tbuckley/cabot-search huggingface dataset:
Phase I Study of Bortezomib and Romidepsin in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Indolent B-Cell Lymphoma, or Peripheral T-Cell Lymphoma
Authors: Beata Holkova, Thomas C. Shea, Prithviraj Bose, Mary Beth Tombes, Ellen Shrader, Wen Wan, Caryn Weir-Wiggins, Elizabeth Stoddert, Heidi Sankala, Maciej Kmieciak, John D. Roberts, Steven Grant
Journal: Blood (2012)
560. Generation of Functional Regulatory T Cells by FOXP3 Gene Transfer into CD4 T Cell from IPEX Patients
Authors: Emmanuelle Six, Nelly Sigrist, David Zemmour, Marie-Andrée Bessard, Fabienne Mazerolles, Samia Martin, Fulvio Mavilio, Frederic Rieux-Laucat, Christophe Benoist, Isabelle André-Schmutz, Marina Cavazzana
Journal: Molecular Therapy (2016)

IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked) syndrome is the prototype of primary immunodeficiency with prevailing autoimmunity. The disease is caused by mutations in the gene encoding the transcription factor forkhead box P3 (FOXP3), which leads to the loss of function of thymus-derived CD4+CD25+ regulatory T (tTreg) cells. In IPEX patients, the absence of a functional Treg cell compartment leads to the development of multiple autoimmune manifestations (including severe enteropathy, type 1 diabetes and eczema) usually in the first months or years of life. The current treatments for IPEX syndrome include immunosuppressive, hormone replacement therapies. Unfortunately, immunosuppressive treatments are usually only partially effective and their dose is often limited because of the occurrence of infectious complications and toxicity. Currently, the only curative treatment for IPEX syndrome is allogeneic hematopoietic stem cell transplantation (HSCT). The absence of an HLA-compatible donor for all patients and their poor clinical condition particularly expose them to a risk of mortality when HLA partially compatible donors are used. For all these reasons, effective alternative therapeutic approaches are urgently needed. Various preclinical studies have shown that partial donor chimerism is sufficient for complete remission meaning that a small number of functional natural Treg is sufficient to restore immune tolerance. This suggests that T cell gene therapy approaches designed to selectively restore the repertoire of Treg cells is a promising potential cure for IPEX. We demonstrated that FOXP3 gene transfer into CD4+ T cells from IPEX patients enable the generation of potent and stable regulatory T cells. Indeed we showed the functional suppressive properties of the generated CD4IPEX-FOXP3 cells in an optimized flow-cytometry-based in vitro suppression assay. We are currently comparing the transcriptional profile of these regulatory CD4IPEX-FOXP3 cells in comparison to natural Treg by RNA-seq analysis. Therefore, the introduction of a functional copy of the FOXP3 gene into an IPEX patient's T cells may be enough to restore immune tolerance and thus avoid the complications of allogenic HSCT. We will also discuss the challenge of generating a large, homogenous and stable population of cells in vitro for adoptive transfer and whether it can ensure long-term disease correction without generating a context of generalized immunosuppression.
Synergistic Combinations of Histone Deacetylase Inhibitors and Decitabine Induce a Unique Gene Expression and Epigenetic Profile In Models of Diffuse Large B-Cell Lymphoma
Authors: Matko Kalac, Enrica Marchi, Luigi Scotto, Jennifer Amengual, Venkatraman Seshan, Govind Bhagat, Netha Ulahannan, Violetta Leshchenko, Samir Parekh, Benjamin Tycko, Owen A. O'Connor
Journal: Blood (2010)
Abstract 4201: Development of a syngeneic metastatic mouse model of malignant lymphoma
Authors: Takuro Matsumoto, Atsushi Suetsugu, Yuhei Shibata, Nobuhiko Nakamura, Hitomi Aoki, Takahiro Kunisada, Masahito Shimizu, Hisashi Tsurumi, Robert M. Hoffman
Journal: Cancer Research (2015)

Abstract We have developed a mouse model of highly malignant lymphoma. The EL4 cell line was established from a lymphoma induced in a C57/BL6 mouse by 9,10-dimethyl-1,2-benzanthracene. Red fluorescent protein (RFP)-EL4 lymphoma cells were established. EL4-RFP cancer cells were injected in the tail vein of C57/BL6 GFP transgenic mice. EL4-RFP metastasis was observed in the lymph nodes of the superior mediastinum and in the liver 28 days later. The EL4-RFP tumors were visualized in the liver with the Olympus SZX7 microscope. Large EL4-RFP liver metastases in C57/BL6 GFP mice had GFP stromal cells derived from the host animal around the edge of EL4-RFP tumors. In addition, EL4-RFP lymphoma cells metastasis was formed in perigastric lymph node. EL4-RFP lymphoma cells circulated in the peripheral blood. Furthermore, EL4-RFP lymphoma cells were observed in bone marrow of C57/BL6 GFP transgenic mice. In summary, lymph node metastasis, liver metastasis and bone marrow metastasis were found approximately 4 weeks after transplantation. This malignant lymphoma model can be used to study early tumor development, metastasis, the role of stroma and discovery and evaluation of novel therapeuticus for this treatment-resistant disease. Citation Format: Takuro Matsumoto, Atsushi Suetsugu, Yuhei Shibata, Nobuhiko Nakamura, Hitomi Aoki, Takahiro Kunisada, Masahito Shimizu, Hisashi Tsurumi, Robert M. Hoffman. Development of a syngeneic metastatic mouse model of malignant lymphoma. [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 4201. doi:10.1158/1538-7445.AM2015-4201
<i>H-RAS</i> and <i>PIK3CA</i> mutations and response to cetuximab in head and neck squamous cell carcinoma (HNSCC).
Authors: T. Rampias, A. Giagini, K. Florou, P. Gouveris, E. Vaja, N. Haralambakis, P. Katsaounis, D. G. Pectasides, T. Economopoulos, A. Psyrri
Journal: Journal of Clinical Oncology (2011)

5513 Background: Activation of RAS/MAPK/PI3K pathway is implicated in resistance to EGFR-targeted therapy in cancer. The prevalence of H-RAS and PIK3CA mutations has not been studied extensively in Caucasian populations. We sought to determine the impact of H-ras and PIK3CA gene mutations on resistance to cetuximab in head and neck cancer. Methods: We performed mutation analysis for H-RAS and PIK3CA genes in a cohort of 105 untreated HNSCC patients. To investigate whether PI3K/HRAS mutations in head and neck cancer can lead to resistance to EGFR inhibitors, we treated HNSCC cell lines Cal-33 (PIK3CA mutation), HSC-2 (PIK3CA mutation), BB49 (HRAS mutation) and A431 cells with increasing concentrations of cetuximab alone, PI3K inhibitor (LY294002) alone or both and performed MTT cell viability assay 72 hours later. We subsequently treated tumor xenografts derived from the aforementioned cell lines with cetuximab or LY294002 or both and measured tumor volume 4 weeks later. Results: We found that 30 of 105 (29%) HNSCC contained H-ras molecular alterations and 4 of 105 (4%) PIK3CAmutations. Eight of 30 H-RAS genetic alterations were mutations at hotspot codons 12, 13 and 61. We found one mutation in codon 63, 2 in codon 14 and a frequent polymorphism at nucleotide 81T→C in 19 samples. Cal-33, HSC-2 and BB49 cell lines were found to be resistant to cetuximab. Treatment of Cal-33, HSC-2 and BB49 cell lines with the PI3K inhibitor LY294002 either alone or in combination with cetuximab, led to a marked reduction of their viability. Immunoblotting analysis showed that treatment of cetuximab resistant cell lines with the PI3K inhibitor LY294002 +/- cetuximab resulted in marked decrease in levels of phospho-AKT. Xenograft experiments showed that tumor volumes were significantly reduced in LY294002 and LY294002 + cetuximab treated cell lines. Conclusions: These results indicate that the activation of RAS/PI3K signaling pathway is implicated in resistance to cetuximab in HNSCC. The functional significance of mutations in codons 14 and 63 and the 81T→C polymorphism needs to be determined.
33. Ex Vivo Gene Therapy for Lysosomal Storage Disease in the CNS: Patient iPSC-Derived Neural Stem Cells Correct Pathology in the MPS VII Mouse Brain
Authors: Tagan A. Griffin, Hayley C. Anderson, John H. Wolfe
Journal: Molecular Therapy (2015)

Neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) may offer an immunologically compatible delivery vehicle for therapeutic proteins in the brain. We evaluated a complete process of ex vivo gene therapy using patient-derived cells in a well-characterized mouse model of the lysosomal storage disease, MPS VII. Fibroblasts from a patient with MPS VII were reprogrammed into iPSCs, and differentiated into multi-potent NSCs. Patient-derived NSCs were able to engraft across the rostrocaudal axis following transplantation in neonatal NOD/SCID mice but were present in very low densities, similar to that seen with primary NSCs. We used a PiggyBac-based transposon vector to deliver a functional version of the missing GUSB gene to patient NSCs, which then expressed normal levels of enzymatically active GUSB. Genetically corrected iPSC-NSCs transplanted post-symptomatically into the striatum of adult MPS VII mice reversed neuropathology in a zone surrounding the grafts, while control contralateral grafts did not. The patient-derived iPSC-NSCs had similar engraftment properties as iPSC-NSCs from a normal human subject, and both lines engrafted similarly in normal and MPS VII NOD-SCID mouse brains. The results demonstrate the potential for ex vivo gene therapy in the brain using human NSCs from autologous, non-neural tissues.
Phase II study of cladribine with rituximab (R-2-CdA) therapy in patients with relapsed indolent B-cell non-Hodgkin's lymphoma
Authors: H. Nagai, S. Kusumoto, K. Sawada, M. Yamaguchi, N. Takayama, T. Kinoshita, T. Motoji, K. Omachi, M. Ogura, T. Hotta
Journal: Journal of Clinical Oncology (2009)

e19501 Background: Although cladribine has been reported to be one of active purine analogs against indolent B-cell non-Hodgkin's lymphoma (B-NHL), there are few reports of combination usage of cladribine and rituximab. We conducted a multicenter phase II study to investigate efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy for relapsed indolent B-NHL. Methods: Eligibility criteria were as follows: relapsed pts with indolent B-NHL from systemic chemotherapy, ages less than 75 years; PS 0–2 by ECOG's scale. Patients received 0.09mg/kg of cladribine intravenously (2 hrs infusion) on days 1 to 5 and 375mg/m2 of rituximab intravenously on days 1 and 15, every 4 weeks, for a total of 4 cycles. Primary endpoint was overall response rate (ORR). Secondary endpoints were % complete response (%CR), 2 years progression free survival (2-y PFS), and 2 years overall survival (2-y OS). Results: A total of 20 out of 45 planned patients were enrolled and received R-2-CdA therapy from Apr 2005 to Jul 2007. Their median age was 58.5 (42–72), and the median number of prior regimens was 2 (1–3). Histologies included 16 follicular lymphomas, 2 MALT lymphomas, 1 nodal marginal B cell lymphoma, and 1 lymphoplasmacytic lymphoma. Fifteen pts (75%) were previously treated with rituximab. The ORR was 90% with 70% of % CR. Median PFS was 20.1 months (5.6–32.9 months) at a median follow-up time of 27 months. 2-y PFS and 2-y OS were 63.2% (95%CI, 28.1–67.8%), and 89.5% (95%CI, 69.8–97.2%), respectively. Severe neutropenia and thrombocytopenia of grade 3 or 4 were observed in 15% and 10% respectively. Conclusions: R-2CdA therapy was demonstrated to have high activity with durable PFS and acceptable toxicity in relapsed indolent B-NHL, even if patients were previously treated with rituximab. Although a large-scaled further trial remains to be needed, R-2-CdA therapy could be a good option of salvage therapy in relapsed indolent B-NHL. No significant financial relationships to disclose.
High Expression of Transcription Factor Yin Yang 1 and Multidrug Resistance Protein in Early B-Cell Precursors in Childhood Acute Lymphoblastic Leukemia.
Authors: Gabriela Antonio-Andres, Rosana Pelayo, Elisa Dorantes-Acosta, Briseida Lopez-Martinez, Belen Tirado-Rodriguez, Guadalupe Diaz-Elizondo, Mario I. Vega, Lourdes Arriaga-Pizano, Guillermina Juliana Baay-Guzmán, Daniel Hernandez-Cueto, Benjamin Bonavida, Aurora Medina-Sanson, Sara Huerta-Yepez
Journal: Blood (2009)
PWE-031 Orofacial granulomatosis and anti-tumour necrosis factor therapy: a case series
Authors: T Elliott, C Nunes, H Campbell, T Poate, M Escudier, J Hirst, K Barnard, P Shaw, M Lomer, P Patel, J Sanderson, S Challacombe
Journal: Gut (2010)

<h3>Introduction</h3> Anti-tumour necrosis factor (TNF) therapy (infliximab (IFX) or adalimumab (ADA)) has been used as an alternative treatment in patients with Orofacial granulomatosis (OFG) failing conventional therapies, with evidence of promising clinical efficacy. However, concerns regarding safety have been raised and experience is limited. We report on the short and long-term efficacy and safety of anti-TNF therapy for OFG in this case series of 15 patients, the largest reported series to date. <h3>Methods</h3> A retrospective study of all patients who received anti-TNF therapy for OFG±Crohn9s disease (CD) was performed. Diagnoses of OFG and CD were made on conventional clinical and histological grounds. Demographics, clinical details, oral disease activity scores (ODAS) and laboratory results were obtained from patient records. Patients were considered for induction and maintenance anti-TNF therapy after failing other recognised OFG therapies. Clinical response was assessed at 4 months, 1 and 2 years after anti-TNF initiation. Regular monitoring for adverse effects was performed. <h3>Results</h3> Of 207 patients in our OFG clinic database, 15 (9 males) were treated with anti-TNF therapy between 2001 and 2009 (OFG only (n=7), OFG with CD (n=7), OFG with perianal disease (n=1)). Median age at OFG onset and at anti-TNF initiation were 26 years and 36 years. Median time between OFG onset and presentation to clinic was greater for the anti-TNF treated OFG patients than those not requiring anti-TNF (5 vs 2 years, p=0.001). Mean rank ODAS at initial presentation to clinic was higher in anti-TNF treated group than those not requiring anti-TNF (p&lt;0.05). First line anti-TNF therapy was IFX (n=14) and ADA (n=1). Ten patients received concomitant immunosuppression. Median duration of anti-TNF therapy was 12 months (range; 1 dose to 84 months). Short-term response was achieved in 9/15 (60%) patients. Eight of 15 (53%) and 4/13 (31%) patients remained responders at 1 and 2 years follow-up. Two patients failed IFX therapy and were treated with ADA; one remains responsive at 18 months, the other lost response at 12 months. Oral sulcal involvement was the only predictor for response at 1 and 2 years (p&lt;0.05). Concurrent CD did not predict response. The only adverse event leading to cessation of anti-TNF therapy was a patient with an IFX infusion reaction. <h3>Conclusion</h3> Anti TNF therapy has good short and reasonable long-term clinical efficacy (60% and 31%) for patients with OFG failing other therapies. It appears to be safe with a good side effect profile. OFG patients who fail IFX may respond to ADA.
Nonmyeloablative Unrelated Donor (URD) Hematopoietic Cell Transplantation (HCT) for the Treatment of Patients (pts) with Poor-Risk, Relapsed or Refractory Multiple Myeloma.
Authors: George E. Georges, Michael B. Maris, David G. Maloney, Brenda M. Sandmaier, Mohamed L. Sorror, Judith A. Shizuru, Dietger W. Niederwieser, Edward D. Agura, Benedetto Bruno, Peter A. McSweeney, Michael A. Pulsipher, Thomas R. Chauncey, Barry E. Storer, Rainer F. Storb
Journal: Blood (2005)
RTHP-32. RECONSIDERING RADIORESISTANCE: LINAC-BASED STEREOTACTIC RADIOSURGERY FOR INTRACRANIAL METASTASES FROM MELANOMA AND RENAL CELL CARCINOMA
Authors: Christine Feng, Jeffrey Lemons, David R. Raleigh, Murat Surucu, Karl Farrey, Bakhtiar Yamini, Steven J. Chmura, Daniel W. Golden
Journal: Neuro-Oncology (2016)

Melanoma and renal cell carcinoma (RCC) are traditionally classified as radioresistant histologies. Data using stereotactic radiosurgery (SRS) alone for radioresistant brain metastases demonstrate local control similar to non-radioresistant histologies. We report the University of Chicago experience treating melanoma and RCC with linear accelerator (LINAC)-based SRS. Patients treated with SRS alone for brain metastases from melanoma or RCC between 2000-2015 were retrospectively analyzed. Metastases were followed using MRI. Freedom from local failure (FFLF), freedom from distant intracranial failure (FFDICF) and overall survival (OS) were assessed. Log-rank and Cox proportional hazard models were used for analysis. Eighty-one patients were included, with median age 60.9 years and median ECOG=1. Forty patients presented asymptomatically and 31 had neurologic symptoms. Seventy-two patients had extracranial metastases, 32 had single brain metastases and 51 had primary tumor control. Cone-based SRS was used for 35 patients and micro-multi leaf collimators for 46 patients. Median SRS dose was 18Gy (range 15-20Gy) prescribed to median isodose line of 80% (range 56-99%). One hundred seventeen lesions were treated, with median diameter 12.6mm (range 3.3-48.9mm) and median lesion volume 0.80cm3 (range 0.01-12.4cm3). Actuarial OS at 6 months and 1 year was 55.4% and 30.2%, respectively. Actuarial FFDICF at 1 year was 20.6%. Analysis of individual lesions demonstrated 1-year FFLF of 51.5% for melanoma and 79.4% for RCC. On multivariable analysis, there was a trend toward improved FFLF for RCC patients (HR=0.63, p=0.06). Salvage therapy included WBRT (n=7), SRS (n=10), surgery (n=2), WBRT+SRS (n=1) and surgery+SRS (n=2). Four patients developed biopsy-proven radionecrosis. LINAC-based SRS for melanoma and RCC brain metastases was well-tolerated with acceptable toxicity. There is a trend toward improved FFLF for patients with RCC compared to those with melanoma. FFLF was lower than other histologies from historical reports, but consistent with published data for melanoma and RCC.
Abstract 3207: The roles of cancer-associated fibroblasts in stemness maintenance of lung cancer cells
Authors: Chih-An Lin, Chao-Chi Ho, Jeremy J.W. Chen
Journal: Cancer Research (2015)

Abstract Lung cancer is the leading cause of death worldwide including Taiwan. A lot of therapies have been developed to improve cure rate of lung cancer, however the prognosis remains dismal. Cancer cells can acquire resistance to therapies by several known or unknown mechanisms. Microenvironment is also important for acquiring resistance to corresponding treatments of cancer cells. Cancer-associated fibroblasts (CAFs) are known to support many different aspects of tumor initiation, growth and progression by secretion of growth stimulatory, pro-survival and angiogenic factors. In our studies, we compare the differences between normal fibroblasts (NFs) and CAFs which were cultured from surgical specimens of lung cancer patients. CAFs shows increasing tumorous sphere formation ability and significantly up-regulating stem cell markers such as nanog, klf-4, Sox-2, Oct4 and c-myc of cancer cells. We also found that CAFs regulate cancer stem cells (CSCs) growth through numerous paracrine factors such as IGF-II, HGF and SDF1 and by inducing expression of the corresponding receptors in CSCs, including IGF1R, IGF2R, HGFR and CXCR4. In our studies, CAFs obtain more advanced ability compared to NFs, but the mechanisms of how NFs are educated to become CAFs are still unknown, thus we trying to clarify the mechanisms by genome and epigenome-wide high-throughput analysis, including cDNA array, DNA methylation array and miRNA array. Citation Format: Chih-An Lin, Chao-Chi Ho, Jeremy J.W. Chen. The roles of cancer-associated fibroblasts in stemness maintenance of lung cancer cells. [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 3207. doi:10.1158/1538-7445.AM2015-3207
Abstract 2304: The role of methyltransferase, enhancer of zeste homolog 2 (EZH2) in mouse hepatocyte and human hepatocellular carcinoma
Authors: Woo Kyun Bae, Hyun Jeong Shim, Sang Hee Cho, Ik-Joo Chung, In-Kyu Park, Lothar Hennighausen
Journal: Cancer Research (2015)

Abstract To investigate the role of EZH1 and EZH2 in liver homeostasis, mice were generated that carried Ezh1-/- and EZH2fl/fl alleles and an Alb-Cre transgene. Only combined loss of EZH1 and EZH2 in mouse hepatocytes caused a depletion of global H3K27me3 marks and the specific loss over ∼1900 genes at 3 months of age. Ezh1-/-,Ezh2fl/flAlb-Cre mice exhibited progressive liver abnormalities manifested by development of regenerative nodules and concomitant periportal fibrosis, inflammatory infiltration and activation of A6-positive hepatic progenitor cells at 8 months of age. In response to chronic treatment with CCl4, all experimental mice but none of the controls (n = 27 each) showed increased hepatic degeneration associated with liver dysfunction and reduced ability to proliferate. After 2/3ds partial hepatectomy, mutant mice (n = 5) displayed increased liver injury and a blunted regenerative response. Genome-wide analyses at 3-months of age identified 51 genes that had lost H3K27me3 marks and their expression was significantly increased. These genes were involved in regulation of cell survival, fibrosis, and proliferation. H3K27me3 levels and liver physiology were unaffected in mice lacking either EZH1 globally or EZH2 specifically in hepatocytes. This work demonstrates a critical redundancy of EZH1 and EZH2 in maintaining hepatic homeostasis and regeneration. Next, we checked the expression EZH2 and H3K27me3 status in 67 human hepatocellular carcinoma (HCC) samples. We also checked the gene expression by the next-generation sequencing based on EZH2 expression. This work demonstrates candidate EZH2 target genes in human HCC. Citation Format: Woo Kyun Bae, Hyun Jeong Shim, Sang Hee Cho, Ik-Joo Chung, In-Kyu Park, Lothar Hennighausen. The role of methyltransferase, enhancer of zeste homolog 2 (EZH2) in mouse hepatocyte and human hepatocellular carcinoma. [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 2304. doi:10.1158/1538-7445.AM2015-2304