tbuckley/cabot-search huggingface dataset:
AB0333 Overall response pattern of rituximab in ra-single centre experience
Authors: S. Das, K. Takase, S. Dass, M. H. Buch, E. Vital, P. Emery
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Current approach to treatment with rituximab in RA is treat to target<sup>1</sup>. Rituximab requires repeat cycles, usually given as fixed retreatment or on clinical relapse. We have followed a retreat on relapse protocol for ten years <h3>Objectives</h3> To establish different patterns of response with rituximab in RA and there by develop a predictive pathway for retreatment in conjunction with a biomarker <h3>Methods</h3> All RA patients treated with rituximab from our center from November 2002 to December 2012 are included in overall analysis for timing to retreatment and survival on the drug. A subgroup analysis of 119 patients was done to establish pattern of response. Disease activity has been measured using DAS28 and EULAR response. High B cell depletion measured at baseline and at 2 weeks as described in previous paper<sup>2</sup>. I and II was used to classify complete depletion or not respectively at 2 weeks, while A and B has been used to depict clinical response (both EULAR GOOD or MOD) or not respectively, e.g. IIB is non depletion non –response, IA depletion good response <h3>Results</h3> Overall response 483 patients have been treated so far from November 2002 to December 2012. 416 had 2 cycles, 309 had 3 cycles, 201 had 4 cycles, 123 had 5cycles and 85 had 6 cycles of rituximab. The mean (SEM) duration of response to cycles of rituximab remains similar C1[50.6(1.32)],C2[50.6(1.3)],C3[53(1.4)],C4[50.5(1.8)],C6[49.1(1.7)]. In ten years of treatment with rituximab about 70% patients remained on the drug while 25.8% had stopped, switched or died (0.6%, 15.3%, 9.9%). Among 47 patients who died, 7 died within 24 weeks of infusion (usually accepted as maximum period of complete B cell depletion). 3/7 died from infection, of whom 1 had low IgG after 6 cycles (5.5 g/l). Overall persistence on drug at 2 years was 88% with 58 events (24 deaths, 34 switch) Pattern of response to retreatment There was longer duration of response in subsequent cycles patients with initial complete depletion and response (IA). A significant number of patients with incomplete depletion at 2 weeks and no clinical response (IIB) in cycle 1 responded on subsequent cycles. <h3>Conclusions</h3> IA response is associated with prolonged persistence on rituximab. IIB should be retreated with at least one further cycle of rituximab in order to assess if response can be regained <h3>References</h3> Retreatment with rituximab based on a treat to target approach. Emery P et alRheumatologyDec2011 High sensitivity B cell analysis predicts response to rituximab in RA.Dass S et al, A&amp;R.October 2008 <h3>Disclosure of Interest</h3> S. Das: None Declared, K. Takase: None Declared, S. Dass Speakers bureau: Roche, M. Buch Consultant for: Honorary/Advisory board, Abbot, Pfizer, Roche, Chugai, BMS, UCB, E. Vital Grant/research support from: Honorarium Roche, P. Emery Consultant for: Honorary/Advisory board, Abbot, Pfizer, Roche, Chugai, BMS, UCB, MSD
P201 FATTY ACIDS INDUCE A PRO-INFLAMMATORY GENE EXPRESSION PROFILE IN HUH-7 CELLS AND ATTENUATE THE ANTI-HCV ACTION OF INTERFERON
Authors: E.Y. Tse, K.J. Helbig, K. Van der Hoek, E.M. McCartney, J. George, M.R. Beard
Journal: Journal of Hepatology (2014)
PM-01 * TDTM, THE ONLY MODEL TO BIOLOGICALLY REPRODUCE AND STUDY GLIOBLASTOMA DEVELOPMENT IN THE WHOLE BRAIN
Authors: E. Brognaro
Journal: Neuro-Oncology (2014)

The ideal animal model must enable us to biologically replicate and monitor all the dynamics of glioblastoma progression from the beginning to the end of its natural history both in the bulk and in the "apparently healthy" microinfiltrated brain parenchyma. The proposed model, called "The development tumor model" (TDTM), is a xenogeneic orthotopic transplantation model using GBM-derived cell lines from the pre-hypoxic phase of the founding clone (inferred after reconstruction of the phylogenetic tree) cultivated in a neurobasal serum-free medium as transplanted material. The model posits the transplantation of the same number of cells into several genetically identical immunocompromised rodents (an inbred strain of mice or rats) at the same time (time zero). Thus, the model creates a pool of twin immunodeficient transplant animals examined under the same conditions. By sacrificing one animal a week (or choosing any time interval as needed) during the progression of the tumor, we can follow and monitor the entire development of the glioblastoma both in the primary tumor and in the microinfiltrated brain parenchyma. The model can really mirror in one single generation of rodents the natural history of a patient affected by glioblastoma. Indeed, by using TDTM we can obtain multiple biopsies (in the bulk, ipsilateral hemisphere, corpus callosum, contralateral hemisphere) and stainings on sections at all the stages of glioblastoma development both in the bulk and in the microinfiltrated brain parenchyma. TDTM having the possibility to replicate all the steps of GBM progression and brain parenchyma infiltration, is perfectly suitable for studying the entire progression of the bulk and the fascinating concepts of settlement and dormancy (until activation) of CSCs in the parenchymal niche. By adopting TDTM, we can finally shed light on which specific cells and particular markers to focus on in order to find new effective therapeutic strategies.
ASSOCIATION OF CD133 EXPRESSION AND IDH MUTATION WITH RECURRENCE PATTERN IN HIGH GRADE GLIOMAS
Authors: Y. Sonoda, I. Shibahara, Y. Sonoda, T. Kawaguchi, R. Saito, M. Kanamori, Y. Yamashita, T. Watanabe, T. Kumabe, M. Watanabe, H. Suzuki, T. Tominaga
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastoma carries a poor prognosis primarily because of its high rate of recurrence. Similarly, anaplastic gliomas without IDH mutation present poor prognosis similar to glioblastoma. The ability to predict the recurrence pattern and timing would be highly useful for determining effective treatment strategies. We here examined high grade glioma to determine their recurrence pattern and the expression of CD133, a cell surface marker of glioma stem cells. METHODS: We retrospectively analyzed 198 patients with high grade gliomas (glioblastoma 112 cases, anaplastic glioma 86 patients,). Patients' characteristics, recurrence pattern, and prognosis were obtained from medical records. CD133 expression was examined by western blotting and immunohistochemistry, and IDH mutation was examined by direct sequencing. RESULTS: Of the 112 glioblastoma patients, 99 suffered recurrence. The first recurrence was local in 77 patients and distant in 22 patients. Among the factors to predict the pattern of recurrence, CD133 expression was significantly higher in distant than in local recurrence. As for anaplastic gliomas, of the 86 patients, 58 carried IDH mutation and 39 patients experienced recurrence. The first recurrence was local and distant in 26 and 13 patients, respectively. Patients without IDH mutation exhibited significantly higher CD133 expression and more frequent distant recurrence than those with IDH mutation. Patients with high CD133 expression showed shorter overall survival. CONCLUSIONS: The expression of CD133 may be a predictor of the pattern and timing of recurrence of primary glioblastoma. Patients with anaplastic gliomas without IDH mutation experience distant recurrence and exhibit high CD133 expression, indicating that this subset may share some malignant characteristics with glioblastoma. SECONDARY CATEGORY: Clinical Neuro-Oncology.
BM-30 * INTRA CEREBROPSINAL FLUID CONCENTRATIONS OF VEMURAFENIB IN MELANOMA
Authors: L. Sakji-Dupre, B. Blanchet, C. Templier, E. Desmet, J. Bonneterre, L. Mortier, E. Le Rhun
Journal: Neuro-Oncology (2014)

The prognostic of BRAF mutated melanoma has been improved by Vemurafenib. Nevertheless, the cerebral and extracerebral responses to Vemurafenib may differ. Melanoma are one the most frequent causes of central nervous system metastases among solid tumors in adults. Our aim was to compare the serum and cerebrospinal fluid (CSF) concentrations of Vemurafenib in BRAF mutated melanoma patients presenting with brain metastases (BM) and a suspicion of leptomeningeal metastases (LM). A total of 6 patients were enrolled between February 2012 and March 2013. All patients had provided their written consent. The BRAF mutations were V600E in 5 patients and V600K in one patient. All patients had BM (>3 in 5 patients). Malignant cells were observed in the CSF in only one patient. Serum and CSF samples were performed at the same time while patients received Vemurafenib 960 mg twice a day. The concentrations were determined using liquid chromatography. Serum concentrations varied from 28.9 to 96.1 mg/L and CSF concentrations from 0.12 to 1 mg/L. The mean CSF serum ratio of Vemurafenib concentrations was 0.98% (range, 0.28–2.5%). No clear correlation was observed between the serum and CSF values. The higher concentrations of Vemurafenib in the CSF were observed in the 2 patients previously treated with stereotactic surgery. The great variability observed between patients may be explained by different level of expression and activity of efflux proteins (P-gp, BCRP), but also by the CNS metastases and their treatments.
Abstract 57: Validation of Next Generation Sequencing technologies in comparison to current diagnostic gold standards for BRAF, EGFR and KRAS mutational analysis.
Authors: Clare McCourt, Perry Maxwell, Mark Catherwood, Manuel Salto-Tellez
Journal: Cancer Research (2013)

Abstract BACKGROUND: Next Generation Sequencing (NGS) has the potential of becoming an important tool in clinical diagnosis and therapeutic decision-making in oncology owing to its enhanced sensitivity in DNA mutation detection, fast-turnaround of samples in comparison to current gold standard methods and the potential to sequence a large number of cancer-driving genes at the one time. We aim to test the diagnostic accuracy of current NGS technology in the analysis of mutations that represent current standard-of-care, and its reliability to generate concomitant information on other key genes in human oncogenesis. METHODS: Thirteen FFPE clinical samples (8 lung adenocarcinomas, 3 colon carcinomas and 2 malignant melanomas) already genotyped for EGFR, KRAS and BRAF mutations by current standard-of-care methods (Sanger Sequencing and q-PCR), were analyzed for detection of mutations in the same three genes using two NGS platforms and an additional 43 genes with one of these platforms. The results were analyzed using closed platform-specific proprietary bioinformatics software as well as open third party applications (including, among others, the ‘Open’ CLC Genomics Workbench). RESULTS: Our results indicate that the existing format of the NGS technology performed well in detecting the clinically relevant mutations stated above, with apparent improved sensitivity, but may not be reliable for a broader unsupervised analysis of the wider genome in its current design. They also illustrate the relevance of different bioinformatics curation approaches, allowing different degrees of stringency, for the avoidance of potential false positives in the broader choice of genes selected, when compared with the expected mutation frequencies from sources such as the COSMIC database, for the tumor types analyzed. The systems are also able to detect other mutations outside the expected ones representing the current main "standard-of-care," the significance of which are uncertain at this point. CONCLUSIONS: Our study represents a diagnostically lead validation of the major strengths and weaknesses of this technology in its current state of development before consideration for diagnostic use. Citation Format: Clare McCourt, Perry Maxwell, Mark Catherwood, Manuel Salto-Tellez. Validation of Next Generation Sequencing technologies in comparison to current diagnostic gold standards for BRAF, EGFR and KRAS mutational analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 57. doi:10.1158/1538-7445.AM2013-57
Acute Fluoride Poisoning from a Public Water System
Authors: Bradford D. Gessner, Michael Beller, John P. Middaugh, Gary M. Whitford
Journal: New England Journal of Medicine (1994)

Acute fluoride poisoning produces a clinical syndrome characterized by nausea, vomiting, diarrhea, abdominal pain, and paresthesias. In May 1992, excess fluoride in one of two public water systems serving a village in Alaska caused an outbreak of acute fluoride poisoning.
Abstract 448: Mechanisms involved in the tumor-induced thymic involution.
Authors: Roberto Carrio-Jardines, Vijaya Iragavarapu-Charyulu, Stephania Libreros, Ramón A. García-Areas, Marta Torroella-Kouri, Diana M. Lopez
Journal: Cancer Research (2013)

Abstract The thymus is a central lymphoid organ critical for the development and maintenance of an effective peripheral T cell repertoire. Most important, it provides a specialized environment for the selection of rearranged clones that will function appropriately in the adaptive immune response. T cell maturation progresses through well-defined stages in which proliferation, differentiation, and apoptosis are central to the selection of a functional TCR repertoire. During mammary tumorigenesis, there is a profound thymus involution associated with a severe depletion of the most abundant subset of thymocytes, CD4+CD8+ double positive (DP) immature cells. Thymic involution has been observed in several model systems; including graft-vs-host disease, aging, and tumor development, however, the precise mechanisms involved in this phenomenon remain poorly defined. Previous results from our laboratory have reported that the severe thymic atrophy and impaired T cell development seen in mammary tumor bearers are associated with a profound decrease in thymus size accompanied by a disrupture of the normal thymic architecture, an arrest in at least two steps of T cell differentiation, and an increase in thymic apoptosis in tumor-bearers. In our studies we have used the murine D1-DMBA-3 mammary tumor model to elucidate the exact mechanisms associated to the tumor-induced impaired T cell development and thymic involution. We have found that the disruption in the thymic architecture of tumor bearers appears to be related to a downregulated expression of hepatocyte growth factor in the medullar zone of the thymus. Moreover, the progressive increase of apoptosis in thymocytes during the tumor development is associated to a downregulation of Bcl-xL and A1, two important molecules that control programmed cell death. Additionally, the impaired T cell development observed during the tumor-induced thymic involution is associated to a profound decrease of IL-7 and IL-15, two crucial cytokines involved in T cell development; a downregulation in the expression of most of the Jak/Stat signaling proteins; and an increased expression of several suppressor of cytokine signaling (SOCS) members. Our data provides the bases for understanding the mechanisms associated to the impaired T cell development and thymic involution present in the thymuses of tumor bearers. Citation Format: Roberto Carrio-Jardines, Vijaya Iragavarapu-Charyulu, Stephania Libreros, Ramón A. García-Areas, Marta Torroella-Kouri, Diana M. Lopez. Mechanisms involved in the tumor-induced thymic involution. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 448. doi:10.1158/1538-7445.AM2013-448
Abstract LB-254: Efficiently targeting cancer stem cells requires tactical activation from their dormant state and subsequent exhaustion
Authors: Edward H. Lin, Xi C. He, Xiaowei Yan, Yanhong Deng, Raymond Yeung, Jian Gu, Stephen Curley, Jeff Haug, Anthony Blau, Xifeng Wu, Qiang Tian, Linheng Li
Journal: Cancer Research (2010)

Abstract Akin to normal tissue stem cells (NTSCs), cancer stem cells (CSCs) may have adopted dual active-dormant mechanisms to respectively sustain growth while eluding exhaustion from conventional chemotherapy such as 5-fluorouracil (5-FU). How to effectively target dual active-dormant CSCs while preserving NTSCs is essential to curing cancers. We compared the kinetic states of NTSCs in gut and bone marrow as well as leukemia stem cells following 5-FU treatment and found a narrow window of opportunity when forcibly activated dormant NTSC/CSCs can be targeted following depletion of proliferating progeny. Given that stemness factors predict poor overall survival (OS) in many cancers, we proposed a novel two-step ADAPT strategy_activate from dormancy and potentiate subsequent targeting_ in an attempt to synchronize cytotoxic effects of 5-FU on proliferating cells with stemness inhibitors targeting activated CSCs respectively. We applied the two-step protocol using capecitabine, an oral 5-FU prodrug, and celecoxib, a selective COX-2 inhibitor that is also a stemness inhibitor (it down-regulates LGR5/6, CD133, Oct4/Sox effectors, ALDH, CD24, Wnt, Sonic Hedghog) in patients with unresectable metastatic colorectal cancer. We found that the ADAPT strategy resulted in complete or near complete response rate in 27 patients with surgically unresectable metastatic colorectal cancer, especially if coupled with radiation. The median survival for this group of patients reached 92.7 months (95% CI, 53.5 months - not reached). Paradoxically, patients who had confirmed complete response without surgery but with long-term ADAPT therapy enjoyed 100% 5-year relapse free survival compared to 42% of patients who had undergone surgical resection of metastasis (p=0.04 log rank). Intriguingly, Celecoxib exerted many opposite biologic effects compared to 5-FU on cell cycle, apoptosis, DNA repair/synthesis, particularly stemness genes/pathways, and thus produced conflicting effect in short-term colon cancer cultures when combined with 5-FU. This observation potentially explains the 6 months gain in OS in the responding patients and the lack of OS for all patients in reported phase III BICC-C study that randomized Celecoxib vs placebo with 5FU based chemotherapy.. Thus, optimal ADAPT strategy to target CSCs requires initial cytoreduction of proliferating progeny and activation of dormant/drug-resistant CSCs, and subsequent cyclical exhaustion via long-term exposure to stemness inhibitors along with intermittent cytotoxic agents such as 5-FU. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-254.
The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity
Authors: Rathiga Velaithan, Jia Kang, Jayshree L. Hirpara, Thomas Loh, Boon Cher Goh, Morgane Le Bras, Catherine Brenner, Marie-Veronique Clement, Shazib Pervaiz
Journal: Blood (2011)
Abstract 695: Significant loss of nuclear expression of Actinin-4 in metastatic breast carcinoma and lymph nodes: A novel biomarker for metastatic breast carcinoma
Authors: Cui P. Chen, Marille Herrmann, Achille Akoa, Özgül M. Alper, Özge Alper
Journal: Cancer Research (2012)

Abstract Background: Actinin-4 is an actin cross-linked protein. The expression and subcellular distribution of actinin-4 (ACTN4) has been associated with multiple roles in tumorigenicity and cancer metastasis. In the present study, we developed a novel antibody against human actinin-4 and investigated the clinical utility of actinin-4 as a biomarker in metastatic breast cancer. Methods and findings: We generated a novel monoclonal antibody (AB-Actinin-4) using hybridoma technology and native ACTN4 protein as an immunogen. The antibody specifically recognized both native and denatured human Actinin-4 protein and displayed high affinity as assessed by ELISA, immunohistochemistry assay, western blot and flow cytometry. Using this antibody and ELISA as well as immunohistochemical techniques, we examined plasma levels and tissue expression of actinin-4 in healthy controls’ and breast cancer patients’ samples. 50 plasma samples from healthy controls and breast cancer patients were analyzed for the presence of soluble actinin-4. ELISA results showed significantly decreased actinin-4 levels in plasma samples from patients with breast carcinomas compared to healthy control plasma. A total of 156 cases, including 70 normal, 36 non-metastatic breast carcinoma, 50 breast carcinoma tissues with regional metastasis, and 50 matched metastatic lymph nodes were examined. The immunoreactivity of actinin-4 was located mainly in nucleus and cytoplasm of cells. To assess the difference between groups, the staining intensity and intracellular distribution were compared and the intensity in nucleus and cytoplasm was separately scored as 0, 1+, 2+ and 3+. Grades 0 and 1+ were defined as negative and 2+ and 3+ as positive. Significant differences between the groups were found in nuclear staining. 92% of normal and 89% of non-metastatic breast carcinoma samples displayed positive nuclear staining. In contrast, only 29% of metastatic lymph nodes and 51% of metastatic breast cancer tissues showed strong nuclear staining. Conclusion: Actinin-4 demonstrated significantly decreased expression in plasma from breast cancer patients. Metastasis leads to significant loss of the nuclear expression of Actinin-4 in breast cancer tissues, in comparison to normal and non-metastatic breast carcinoma tissues. Our data suggests that Actinin-4 might have significant impact in breast cancer metastasis. Actinin-4 may serve as a reliable biomarker for the diagnosis and prognosis of metastatic breast cancer as well as could be a therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 695. doi:1538-7445.AM2012-695
Partial Correction of the Phagocyte Defect in Patients with X-Linked Chronic Granulomatous Disease by Subcutaneous Interferon Gamma
Authors: R. Alan B. Ezekowitz, Mary C. Dinauer, Howard S. Jaffe, Stuart H. Orkin, Peter E. Newburger
Journal: New England Journal of Medicine (1988)

Chronic granulomatous disease, a disorder of host defense, is characterized by an impairment in the killing of microbes that results from a defect in the production of Superoxide anion by phagocytes. We examined the efficacy of interferon gamma, a physiologic activator of phagocytic-cell function, in the treatment of the disease. Two subcutaneous injections of recombinant interferon gamma (0.1 mg per square meter of body-surface area per dose) were administered on consecutive days to four patients with the X-linked form of the disease. Treatment resulted in 5- to 10-fold increases in superoxide production by granulocytes and monocytes; the improvement was sustained for more than two weeks. Granulocyte bactericidal activity rose proportionally. In the two most responsive patients, both phagocytic functions reached the normal range of activity. In association with these functional changes, we observed an increase in cellular contents of phagocyte cytochrome b (a critical component of the superoxide-producing oxidase) and immunoreactive cytochrome b heavy chain (the product of the gene that is defective in X-linked chronic granulomatous disease). Levels of cytochrome b detected by spectrophotometry rose from near zero to 10 to 50 percent of normal values. This study demonstrates partial correction of the cellular defects in chronic granulomatous disease by interferon gamma and provides a basis for clinical trials of the agent. (N Engl J Med 1988; 319:146–51.)