tbuckley/cabot-search huggingface dataset:
Multicenter phase II study of rituximab-ABVD in classic Hodgkin lymphoma (cHL).
Authors: Y. L. Kasamon, H. A. Jacene, L. J. Swinnen, L. Popplewell, B. K. Link, T. M. Habermann, J. M. Herman, R. J. Jones, R. F. Ambinder
Journal: Journal of Clinical Oncology (2011)

8039 Background: Unlike Hodgkin and Reed Sternberg (HRS) cells, cHL cancer stem cells (CSC) may have a CD20+, memory B cell phenotype and circulate in high frequencies (Jones RJ et al, Blood 2009;113:5920), potentially explaining rituximab’s activity in cHL. Methods: An inter-SPORE study of rituximab-ABVD, to explore the activity of rituximab in cHL using both correlative assays of cHL CSC and clinical outcome, was conducted and accrual completed in 6/2009. Eligibility criteria included stage II, III or IV untreated cHL; age ≥ 18 y; HIV and hepatitis B surface antigen negative; creatinine ≤ 2 mg/dL; bilirubin ≤ 5 mg/dL. Planned treatment was 6 cycles of ABVD with addition of rituximab 375 mg/m2 1 week prior to first ABVD; on days 1, 8, 15, 22 of cycle 1 ABVD; and on day 1 of cycles 2, 4, 6. Dose delays, growth factors and radiation were at physician discretion. Results: Clinical outcomes of all 49 evaluable patients (pts) are presented. Median age was 33 (range 18-66); 26 (53%) were male; stage was IIA in 15 pts, IIB in 5, III-IV in 29 (59%); and 17 (35%) had bulky mediastinal disease. HRS cells were CD20+ in 4 of 47 cases assessed (8.5%). International Prognostic Score (IPS) was 0-1 in 20 pts (41%); 2 in 14 (29%); ≥ 3 in 15 (31%). In urgent cases omission of first rituximab was permitted, and this occurred in 17 pts (35%). Addition of rituximab was generally well tolerated. One death from sepsis occurred during cycle 2. Mean delivered relative dose intensity with 6 cycles was high: 92% for the ABVD combination (96% for AVD, 80% for bleomycin). After 6 cycles, 39 pts (81%) had CR, 6 (12.5%) PR, 1 SD (2%), 2 (4%) progressive disease by 2007 IWG criteria. Only 4 pts received radiation. On centralized review of cycle 2 PET (41 pts), 36 (88%) were PET negative (tumor uptake < liver) and 5 (12%) were PET positive by modified London criteria. Pts with positive interim PET had inferior EFS (P < 0.004). With median 28 month follow-up (range 1.5-48 months), actuarial EFS after treatment initiation is 92% at 2 y and 83% at 3 y (90% at 3 y if IPS ≥ 2). Actuarial overall survival is 98%. Analysis of biomarkers in relation to disease status is ongoing to define cHL CSC biology. Conclusions: Rituximab-ABVD yields encouraging clinical results in cHL, despite a minority of tumors expressing CD20.
Treatment of Light Chain (AL) Amyloidosis and Light Chain Deposition Disease (LCDD) with the Combination of Bortezomib and Dexamethasone.
Authors: Efstathios Kastritis, Athanasios Anagnostopoulos, Maria Roussou, Savvas Toumanidis, Constantinos Pamboukas, Anna Tassidou, Irini Xilouri, Sossana Delimpassi, Erasmia Psimenou, Sofia Mellou, Evangelos Terpos, John Nanas, Meletios Athanasios Dimopoulos
Journal: Blood (2007)
An Early CT-Diagnosis Based Treatment Strategy for Invasive Fungal Infection in Allogeneic Transplant Recipients Using Caspofungin First Line: An Effective Strategy with Low Mortality.
Authors: Fiona L Dignan, Stephen O Evans, Mark E Ethell, Bronwen E. Shaw, Unell BG Riley, Faith Davies, Jennifer G. Treleaven, Claire E. Dearden, Gareth J. Morgan, Michael N Potter
Journal: Blood (2008)
Monitoring T-cell responses in a phase II study of AGS-003, an autologous dendritic cell-based therapy in patients with newly diagnosed advanced stage renal cell carcinoma in combination with sunitinib.
Authors: R. A. Figlin, C. A. Nicolette, A. Amin, A. Dudek, T. Logan, R. S. Lance, J. M. Holzbeierlein, S. K. Pal, V. A. Master, M. DeBenedette, I. Y. Tcherepanova, R. Jain, W. L. Williams, F. Miesowicz, T. Monesmith
Journal: Journal of Clinical Oncology (2011)

2532 Background: Dendritic cells (DC) are a powerful tool for stimulating cell-mediated immunity through the effects of CD4+ and CD8+ T cells. This phase II study investigated AGS-003, an autologous amplified tumor RNA-loaded DC–based immunotherapy in patients with RCC in combination with sunitinib. AGS-003 stimulates proliferation of CD28 expressing cytotoxic T lymphocytes (CTL), targeted directly to autologous RCC tumor antigens. While sunitinib is capable of inducing tumor regression through inhibition of VEGF activity, it also possesses non-specific immune modulatory effects, which include a noted decrease in regulatory T cells. Therefore, the combination of AGS-003 and sunitinib could result in synergistic effects over that which could be achieved with either modality alone. Methods: Immune monitoring (IM) analysis using multiparametric flow cytometry was performed on PBMC isolated from blood draws collected prior to treatment and after treatment with AGS-003 during combination administration with sunitinib. Results: Results revealed that for all subjects tested, there was a decrease in the percentage of T regulatory cells during combination treatment with AGS-003 and sunitinib compared to pre-therapy baseline levels. With the exception of one outlier, there was a correlation between decreased regulatory T cells and PFS (r2=0.7662). Also, patients treated concurrently with AGS-003 in the presence of sunitinib were able to expand CD28+ memory CTL with a broad range of effector functions. The expansion of tumor antigen-reactive CD28+ CTL revealed a trend between PFS and the change in CD28+ effector memory CTL post-treatment. Nine of 11 subjects with PFS of >10 months demonstrated CTL population increases whereas 2 of 4 subjects with PFS <10 months showed increases in this specific CTL population. Conclusions: We conclude that the combination of sunitinib and AGS-003 can decrease the percentage of T regulatory cells with a concurrent expansion of CD28+ effector memory CTL thereby overcoming tumor-induced immunosuppression and potentially leading to better clinical outcome in terms of PFS.
Abstract 993: The relationship between autophagy, senescence, and DNA repair
Authors: Moureq R. Alotaibi, Lawrence Povirk, Daivd Gewirtz
Journal: Cancer Research (2015)

Abstract Radiotherapy is used along with other modalities such as surgery, chemotherapy, and immunotherapy to either shrink tumors before surgery or kill surviving tumor cells post surgery. Although radiation (and chemotherapy) induce different modes of cell death, recurrence of cancer may occur. It has been shown that DNA damage can induce cells to undergo both autophagy and senescence where both responses can function either as a pro-survival mechanism or in promoting loss of self-renewal capacity in the tumor cell. The relationship between autophagy, senescence, and the DNA repair system has not been well-characterized. The primary aims of this work were to understand whether autophagy and senescence might be permissive for DNA repair, thereby allowing the tumor cells to overcome the persistent DNA damage and recover using HCT116 WT and HCT116 Ligase IV (-/-) human colon carcinoma cells. Irradiation caused HCT116 Ligase IV (-/-) cells to lose their capacity to proliferate followed by delayed cell death, whereas HCT116 WT cells showed proliferative recovery 72 hours post-treatment, consistent with deficiencies in DNA repair in the Ligase IV (-/-) cells. Irradiation of both cell lines resulted in enlargement in cell size and accumulation of acidic vacuoles, indicative of the induction of autophagy. Inhibition of autophagy by Bafilomycin and Choroquine resulted in radio-sensitization in HCT116 WT cells but not in HCT116 Ligase IV (-/-) cells, indicating that radiation-induced autophagy in HCT116 WT cells is likely to be cytoprotective. Both repair competent HCT116 colon carcinoma cells and Ligase IV deficient cells demonstrated significant increases in senescent populations upon irradiation based on β-galactosidase staining and enlargement of treated cells. The PARP inhibitor, Olaparib, enhanced the efficacy of radiation through interference with DNA repair and the promotion of both autophagy and senescence but not apoptosis. Taken together, it appears that both autophagy and senescence may facilitate DNA repair during exposure to genotoxic stress, and that autophagy and senescence are closely linked responses in irradiated tumor cells. Citation Format: Moureq R. Alotaibi, Lawrence Povirk, Daivd Gewirtz. The relationship between autophagy, senescence, and DNA repair. [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 993. doi:10.1158/1538-7445.AM2015-993
Markers of Hypercoagulability in Breast Cancer: What Is Their Clinical Relevance?
Authors: Mourad Chaari, Grigoris T Gerotziafas, Ines Ayadi, Vassiliki Galea, Lilia Ghorbal, Patrick Van Dreden, Aurélie Rousseau, Racem Bouzguenda, Mounir Frikha, Jamel Daoud, Choumous Kallel, Barry J Woodhams, Ismail Elalamy
Journal: Blood (2012)
Abstract 262: Inhibition of the novel immune checkpoint CEACAM1 enhances antitumor immunological activity
Authors: Gal Markel, Ilana Mandel, Yair Sapir, Motti Hakim, Sharon Hashmueli, Tehila Ben-Moshe
Journal: Cancer Research (2015)

Abstract Blockade of co-inhibitory immune receptors has become a promising approach for the activation of anti-tumor immunity. CEACAM1, a recently characterized immune checkpoint, is a member of the Ig superfamily expressed by activated effector lymphocytes and cancer cells. Expression of CEACAM1 on cancer cells induces a co-inhibitory signal to T and NK cells through homophilic CEACAM1 interactions. CEACAM1 is expressed across multiple tumor types and its presence is independent of PD-L1 expression. CM-24 is a humanized anti-CEACAM1 IgG4 antibody with high affinity and selectivity for CEACAM1. We investigated the activity of CM-24 and its ability to reverse CEACAM1-induced immune evasion alone and in combination with other checkpoint inhibitors. CM-24 was demonstrated to be a potent blocker of intercellular CEACAM1-CEACAM1 interactions and reversed inhibition of activated lymphocytes by restoring the phosphorylation signal of ZAP70. CM-24 enhanced the cytotoxic activity of cytotoxic T cell and NK cells against various cancer types, which was accompanied by higher secretion of Granzyme B and IFNγ. In addition, a synergistic activity with various immune checkpoint blockers was observed, including ones that target the PD-1 pathway. Various in vivo tumor xenograft models demonstrated that CM-24 has clear anti-tumor activity accompanied by an increase in immunological activity of T cells within the tumor. Collectively, preclinical data show that CM-24 has effective anti-tumor activity in various in vitro and in vivo models and demonstrate that CM-24 has the potential to enhance the cytotoxic activity of lymphocytes against malignant cells. CM-24 is now moving towards phase 1 clinical study. Citation Format: Gal Markel, Ilana Mandel, Yair Sapir, Motti Hakim, Sharon Hashmueli, Tehila Ben-Moshe. Inhibition of the novel immune checkpoint CEACAM1 enhances antitumor immunological activity. [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 262. doi:10.1158/1538-7445.AM2015-262
Effects of the Redox Mediator Motexafin Gadolinium in a Pilot Phase I Trial in Refractory Chronic Lymphocytic Leukemia (CLL).
Authors: Thomas S. Lin, Sabyasachi Biswas, Louie Naumovski, Phillip Lecane, Margaret S. Lucas, Mollie E. Moran, Andrew P. Mone, David M. Lucas, See-Chun Phan, Richard A. Miller, John C. Byrd
Journal: Blood (2004)
Antineutrophil cytoplasmic antibodies: appropriate use and interpretation
Authors: Jan Damoiseaux, Elena Csernok, Niels Rasmussen, Jan-Willem Cohen Tervaert, Xavier Bossuyt
Journal: Annals of the Rheumatic Diseases (2017)

It was with much interest that we read the letter of Novikov et al 1 on testing for antineutrophil cytoplasmic antibodies (ANCAs) in patients with ANCA-associated vasculitides (AAV) and other diseases. In their letter, the authors (1) share their experience with direct testing for proteinase-3 (PR3) ANCA and myeloperoxidase (MPO) ANCA and (2) raise some important issues regarding interpretation of ANCA test results.

Novikov et al 1 abandoned indirect immunofluorescence (IIF) for ANCA screening more than 10 years ago and since then have been directly testing for PR3-ANCA and MPO-ANCA by immunoassay. They identified antibodies in 96.9% of patients with microscopic polyangiitis (MPA), in 72.7% of patients with granulomatosis with polyangiitis (GPA) and in 92.2% …
138. Potential Therapeutic Treatment of Friedrich's Ataxia Using Highly Specific Engineered Meganucleases
Authors: Roshni Davey, Armin Hekele, Jo Ann Hux, Caitlin Turner, Wendy Sharer, Victor Bartsevich, Ginger Tomberlin, Gene Liau, Michael G. Nicholson, Clayton W. Beard, Jeff Smith, Derek Jantz
Journal: Molecular Therapy (2016)

Friedreich's ataxia (FRDA) is a recessive genetic disorder that results in progressive neuromuscular deterioration. The most common causative genetic alteration of this disorder is an expansion of a trinucleotide (GAA/TTC) repeat within the first intron of the Frataxin (FXN) gene. This triplet expansion causes transcriptional defects, resulting in low FXN mRNA and protein levels. In patients, the correlation between number of repeats and severity of the disease, age of onset and cardiomyopathy indicates that the repeat expansion is the primary cause of FRDA, thus making it a potential therapeutic target. We are investigating the potential use of our engineered meganuclease technology to precisely remove these trinucleotide repeats as a therapeutic treatment for FRDA. We have designed a pair of meganucleases that introduce double-strand breaks on either side of the FXN trinucleotide repeat region, generating compatible 3' overhangs that can be repaired by direct ligation, resulting in precise excision of the intervening region. Introduction of this pair of meganucleases into FRDA patient fibroblasts in cell culture results in the successful deletion of the causative repeat region in greater than 15% of the transfected cells. This removal of the FRDA repeat region has been confirmed using both digital PCR-based analytics and deep sequencing. Additional analysis of Frataxin mRNA production, Frataxin protein levels, and cellular metabolism will further demonstrate the utility of the repeat excision approach for FRDA gene therapy.
High Dose 90Yttrium Ibritumomab Tiuxetan with PBSC Support in Refractory-Resistant NHL Patients.
Authors: Anna Vanazzi, Pier Francesco Ferrucci, Chiara Grana, Marta Cremonesi, Margherita Clerici, Davide Radice, Stefano Papi, Liliana Calabrese, Giovanni Paganelli, Giovanni Martinelli
Journal: Blood (2007)
366. Development of Engineered Magnetic Nanoparticles Coupled With Lentiviral Vectors for Targeted Cancer Therapy and Hyperthermia
Authors: Ester Borroni, Marta Miola, Andrea Cochis, Sara Ferraris, Enrico Catalano, Sasha Novak, Maria Prat, Lia Rimondini, Enrica Verne’, Antonia Follenzi
Journal: Molecular Therapy (2015)

Background In recent years, considerable efforts have been spent to develop magnetic nanoparticles (MNPs) and to improve their applicability in several areas including hyperthermia and target cancer gene therapies. The aim of the present study was to synthesize and characterize Fe3O4, magnetite core-silica shell and magnetite core-silica shell doped with calcium ions nanoparticles (NPs) in combination with lentiviral vectors to deliver therapeutic genes in vivo. Materials and Methods Magnetite NPs were prepared by co-precipitation method, the silica shell was obtained by wet chemistry on the magnetic core stabilized with citric acid. Calcium ions were added to the silica shell modulating the NPs surface reactivity. The NPs were characterized with X-Ray diffraction, transmission electron microscopy, Vibrating Sample Magnetometer and zeta potential. Cytocompatibility tests were performed using both direct and not-direct contact models with murine endothelial cells (MS1) both in static and dynamic conditions using MNP coupled with/out LV. MNP and MNP-LV were tail vein injected intravenously in C57/Bl6 mice, biodistribution and expression studies were performed by histology and immunofluorescence using GFP as a marker gene. Results Spherical magnetite nanoparticles of about 15 nm in diameter were obtained with good dispersion in water. Addition of silica and calcium allowed obtaining a thin and amorphous silica or Ca-enriched silica shell, maintaining good dispersion in water. All the MNPs displayed a superparamagnetic behaviour. The MNP+/-LV used demonstrated to be cytocompatible in both static traditional and dynamic cytocompatibility models. Moreover when MNP-LV injected in mice we detected GFP expression mainly in the liver and spleen with biodistribution differences based on the MNPs-LV combination used. Conclusion These results suggest these NPs as promising for in vivo applications. Biodistribution studies in vivo of Fe3O4 NPs in mice models were performed and accumulation of NPs into vital organs was minimal with no toxicity in mice up to 1 month later and sustained GFP expression detected with no inflammatory responses. The present studies can significantly improve the cancer therapy effectiveness by means of a selective and localized delivery of transgenes together with the opportunity to conjugate hyperthermic and genetic approaches using therapeutic transgenes.
Is Less Chemotherapy Detrimental in Adults with Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) Treated with High-Dose Imatinib? Results of the Prospective Randomized Graaph-2005 Study
Authors: Yves Chalandon, Xavier Thomas, Sandrine Hayette, Jean-Michel Cayuela, Claire Abbal, Françoise Huguet, Emmanuel Raffoux, Thibaut Leguay, Stéphane Leprêtre, Martine Escoffre-Barbe, Sébastien Maury, Céline Berthon, Emmanuelle Tavernier, Jean-Francois Lambert, Marina Lafage, Véronique Lhéritier, Sylvie Chevret, Norbert Ifrah, Hervé Dombret
Journal: Blood (2012)
Pharmacokinetics and Tolerability of Intravenous Busulfan in Hematopoietic Stem Cell Transplantation.
Authors: Sung-Soo Yoon, Yo-Han Cho, Hyun-Ae Lim, Inho Kim, Soo-Mee Bang, Jong Seok Lee, Seonyang Park, Byoung KooK Kim
Journal: Blood (2006)
326. Improving CRISPR-Cas9 Precision Through Directly or Indirectly Tethered DNA-Binding Domains
Authors: Scot Wolfe, Mehmet F. Bolukbasi, Ankit Gupta, Lihua J. Zhu
Journal: Molecular Therapy (2016)

Type II CRISPR-Cas9 systems provide a robust and versatile platform to study gene function in complex genomes, but the standard CRISPR-Cas9 system is sub-optimal for many clinical-level genome editing applications due to insufficient precision. To establish a Cas9-based system that will cut at only a single site within a genome, we have developed an attenuated CRISPR-Cas9 platform fused to a programmable DNA-binding domain. This combination adds an extra specificity determinant to the engagement of a DNA sequence prior to cleavage. The appended DNA-binding domain increases the design density of Cas9 target sites and provides dramatically improved on- vs off-target selectivity as assessed by targeted deep sequencing based on GUIDE-seq analysis. In addition, the DNA-binding domain provides a tunable system that can be used to eliminate residual off-target activity to increase the precision of our nuclease system. We have extended the functionality of this platform through the incorporation of drug-dependent dimerization domains that facilitate the temporal control of gene editing via the presence of a small molecule. This novel platform has the potential to generate regulatable site-specific nucleases with single-site precision for targeted-genome editing, bringing programmable nuclease technology one step closer toward the ultimate goal of facilitating gene therapy-based therapeutics for a multitude of diseases.
Study of Renal Iron Overload by T2* MRI in a Large Cohort of Thalassemia Major Patients
Authors: Antonella Meloni, Daniele De Marchi, Vincenzo Positano, Gaetano Giuffrida, Sabrina Armari, Saveria Campisi, Mario Furbetta, Aurelio Maggio, Gianluca Valeri, Elisabetta Chiodi, Massimo Lombardi, Alessia Pepe
Journal: Blood (2012)
Impact of time to surgery after neoadjuvant chemotherapy in patients with operable breast cancer
Authors: F. Piacentini, M.E. Filieri, G. Grizzi, C. Omarini, M. Maur, G. Guaitoli, G. Tazzioli, S. Madrigali, F. Caggia, G. Luppi
Journal: Annals of Oncology (2015)
Klotho Polymorphisms and Priapism In Sickle Cell Disease.
Authors: Claudia R Lustosa Souza, Marily M Azevedo Shimmoto, Perla Vicari, Martha Mariana A S Arruda, Marina Roizenblatt, Ana C Cabanas Pedro, Debora Y Hayashida, Grazielle Mecabo, Maria Stella Figueiredo
Journal: Blood (2010)
526. Specific Companion Cells Enhance the Engraftment of Ex-Vivo Expanded HSCs (CD34 + /CD38 − /CD90+)
Authors: Nikoleta Psatha, Thalia Papayannopoulou
Journal: Molecular Therapy (2016)

Efforts to expand in vitro the number of engraftable hematopoietic stem cells (HSCs) for transplantation, is an ongoing quest in stem cell biology. Success in this endeavor is critical for increasing insufficient donor cells for transplantation and/or for the in vitro manipulation of autologous stem cells in gene therapy approaches. Recent studies have revealed that a number of novel small molecules can efficiently enhance the HSC-like phenotype of cultured cells with Stem Regenin1 (SR1) and UM171 showing the most promising outcomes. However, most of the published studies were focused mainly on CB-derived HSPCs, whereas adult HSPC expansion has been largely understudied. Here, we explored the effect of some of the most successful small molecules (SR1,UM171,and Ly2228820 (Ly)) alone or in combination on mobilized adult CD34+ cells, all in the presence of the same 3 cytokines (SCF, Flt-3, TPO). Within a week the absolute number of nucleated cell and CD34+ cells was similarly increased in all conditions. Highly enriched HSCs ,as defined by CD34+/CD38-/CD90+ or CD34+/CD45RA-/CD133+ expression,were comparable in UM171 alone or in SR-1+Ly (fold difference over control: 34/38/90: 6.54 and 5.94 34/45RA/133: 3.91 and 5.16, respectively), but the combination of all 3 rendered significantly higher numbers of these cells (fold difference over control: 34/38/90:12.9, 34/45RA/133: 9.3). Apart from the phenotypically defined HSCs, however, other cell populations were distinctly different under these conditions. Under SR1+Ly stimulation there was a significant number of morphologically recognizable Megakaryocytes (CD41+/CD42+) and an increase of CFU-Meg even in the absence of TPO. This was not the case in UM171 stimulated cultures despite the presence of CD41+ cells (12.5±1.5%). The engraftment potential of ex vivo expanded cells under UM171 or SR1+Ly and UM171+SR1+Ly, was tested in xenogeneic animals (NSG) in vivo. Cells cultured in SR1+Ly (±UM171) displayed a transient benefit over the UM171 alone at 4 -8wks post transplantation, as higher proportions of human CD45+ cells (3- 4 fold) and higher numbers of human Platelets (2 fold) were detected in peripheral blood of transplanted mice. This early benefit was not related to the number of CFU present in the inoculum, as UM171 expanded cells had higher number of CFUs (1.7 fold). It is tempting to speculate that the presence of mature Megs in the SR1+Ly treated grafts is responsible for this outcome. Thus we conclude that a) the combinations of SR1+Ly or UM171 efficiently maintain and even enhance the engraftable HSCs from adult mCD34+ cells, b) presence of SR1+Ly in the expansion media favorably influence short term engraftment, especially platelet recovery, and c) highlight the fact that more differentiated companion cells (i.e Megs) under certain combinations of the right molecules can enhance transplant outcomes.
An Open-Label Phase I Pharmacokinetic Study of [14c] Bendamustine in Patients with Relapsed or Refractory Malignancy
Authors: Anne-Charlotte Dubbelman, Hilde Rosing, Mona Darwish, Denise D'Andrea, Mary Bond, Edward T. Hellriegel, Jos H. Beijnen, Jan H. M. Schellens
Journal: Blood (2011)