response to CRT was determined by RECIST and histopathologic examination of surgically resected specimens and classified as responders (CR, PR and grade 2, 3) or nonresponders (SD, PD and grade 0, 1). Results: UFT group (n=25) and S-1 group (n=25) were enrolled. Response rate (grade 2 or 3) to CRT determined by histopathologic examination of surgically resected specimens was 58% in the UFT group and was 75% in the S-1 group. Response rate evaluated by RECIST criteria was 62% in the UFT group and was 77% in the S-1 group. National Cancer Institute Common Toxicity Criteria grade 2 or 3 toxicity was observed in 8% of the patients in the UFT group and 23% of patients in the S-1 group. Grade 2 or 3 toxicity in the UFT group was neutropenia and was diarrhea, neutropenia and dermatitis in the S-1 group. In ASCO 2010, we will report each candidate biomarker genes for response to CRT in the UFT and S-1 group. Conclusions: The results have suggested that CRT using UFT or S-1 is feasible and effective for patients with locally advanced rectal cancer. [Table: see text]
Onconase, a cytotoxic ribonuclease, in combination with standard of care agents in non-small cell lung tumorgraft models.
Authors: M. Loyo, E. Bruckheimer, S. J. Strawn, M. J. Wick, F. Nieves, S. K. Saxena, M. Hidalgo, W. Ardelt, E. K. Rowinsky, D. Sidransky
Journal: Journal of Clinical Oncology (2011)

e13520 Background: Onconase is a cytotoxic amphibian ribonuclease of the RNAse A superfamily. It is currently being evaluated in phase I/II trials and has been shown to possess anti-tumor activity in many preclinical studies. In an effort to identify clinical indications for Onconase, non-small cell lung tumografts were treated with a combination of onconase and cisplatin or caboplatin-pemetrexed which currently constitute standard of care for this type of malignancy. Tumorgrafts are human solid tumors passed as heterogeneous whole-tumor fragments in immunocompromised mice and not cell line xenografts. Methods: Adenocarcinoma tumor graft models were treated pemetrexed 100 mg/kg, i.p. days 0-4, 7-11; carboplatin 60 mg/kg i.p. days 0, 7, 15; Onconase 5mg/kg i.v. days 0, 7, 14. Tumor volumes determined by caliper measurements. Tumor growth inhibition (TGI) was determined at study endpoint. Tumor samples were collected for further analysis of potential signatures of response by mutation and miRNA analysis. Results: A statistically significamt increased anti-tumor activity and TGI (p<0.05) compared to control and pemetrexed + carboplatin groups. TGI increased from 33-42% following treatment with carboplatin-pemetrexed to 67-85% with carboplatin-pemetrexed plus onconase. The mutation analysis is decribed. No signature miRNA was found. Conclusions: Onconase in combination with standard of care agents such as cisplatin and/or carboplatin plus pemetrexed may be applied clinically with the potential for greater success.
P2-095: Prognostic value of the determination of K-ras mutations plasma in advanced non-small cell lung cancer (NSCLC) patients
Authors: Rafael Sirera, Carlos Camps, José-Luis González-Larriba, Juan Lao, R García-Gómez, Nuria Viñolas, María José Safont, Joaquín Gavilá, Miquel Tarón, Rafael Rosell
Journal: Journal of Thoracic Oncology (2007)
Minimal residual disease- and graft-vs.-host disease-guided multiple consolidation chemotherapy and donor lymphocyte infusion prevent second acute leukemia relapse after allotransplant
Authors: Chen-Hua Yan, Yu Wang, Jing-Zhi Wang, Yu-Hong Chen, Yao Chen, Feng-rong Wang, Yu-Qian Sun, Xiao-Dong Mo, Wei Han, Huan Chen, Xiao-hui Zhang, Lan-Ping Xu, Kai-Yan Liu, Xiao-Jun Huang
Journal: Journal of Hematology & Oncology (2016)

Persons with acute leukemia relapsing after allotransplant and who respond to anti-leukemia interventions are at high risk of a second relapse. We studied the impact of minimal residual disease (MRD)- and graft-vs.-host disease (GvHD)-guided multiple consolidation chemotherapy and donor lymphocyte infusions (DLIs) to prevent second relapse in patients with acute leukemia relapsing post-transplant and who achieved complete remission after induction chemotherapy and DLI. Forty-seven subjects with acute leukemia relapsing after an allotransplant and who achieved complete remission after post-relapse induction chemotherapy and DLI were eligible. The use of consolidation chemotherapy and DLI was guided by the results of MRD testing and whether or not DLI caused acute and/or chronic GvHD. Outcomes were compared with those of 34 similar historical controls who did not receive consolidation chemotherapy and DLIs after induction chemotherapy and DLI. One-year cumulative incidence of relapse (CIR; 22 % 95 % confidence interval (10, 35 %) vs. 56 % (39, 73 %); P < 0.0001), leukemia-free survival (LFS; 71 % (57, 84 %) vs. 35 % (19, 51 %); P < 0.0001), and survival (78 % (66, 90 %) vs. 44 % (27, 61 %); P < 0.0001) was significantly better in subjects than controls. In multivariate analyses, no chronic GvHD after therapy (hazard ratio (HR) = 3.56 (1.09, 11.58); P = 0.035) and a positive MRD test after therapy (HR = 21.04 (4.44, 94.87); P < 0.0001) were associated with an increased CIR. These data suggest MRD- and GvHD-guided multiple consolidation chemotherapy and DLIs reduce CIR and increase LFS and survival compared with controls in persons relapsing after allotransplant for acute leukemia. ChiCTR-ONC-12002912 . Donor lymphocyte infusion for the treatment of leukemia relapse following allogeneic hematopoeitic stem cell transplant.
The inhibition of CCR2 to modify the microenvironment in pancreatic cancer mouse model and to support the profiling of the CCR2 inhibitor CCX872-B in patients.
Authors: Andrea Wang-Gillam, Marcus Smith Noel, Stefan Sleijfer, Heiyoun Jung, Lisa Lohr, Niky Zhao, Shichang Miao, Antonia Potarca, Israel Charo, Petrus Bekker, Thomas J. Schall
Journal: Journal of Clinical Oncology (2016)

e15743 Background: The CCL2/CCR2 axis regulates the recruitment of monocytes to sites of inflammation. We implanted a murine K-Ras+ pancreatic cancer cell line into mice to determine if inhibition of CCR2 altered the tumor microenvironment. These studies complement the ongoing clinical trial with CCX872-B (“B” refers to the salt form), a potent, orally administered CCR2 inhibitor. An update on the progress of the trial will be presented. Methods: KCKO cells were implanted into the pancreas of mice. Dosing with a small molecule CCR2 antagonist was begun at week 4, tumors were excised at week 8, and the proportion of M-MDSC and G-MDSC suppressor cells was quantified. The ongoing clinical trial consists of a single-dose (150 mg CCX872-B) regimen in the first 4 patients with pancreatic adenocarcinoma, followed by a multiple dose regimen in up to 50 additional patients, in combination with FOLFIRINOX therapy for up to 12 cycles. PK, PD, and safety were evaluated. PD studies included ex-vivo measurements of the inhibition of patient monocyte chemotaxis, and quantification of receptor occupancy and internalization. The primary endpoint of this study is progression free survival at week 24. Secondary endpoints include objective response rate, assessed by CT scans obtained every 12 weeks. Results: In the mice, one week of CCR2 inhibition resulted in a 42% decrease in tumor size and a selective decrease of 45% in the proportion of M-MDSCs. In the clinical study, mean Cmax was 8580 ng/mL, AUClast was 164,000 hr*ng/mL, and terminal t1/2 was 35h with a dose of 150 mg. RO and RI assays indicated excellent CCR2 coverage by CCX872-B. To date, more than 30 patients have been enrolled and dosed in the multi-dose part of the study. CCX872-B appeared to be well tolerated and no unexpected safety events have occurred to date. Conclusions: Preclinical data support the hypothesis that CCR2 inhibition can mechanistically alter the tumor microenviroment in a favorable manner. The safety, PK, and PD data of CCX872-B in pancreatic cancer patients indicate that 150 mg CCX872-B provides excellent CCR2 blockade. The study is progressing very well with more than 60% of enrollment completed. Clinical trial information: NCT02345408.
Visualizing Epithelial–Mesenchymal Transition Using the Chromobody Technology
Authors: Julia Maier, Bjoern Traenkle, Ulrich Rothbauer
Journal: Cancer Research (2016)

Abstract The epithelial–mesenchymal transition (EMT) is a complex cellular program involved in the progression of epithelial cancers to a metastatic stage. Along this process, epithelial traits are repressed in favor of a motile mesenchymal phenotype. A detailed characterization and monitoring of EMT-related processes is required for the design of screening strategies needed to develop novel antimetastatic therapies. Overexpression of the canonical EMT biomarker vimentin correlates with increased tumor growth and invasiveness, as well as with reduced patient survival across various epithelial cancers. Moreover, recent findings have demonstrated an active role of vimentin in regulating and reorganizing the cellular architecture toward a migratory and invasive phenotype. However, current studies suffer from a lack of appropriate methods to trace the induction and dynamics of vimentin in cell-based assays. Recently, we have reported a novel intrabody (chromobody)–based approach to study the spatiotemporal organization of endogenous vimentin upon induction of EMT by high-content imaging. In this review, we discuss the relevance of the chromobody technology with regard to the visualization of EMT-related processes in living systems. Cancer Res; 76(19); 5592–6. ©2016 AACR.
Prevalence of microcephaly in Europe: population based study
Authors: Joan K Morris, Judith Rankin, Ester Garne, Maria Loane, Ruth Greenlees, Marie-Claude Addor, Larraitz Arriola, Ingeborg Barisic, Jorieke E H Bergman, Melinda Csaky-Szunyogh, Carlos Dias, Elizabeth S Draper, Miriam Gatt, Babak Khoshnood, Kari Klungsoyr, Jennifer J Kurinczuk, Catherine Lynch, Robert McDonnell, Vera Nelen, Amanda J Neville, Mary T O’Mahony, Anna Pierini, Hanitra Randrianaivo, Anke Rissmann, David Tucker, Christine Verellen-Dumoulin, Hermien E K de Walle, Diana Wellesley, Awi Wiesel, Helen Dolk
Journal: BMJ (2016)

<b>Objectives</b>&nbsp;To provide contemporary estimates of the prevalence of microcephaly in Europe, determine if the diagnosis of microcephaly is consistent across Europe, and evaluate whether changes in prevalence would be detected using the current European surveillance performed by EUROCAT (the European Surveillance of Congenital Anomalies). <b>Design</b>&nbsp;Questionnaire and population based observational study. <b>Setting</b>&nbsp;24 EUROCAT registries covering 570 000 births annually in 15 countries. <b>Participants</b>&nbsp;Cases of microcephaly not associated with a genetic condition among live births, fetal deaths from 20 weeks' gestation, and terminations of pregnancy for fetal anomaly at any gestation. <b>Main outcome measures</b>&nbsp;Prevalence of microcephaly (1 Jan 2003-31 Dec 2012) analysed with random effects Poisson regression models to account for heterogeneity across registries. <b>Results</b>&nbsp;16 registries responded to the questionnaire, of which 44% (7/16) used the EUROCAT definition of microcephaly (a reduction in the size of the brain with a skull circumference more than 3 SD below the mean for sex, age, and ethnic origin), 19% (3/16) used a 2 SD cut off, 31% (5/16) were reliant on the criteria used by individual clinicians, and one changed criteria between 2003 and 2012. Prevalence of microcephaly in Europe was 1.53 (95% confidence interval 1.16 to 1.96) per 10 000 births, with registries varying from 0.4 (0.2 to 0.7) to 4.3 (3.6 to 5.0) per 10 000 (χ<sup>2</sup>=338, df=23, I<sup>2</sup>=93%). Registries with a 3 SD cut off reported a prevalence of 1.74 per 10 000 (0.86 to 2.93) compared with those with the less stringent 2 SD cut off of 1.21 per 10 000 (0.21 to 2.93). The prevalence of microcephaly would need to increase in one year by over 35% in Europe or by over 300% in a single registry to reach statistical significance (P&lt;0.01). <b>Conclusions</b>&nbsp;EUROCAT could detect increases in the prevalence of microcephaly from the Zika virus of a similar magnitude to those observed in Brazil. Because of the rarity of microcephaly and discrepant diagnostic criteria, however, the smaller increases expected in Europe would probably not be detected. Clear diagnostic criteria for microcephaly must be adopted across Europe.
Adoptive Transfer of Tumor-Specific Th2 Cells Eradicates Tumors by Triggering an<i>In Situ</i>Inflammatory Immune Response
Authors: Kristina Berg Lorvik, Clara Hammarström, Marte Fauskanger, Ole Audun Werner Haabeth, Michael Zangani, Guttorm Haraldsen, Bjarne Bogen, Alexandre Corthay
Journal: Cancer Research (2016)

Adoptive cell therapy (ACT) trials to date have focused on transfer of autologous tumor-specific cytotoxic CD8+ T cells; however, the potential of CD4+ T helper (Th) cells for ACT is gaining interest. While encouraging results have been reported with IFNγ-producing Th1 cells, tumor-specific Th2 cells have been largely neglected for ACT due to their reported tumor-promoting properties. In this study, we tested the efficacy of idiotype-specific Th2 cells for the treatment of mice with MHC class II-negative myeloma. Th2 ACT efficiently eradicated subcutaneous myeloma in an antigen-specific fashion. Transferred Th2 cells persisted in vivo and conferred long-lasting immunity. Cancer eradication mediated by tumor-specific Th2 cells did not require B cells, natural killer T cells, CD8+ T cells, or IFNγ. Th2 ACT was also curative against B-cell lymphoma. Upon transfer, Th2 cells induced a type II inflammation at the tumor site with massive infiltration of M2-type macrophages producing arginase. In vivo blockade of arginase strongly inhibited Th2 ACT, consistent with a key role of arginase and M2 macrophages in myeloma elimination by Th2 cells. These results illustrate that cancer eradication may be achieved by induction of a tumor-specific Th2 inflammatory immune response at the tumor site. Thus, ACT with tumor-specific Th2 cells may represent a highly efficient immunotherapy protocol against cancer. Cancer Res; 76(23); 6864-76. ©2016 AACR.