tbuckley/cabot-search huggingface dataset:
HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-Related Membranous Nephropathy
Authors: Wei-Bo Le, Jing-Song Shi, Tao Zhang, Lei Liu, Hua-Zhang Qin, ShaoShan Liang, Yuan-Wei Zhang, Cun-Xia Zheng, Song Jiang, Wei-Song Qin, Hai-Tao Zhang, Zhi-Hong Liu
Journal: Journal of the American Society of Nephrology (2016)

Idiopathic membranous nephropathy (MN) is associated with HLA; however, the HLA allele involved remains unknown. To identify the HLA risk alleles associated with phospholipase A2 receptor (PLA2R)-related MN in the Chinese population, we sequenced the entire MHC region in DNA samples from 99 patients with PLA2R-related MN, 50 patients with PLA2R-unrelated MN, and 100 healthy subjects. Two HLA risk alleles, HLA-DRB1*15:01 and HLA-DRB3*02:02, independently and strongly associated with an increased risk of PLA2R-related MN. After adjusting for HLA-DRB1*15:01 and HLA-DRB3*02:02, no other alleles showed significant association with PLA2R-related MN. A replication study in an independent cohort of 293 participants with PLA2R-related MN and 285 healthy controls validated these findings. In a joint analysis, a multivariate logistic regression model confirmed that HLA-DRB1*15:01 (odds ratio [OR], 24.9; 95% confidence interval [95% CI], 15.3 to 42.6; P=2.3×10-35) and HLA-DRB3*02:02 (OR, 17.7; 95% CI, 11.0 to 30.3; P=8.0×10-29) independently and strongly associated with PLA2R-related MN. As many as 98.7% of patients with PLA2R-related MN, compared with 43.9% of control subjects, carried at least one HLA risk allele. Subjects with either risk allele had higher odds of developing PLA2R-related MN than those without a risk allele (OR, 98.9; 95% CI, 44.4 to 281.7; P=2.5×10-23). These HLA risk alleles also associated with the age at disease onset in patients with PLA2R-related MN. In conclusion, our findings provide clear evidence that the HLA-DRB1*15:01 and HLA-DRB3*02:02 alleles independently and strongly associate with PLA2R-related MN in the Chinese population.
Abstract 3854: Inhibition of uracil DNA glycosylase (UDG) sensitizes cancer cells to thymidylate synthase inhibitors
Authors: Yan Yan, Allison Condie, Stanton Gerson
Journal: Cancer Research (2015)

Abstract Thymidylate synthase (TS) is responsible for the de novo synthesis of thymine nucleotides that are used as building blocks for DNA synthesis. Two classes of therapeutic agents inhibit TS including fluropyrimidines (eg, 5-FU, 5-FdU) and antifolates (eg, pemetrexed), which lead to depletion of deoxythymidine triphosphate (dTTP) and expansion of deoxyuridine triphosphate (dUTP). Fluropyrimidines are also metabolized to 5-fluorouridine triphosphate (5FdUTP). As a result, both elevated dUTP and 5FdUTP are incorporated into DNA. Uracil DNA N-glycosylase (UDG or UNG) is the primary DNA repair enzyme to remove uracil and 5-FU bases from DNA and creates abasic (AP) sites, thus initiating base excision repair (BER) pathway. However, whether the cytotoxic effects of TS inhibitors are dependent on UDG activity still remains controversial. Previously, our lab has shown that in DLD1 colon cancer cells, knockout of UDG hypersensitized cells to pemetrexed treatment and the cell death was accompanied by remarkable S phase arrest and stalled replication fork. In this study, we examined the cytotoxicity of both pemetrexed and 5-FdU in SW480, HCT116, DLD1, and HEC1A cancer cell lines after performing stable UDG knockdown (KD) by shRNA. We hypothesized that loss of UDG would sensitize cancer cells to TS inhibitors treatment with accumulation of a large amount of uracil and 5-FU bases in DNA and ultimately lead to replication folk collapse. Results showed that reduced UDG protein and activity levels enhanced the cell killing effect, increased the sub-G1 populations, and delayed cell cycle recovery following TS inhibitors treatment. In response to 5-FdU treatment, cells with UDG shRNA were mainly arrested at late G1 and early S phase by 24 hours of treatment. After releasing cells in drug free medium, loss of UDG displayed delayed recovery from cell cycle arrest in comparison to shRNA scramble control cells. We have also detected a significant induction of the amount of AP sites after incubation of extracted DNA from UDG shRNA KD cells with purified UDG protein following 5-FdU treatment, indicating the accumulation of uracil and 5-FU in DNA as a consequence of 5-FdU treatment. Now, further studies are undergoing to determine the actual levels of uracil and 5-FU incorporation into DNA and the replication status after TS inhibitors treatment. These studies confirm that uracil and 5-FU incorporation due to loss of UDG accelerates stall of replication, collapse of the replication fork, and increased cytotoxicity of TS inhibitors. Citation Format: Yan Yan, Allison Condie, Stanton Gerson. Inhibition of uracil DNA glycosylase (UDG) sensitizes cancer cells to thymidylate synthase inhibitors. [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 3854. doi:10.1158/1538-7445.AM2015-3854
Have Clinicians Adopted the International Uniform Response Criteria (IURC) for Multiple Myeloma (MM)? Adherence to the IURC for Posttransplant Evaluations In Patients with Multiple Myeloma
Authors: Kenneth Utz, Bonita Neumon, Brenda L. Frye, Ju-Hsien Chao, Juan Toro, David Haile, Cesar Freytes
Journal: Blood (2010)
685. Efficient Targeted Gene Modification in Primary Human Hematopoietic Cells Using Co-Delivery of Nuclease mRNA and AAV Donors
Authors: Guillermo S. Romano Ibarra, Gabrielle Curinga, Blythe D. Sather, Karen M. Sommer, Malika Hale, Iram Khan, Swati Singh, Youmei Song, Kamila Gwiazda, Jaya Sahni, Socheath Khim, Alexander Astrakhan, Thor Wagner, Andrew M. Scharenberg, David J. Rawlings
Journal: Molecular Therapy (2015)

Current clinical HIV treatment strategies applying gene-editing technologies to disrupt the HIV co-receptor CCR5 via nuclease delivery are limited by inefficient bi-allelic disruption and the lack of a combinatorial approach to control HIV infection. The ability to target additional factors conferring HIV resistance to the CCR5 locus with efficient bi-allelic disruption has the potential to translate to improved clinical outcomes. Here we demonstrate a novel method in which RNA-based nuclease expression is paired with AAV-mediated delivery of a homologous gene-targeting donor template to achieve highly efficient targeted recombination in primary human T-cells. This method consistently achieves an average of 60% rates of homology directed recombination into the CCR5 locus in T-cells (>20 experiments with multiple donors); with up to 90% of the gene-modified population exhibiting bi-allelic modification. T-cells modified with this protocol maintain a diverse repertoire and engraft in immune deficient, NOD/SCID/gc-/- (NSG) mice as efficiently as unmodified control T-cells. Using this method, we have integrated chimeric antigen receptors (CARs) into the CCR5 locus; and show that the resulting "targeted CAR" or tCAR T-cells exhibit anti-tumor activities indistinguishable from those generated using lentiviral random integration. Alternatively, we introduced the C46 HIV fusion inhibitor by targeted recombination generating T cell populations with very high-rates of bi-allelic CCR5 disruption paired with protection from HIV with CXCR4 co-receptor tropism. Next, as proof of principle, we utilized the CCR5 site as a 'safe harbor' locus for targeted gene addition of the human Wiskott-Aldrich syndrome (WAS) gene. Finally, this novel protocol was also successfully applied to adult human mobilized CD34+ cells, resulting in 10-20% homologous gene targeting, the first such report in adult human CD34+ cells at the CCR5 locus. Our results demonstrate that high-efficiency targeted integration is feasible in primary human cells, and highlight the potential of gene editing technologies to engineer CAR T-cells or other T cell products with myriad novel functional properties.
BCL-2 Phosphorylation Modulates Sensitivity to the BH3-Mimetic GX15-070 (Obatoclax) and Reduces Its Synergistic Interaction with Bortezomib in Chronic Lymphocytic Leukemia Cells.
Authors: Patricia Perez Galan, Gael Roue, Monica Lopez Guerra, Neus Villamor, Emili Montserrat, Elias Campo, Dolors Colomer
Journal: Blood (2007)
Abstract 3159: In vitro characterization of third-generation chimeric antigen receptor T cells directed toward GD2-expressing and BRAF-inhibitor resistant melanoma target cells
Authors: Tessa Gargett, Michael P. Brown
Journal: Cancer Research (2015)

Abstract Advances in the treatment of metastatic melanoma include the recent approval of the immunotherapy ipilimumab, an anti-CTLA-4 monoclonal antibody, and of the targeted therapies vemurafenib, dabrafenib and trametinib, which are mitogen-activated protein kinase (MAPK)-pathway inhibitors. Cancer immunotherapy also includes adoptive transfer of autologous tumor-specific chimeric antigen receptor (CAR) T cells. CAR T cells are responsible for significant tumor responses in leukemia and neuroblastoma patients. We have manufactured third-generation GD2-specific CAR T cells to be used in our open CARPETS Phase I clinical trial of autologous GD2-CAR T cells in patients with advanced GD2-expressing melanoma (ACTRN12613000198729). However, although these promising new targeted- and immuno-therapies can produce complete or partial tumor responses, tumor resistance via alteration or bypass of the targeted molecules inevitably occurs.Combination therapies have been proposed as a way to exploit the high-level but short-term responses associated with kinase-inhibitor therapies and the low-level but longer-term responses associated with immunotherapy, and could potentially overcome tumor resistance by targeting multiple tumor-associated molecules. To this end, we have investigated the effects of vemurafenib, dabrafenib and trametinib on the function of our GD2-CAR T cells and found that dabrafenib does not inhibit effector functions at concentrations equivalent to reported plasma concentrations in treated patients. We have also observed that although GD2-CAR T cells have reduced killing of BRAF inhibitor -resistant melanoma cell lines, their function is not inhibited by PD1 blockade in vitro.These effects depend on whether GD2-CAR T-cell activation occurs via the native TCR or the CAR and upon the nature of apoptosis resistance in the GD2-expressing melanoma target cells. Citation Format: Tessa Gargett, Michael P. Brown. In vitro characterization of third-generation chimeric antigen receptor T cells directed toward GD2-expressing and BRAF-inhibitor resistant melanoma target 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 3159. doi:10.1158/1538-7445.AM2015-3159
Early Allogeneic Hematopoietic Cell Transplantation in Patients with High Risk AML - Final Results From the Randomized AML 2003 Trial
Authors: Johannes Schetelig, Markus Schaich, Christoph Röllig, Kerstin Schäfer-Eckart, Matthias Hänel, Walter E. Aulitzky, Hermann Einsele, Hubert Serve, Norbert Schmitz, Wolfgang E. Berdel, Matthias Stelljes, Wolf Rösler, Jiri Mayer, Albrecht Reichle, Claudia D Baldus, Anthony D. Ho, Michael Kramer, Uwe Platzbecker, Christian Thiede, Martin Bornhäuser, Gerhard Ehninger
Journal: Blood (2012)
Analysis of pO<sub>2</sub> in malignant ascites of patients with peritoneal dissemination of gastric cancer.
Authors: S. Emoto, J. Kitayama, H. Ishigami, H. Yamaguchi, H. Yamashita, S. Kaisaki, H. Nagawa
Journal: Journal of Clinical Oncology (2011)

63 Background: Peritoneal metastasis is considered to develop from carcinoma cells detached from the serosal surface of the primary site and dispersed in the peritoneal cavity. And oxygen is one of the most important environmental factors for tumor development. To investigate the oxygenation condition in the abdominal cavity, that is largely unknown, we collected ascitic fluid from patients with peritoneal dissemination of gastric cancer and measured pO 2 of it. Methods: In 19 patients with peritoneal dissemination of gastric cancer, who had a considerable amount of ascites and was receiving systemic and/or intraperitoneal chemotherapy, ascitic fluid was collected at the bedside in room air, and its pH, pCO 2 and pO 2 were measured using a blood gas analyzer immediately. Results: In 19 patients, pH of malignant ascites was significantly lower than that of arterial blood (7.39 ± 0.069 vs 7.44 ± 0.025 mmHg, p &lt; 0.05). pCO 2 tended to be higher in ascites than in arterial blood. Unexpectedly, pO 2 in malignant ascites showed relatively high values (85.47 ± 23.31 mmHg), which were mostly the same as that of arterial blood (97.19 ± 10.40 mmHg, p = 0.149), and appeared to be higher than that in solid tumor tissue. Conclusions: Malignant ascites in gastric cancer patients showed an unexpectedly high oxygen tension, which was almost the same as that of arterial blood. The hyperpermeability condition may enable efficient oxygen delivery to peritoneal fluid via the microvessels lining the peritoneal cavity. Since the oxygen level critically affects the sensitivity of tumor cells to chemotherapeutic agents through metabolic transformation, aerobic conditions may be beneficial for the progression of peritoneal metastasis and also clinically important in considering the efficacy of chemotherapy. No significant financial relationships to disclose.
Abstract B04: NRF2 regulates serine biosynthesis in pancreatic ductal adenocarcinoma
Authors: Gina M. DeNicola, Pei-Hsuan Chen, Edouard Mullarky, Christine Chio, John M. Asara, John D. Minna, David A. Tuveson, Ralph J. DeBerardinis, Lewis C. Cantley
Journal: Cancer Research (2016)

Abstract Tumors have high energetic and anabolic needs for rapid growth and proliferation, and the serine biosynthetic pathway has recently been identified as an important source of metabolic intermediates for these processes. We recently demonstrated that a substantial fraction of NSCLC cell lines displayed significant serine/glycine biosynthetic activity due to KEAP1 and NRF2 mutations (DeNicola et al. Nature Genetics 2015). We demonstrated that NRF2 regulates glucose flux to serine by controlling transcription of serine biosynthetic genes through the transcription factor ATF4. Importantly, elevated expression of these genes conferred poor prognosis in human NSCLC. Thus, a substantial fraction of human NSCLC activates an NRF2-dependent transcriptional network that regulates serine and glycine metabolism and is linked to clinical aggressiveness. Pancreatic ductal adenocarcinoma (PDAC) also demonstrates high NRF2 activity due to mutations in KRAS and high MAPK signaling (DeNicola et al. Nature 2011). We demonstrate that serine biosynthesis enzyme expression is elevated in a mouse model of PDAC and that NRF2 regulates PHGDH expression in human PDAC cell lines. Furthermore, PDAC cell lines are resistant to serine starvation. PHGDH knockdown impairs the growth of tumor organoid orthotopic transplants, and the role of PHGDH in tumor maintenance is currently being investigated. These results suggest that the serine biosynthesis pathway is regulated by NRF2 in multiple cancers and may be an important therapeutic target. Citation Format: Gina M. DeNicola, Pei-Hsuan Chen, Edouard Mullarky, Christine Chio, John M. Asara, John D. Minna, David A. Tuveson, Ralph J. DeBerardinis, Lewis C. Cantley.{Authors}. NRF2 regulates serine biosynthesis in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B04.
First Line Treatment of Probable and Proven Invasive Aspergillosis with Caspofungin in Oncohemopatic Patients. A Single Centre Experience
Authors: Alessandro Bonini, Alessia Tieghi, Barbara Gamberi, Annalisa Imovilli, Cristiano Carbonelli, Luigi Zucchi, Lucia Spaggiari, Franco Nicoli, Alberto Cavazza, Maria Parmeggiani, Luigi Gugliotta
Journal: Blood (2008)
Pegylated Interferon Alpha-2a Therapy for Patients with High Risk Essential Thrombocytemia: a Retrospective Analysis on 59 Patients.On Behalf of the French Intergroup of Myeloproliferative Disorders (FIM)
Authors: Lydia Roy, Jean Christophe Ianotto, Joelle Guilhot, Emmanuel Raffoux, Emmanuel Gyan, Benoit de Renzis, Laurence Legros, Jean-François Viallard, Françoise Boyer, Cony Makhoul, Franck E Nicolini, Jean Gunecht, Stephane Giraudier
Journal: Blood (2010)
Development of a Microscopic Colitis Disease Activity Index: a prospective cohort study
Authors: Thomas G Cotter, Moritz Binder, Edward V Loftus, Rami Abboud, Meredythe A McNally, Thomas C Smyrk, William J Tremaine, William J Sandborn, Darrell S Pardi
Journal: Gut (2016)

Objective Microscopic colitis (MC) is a common cause of chronic diarrhoea, often with additional symptoms. No validated instruments exist to assess disease activity in MC, making it difficult to compare efficacy of treatments between clinical trials. We aimed to identify clinical features that independently predicted disease severity and create a Microscopic Colitis Disease Activity Index (MCDAI). Design Patients with MC were prospectively administered a survey assessing their GI symptoms and the IBD Questionnaire (IBDQ). A single investigator also scored a physician global assessment (PGA) of disease severity on a 10-point scale. Multiple linear regression identified which symptoms best predicted the PGA. These symptoms were then combined in a weighted formula to create the MCDAI. The relationship between MCDAI and the IBDQ was investigated. Results Of the 175 patients enrolled, 13 (7.4%) did not complete the survey. The remaining 162 had a median age of 66 years (range, 57–73) and 74% were female. Several clinical features were independently associated with PGA (number of unformed stools daily, presence of nocturnal stools, abdominal pain, weight loss, faecal urgency and faecal incontinence). These parameters were combined to create the MCDAI, which strongly predicted the PGA (R 2 =0.80). A 1-unit decrease in disease activity (ΔMCDAI) was associated with a 9-unit increase in quality of life (ΔIBDQ). Conclusions The MCDAI strongly predicted the PGA and correlated with a validated measure of quality of life. Several symptoms in addition to diarrhoea are associated with disease severity in MC.
Vaso-Occlusion-Promoting Neutrophil Mac-1 Integrin Activation in Human Sickle Cell Crises Is Stabilized By a Single Dose of Intravenous Gammaglobulin
Authors: Deepa Manwani, Grace Chen, Veronica Carullo, Hillel W Cohen, Stelian Serban, Olugbenga Olowukere, Jungeun Jang, Matthew Huggins, Henny H Billett, George F. Atweh, Paul S. Frenette, Patricia A Shi
Journal: Blood (2014)
Abstract 195: Insight into microRNA regulation of autophagy genes expression in crizotinib-treated Anaplastic Large Cell Lymphoma
Authors: Julie Frentzel, Geraldine Mitou, Pierre Brousset, Sylvie Giuriato
Journal: Cancer Research (2015)

Abstract The anaplastic lymphoma kinase (ALK) is an oncogenic tyrosine kinase involved in 80% of Anaplastic Large Cell Lymphoma (ALCL), and 5% of non-small cell lung carcinoma (NSCLC), among other cancers. The ongoing therapies in ALK+ ALCL, based on aggressive chemotherapy, are not optimal. One compound so far, the crizotinib, is used in clinics for the treatment of ALK-dependent lung cancers. However, the first mutations conferring resistance to crizotinib, have been reported and hampered its use for the treatment of ALK+ ALCL. Thus, despite the therapeutic success of tyrosine kinase inhibitors in cancer treatments, acquired drug resistances universally develop. In this context, cytoprotective autophagy has been proposed as the next target for elimination of resistance to tyrosine kinase inhibitors. We recently demonstrated that cytoprotective autophagy is indeed activated shortly upon ALK inactivation in ALCL and that its inhibition enhances the anti-tumoral action of Crizotinib. A transcriptome analysis showed an increased expression of many genes from the autophagy machinery such as ULK1, MAP1LC3B, or ATG16L2 after crizotinib treatment in ALCL. Moreover, new preliminary results enabled us to identify a set of miRNAs differentially expressed in ALCL upon Crizotinib treatment. As miRNAs are known as fine regulators of gene expression, we anticipate that some of them could be efficient regulators of core autophagy genes expression. The aim of our study is to select a few miRNAs of interest and to confirm their regulatory role on the autophagic machinery. This could lead to the development of new therapeutical strategies which could ultimately help to overcome emerging resistances against crizotinib. Citation Format: Julie Frentzel, Geraldine Mitou, Pierre Brousset, Sylvie Giuriato. Insight into microRNA regulation of autophagy genes expression in crizotinib-treated Anaplastic Large Cell 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 195. doi:10.1158/1538-7445.AM2015-195
Dual <i>ALK</i> and <i>CDK4/6</i> Inhibition Demonstrates Synergy against Neuroblastoma
Authors: Andrew C. Wood, Kateryna Krytska, Hannah T. Ryles, Nicole R. Infarinato, Renata Sano, Theodore D. Hansel, Lori S. Hart, Frederick J. King, Timothy R. Smith, Edward Ainscow, Kathryn B. Grandinetti, Tove Tuntland, Sunkyu Kim, Giordano Caponigro, You Qun He, Shiva Krupa, Nanxin Li, Jennifer L. Harris, Yaël P. Mossé
Journal: Clinical Cancer Research (2016)

Purpose: Anaplastic lymphoma kinase (ALK) is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an in vitro screen for synergistic drug combinations that target neuroblastomas with mutations in ALK to determine whether drug combinations could enhance antitumor efficacy.Experimental Design: We screened combinations of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines. We investigated the combination of ceritinib and ribociclib on in vitro proliferation, cell cycle, viability, caspase activation, and the cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status. We performed in vivo trials in CB17 SCID mice bearing conventional and patient-derived xenograft models comparing ceritinib alone, ribociclib alone, and the combination, with plasma pharmacokinetics to evaluate for drug-drug interactions.Results: The combination of ribociclib, a dual inhibitor of cyclin-dependent kinase (CDK) 4 and 6, and the ALK inhibitor ceritinib demonstrated higher cytotoxicity (P = 0.008) and synergy scores (P = 0.006) in cell lines with ALK mutations as compared with cell lines lacking mutations or alterations in ALK Compared with either drug alone, combination therapy enhanced growth inhibition, cell-cycle arrest, and caspase-independent cell death. Combination therapy achieved complete regressions in neuroblastoma xenografts with ALK-F1174L and F1245C de novo resistance mutations and prevented the emergence of resistance. Murine ribociclib and ceritinib plasma concentrations were unaltered by combination therapy.Conclusions: This preclinical combination drug screen with in vivo validation has provided the rationale for a first-in-children trial of combination ceritinib and ribociclib in a molecularly selected pediatric population. Clin Cancer Res; 23(11); 2856-68. ©2016 AACR.
Fludarabine Exposure Is Associated with Increased Treatment Related Mortality after Nonmyeloablative Hematopoietic Cell Transplantation (HCT)
Authors: Pamala A. Jacobson, Janel R Long, John Rogosheske, Kathleen Green, Claudio Brunstein, John E Wagner, Qing Cao, Jeffrey S. Miller, Philip McGlave, Daniel Weisdorf
Journal: Blood (2008)