tbuckley/cabot-search huggingface dataset:
273. Genome Editing Using CRISPR-Cas9 to Increase the Therapeutic Index of Antigen-Specific Immunotherapy in Acute Myeloid Leukemia
Authors: Miriam Y. Kim, Saad S. Kenderian, Daniel Schreeder, Michael Klichinsky, Miroslaw Kozlowski, Olga Schestova, Marco Ruella, Saar Gill
Journal: Molecular Therapy (2016)

Antigen-specific immunotherapy using chimeric antigen receptor (CAR) T cells or bispecific T cell engaging (BITE) antibodies directed against CD19 leads to elimination of malignant and normal B cells. These approaches have a broad therapeutic index in acute lymphoid leukemia (ALL) due to a combination of high anti-tumor activity and tolerability of prolonged B cell depletion. In contrast, in acute myeloid leukemia (AML) the absence of surface antigens specific to leukemia implies that potent myeloid-directed immunotherapy will eradicate normal as well as malignant cells, leading to protracted myeloablation and bone marrow failure, as has been shown in several preclinical studies of CD33 or CD123 directed CART cell therapy. We developed a novel approach to circumvent this problem by genetically modifying normal hematopoietic stem cells (HSCs) so that they do not express the antigen recognized by CART cells, thus generating normal myeloid progeny that is resistant to CART cell therapy. CD33 is expressed on the majority of AML as well on normal myeloid progenitors and its function is poorly characterized. We hypothesized that CD33 knockout HSCs and their myeloid progeny would develop normally yet be resistant to treatment with anti-CD33 CART cells (CART33). Electroporation of human CD34+ cells with Cas9 protein and in-vitro transcribed sgRNA generated deleterious mutations in the CD33 gene with 70-80% efficacy as measured by flow cytometry and DNA sequencing. Addition of a single-stranded oligonucleotide template with a short insertional mutation at the sgRNA cut site increased the knockout efficacy up to 90%. In vitro cytotoxicity assays showed CD33 KO HSC progeny are resistant to killing by CART33 compared to wild-type HSC controls (% live cells after CART33 co-culture: 60% vs. 18%, p=0.005). CD33 KO HSC progeny showed a similar growth and differentiation profile in Methocult semi-solid media compared to control cells that were electroporated with an unrelated sgRNA. The differentiated cells had normal neutrophil and macrophage morphology and immunophenotype. We also found that phagocytosis and cytokine secretion capabilities of the CD33 KO progeny were identical to WT control. NOD-SCID-g-/- (NSG) mice injected with CD33 KO HSCs showed normal engraftment with differentiation of both myeloid and lymphoid lineages. As expected, the percentage of CD33+ myeloid cells was lower in CD33 KO recipients than WT control (24% vs 63%, p<0.0001), yet the percentage of CD14+CD11b+ monocytes (45% vs 47%, p=0.77) and CD14-CD11b+ neutrophils (34% vs. 33%, p=0.87) were unaltered. This approach yields a potential strategy to treat AML with potent CD33-specific immunotherapy, followed by infusion of gene-modified CD33 KO HSCs, which will allow persistent antigen-specific immune attack along with reconstitution of effective hematopoiesis.
Subunit a of Coagulation Factor XIII As a New Biomarker in Childhood Acute Lymphoblastic Leukemia?
Authors: Csongor Kiss, Katalin Gyurina, László Csáthy, Silvia Bresolin, Geertruy te Kronnie, Zsuzsa Hevessy, István Szegedi, Beáta Scholtz, János Kappelmayer, Giuseppe Basso
Journal: Blood (2014)
Impact of antihypertensive therapy compliance on risk of first-ever cerebral infarction among patients with essential hypertension
Authors: Xu Xin, Song Ying-kui, Geng Qing, Kong Xiao-guang, Tao Li, HU Xiao-lei
Journal: BMJ (2009)

Objective To evaluate the impact of compliance with antihypertensive therapy in pailents with essential hypertension on risk for their first-ever cerebral infarction.Methotis Questionnaire survey and auxiliary examinations were conducted in 114 patients with essential hypertension hospitalized for acute cerebral infaretion at the First Hospihal Affiliated to Harbin Medical University during December 2006 to December 2007,as well as in another 114 patients with essential hypertensive without history of cerebral infarction as controls during the sanle period.Univariate and multivariate 10gistic regression analyses were performed to study the relationship between first-ever cerebral infarction and compliance with antihypertensive agents and other relevant factors.Results Antihypertensive agents compliance,course of hypertension,and history of smoking and alcohol drinking could significantly affect their first occurrence of cerebral infarction in patients with essential hypertension(P＜0.05),with odds ratios(OR)of 0.429(95%C10.186-0.993) and 2.142(95% CI 1.052-4.364)for good and poor compliance with antihypertensive agents,respectively,as compared to those without antihypertensive treatmenL Mild drinking was a protective factor for cerebral infarction with an OR of 0.494(95%CI 0.252-0.968).kngth of hypertension with 10-19-years and more than or equal to 20 years.as compared to those with le88 than five years of hypertension,was also a risk factor for it,with an OR of 2.118(95% CI 1.075-4.174).Conclusions Compliance of essential hypertensive patients with antihypertensive therapy was an important factor that affect their contracting first-ever cerebral infarction.Good compliance could obviously refrain them from it.Patients with poor-compliance or without treatment prone to contract cerebral infarction more easily than those with good compliance.It is necessary to improve compliance with antihypertensive agents in patients with essential hypertension as soon as possible.as well as quitting smoking and limiting alcohol drinking for prevention and control for their first-ever cerebral infarction.

Key words: 
Antihypertensive agents; Patient compliance; Cerebral infarction
Abstract 953: An anti-CD38 antibody drug conjugate for the treatment of diverse hematologic malignancies
Authors: James R. Prudent, David J. Marshall, John Murphy, Fabio Malavasi
Journal: Cancer Research (2015)

Abstract Purpose: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, acute promyelocytic leukemia (PML), B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (ALL), B-cell chronic lymphocytic leukemia (B-CLL),and T-cell ALL. Here, we assessed the antitumor activity of novel extracellular drug conjugates composed of anti-CD38 monoclonal antibodies conjugated to various steroidal derivatives via flexible stable linkers. Experimental Design: Activity of EDC8 was examined on lymphoma, leukemia and multiple myeloma cell lines and a B-cell lymphoma xenograft model in immunodeficient mice. Results: We identified that multiple anti-CD38 antibodies when conjugated to a novel small molecule steroids through long stable linkers could provide picomolar apoptotic activity independent of effector functions. These antibody drug conjugates, termed EDC8s, inhibited cytotoxic activity through a mechanism that was dependent on CD38 expression, as CD38 induction by ATRA could turn EDC8 resistant cells, sensitive, and naked anti-CD38 antibodies could compete with the EDC8s rendering them inactive. The activity of the EDC8s was also dependent on linker length and steroid chemistry. In vivo, EDC8 was active on a B-cell lymphoma CD38+ tumor xenograft model. Results from one of the EDC8s demonstrated in vivo tumor regression and cures when 5mgs/kg of the conjugate was administered and this anti-CD38 antibody drug conjugate had impressive single-agent activity greatly surpassing the activity of CHOP. Conclusion: These results support efforts to further evaluate these unique CD38-targeting antibody drug conjugates and may lead to phase I clinical trials in patients with certain CD38+ malignancies. Citation Format: James R. Prudent, David J. Marshall, John Murphy, Fabio Malavasi. An anti-CD38 antibody drug conjugate for the treatment of diverse hematologic malignancies. [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 953. doi:10.1158/1538-7445.AM2015-953
BCR-ABL Kinase Domain Mutations and Their Kinetics on Second Line Dasatinib or Nilotinib Therapy in CML Patients after Imatinib Failure: A Cooperative Evaluation of Four Different Detection Methods.
Authors: Thomas Ernst, Franz Gruber, Oliver Pelz-Ackermann, Martin C. Mueller, Ingvild Mikkola, Kimmo Porkka, Dietger Niederwieser, Andreas Hochhaus, Thoralf Lange
Journal: Blood (2007)
P1291 : Incidence of budd chiari syndrome (BCS): An exhaustive nationwide French study
Authors: M. Allaire, N. Goutte, N. Bendersky, O. Farges, A. Plessier, R. Morello, G. Delaval, T. Dao, D. Valla, I. Ollivier-Hourmand
Journal: Journal of Hepatology (2015)
Abstract 1098: Epistasis analysis of the PTHLH region in European subjects of the iCOGS breast cancer GWAS suggest multiple genes may be implicated in its role in breast cancer
Authors: Adam N. Freeman, Michael A. Henderson, T John Martin, Enes Makalic, Miroslaw K. Kapuscinski, Daniel Schmidt, John Hopper
Journal: Cancer Research (2015)

Abstract Parathyroid hormone-related protein (PTHrP), the product of the PTHLH gene, has long been implicated in breast cancer. Its expression is thought to favour and, potentially, facilitate metastasis to bone. Paradoxically, a prospective clinical study clinical suggests that its production in primary breast cancers is actually protective, affording a better prognosis than its absence. Multiple recent Genome-Wide Association Studies (GWAS) have confirmed a single susceptibility locus immediately upstream of the PTHLH gene to be associated with breast cancer. This was again reproduced in the recent iCOGS GWAS, which involved over 90,000 European subjects. In spite of a single SNP, rs10771399, being uniquely reported and reproduced by prior studies, comprehensive analysis of the region reveals multiple significant SNPs stretching for hundreds of kbp across the locus. Epistasis analysis of this region versus the entire iCOGS array was performed using Plink!. These results suggest multiple genes may be implicated in the causation of this signal. Many known functional partners of PTHLH were identified, including IPO8, RUNX1, RUNX3, S100P, SOX9, SOX11, and SOX14. Multiple putative functional partners of PTHLH were likewise identified, including PBXIP1, PMVK, KCNN3, STX12, PPP1R8, CAMTA1, PRKCZ, TGIF1, SPHKAP, MYC, and STAT3. When taken together, these results offer novel potential insights into the function of the locus at PTHLH in breast cancer that may be further investigated. Citation Format: Adam N. Freeman, Michael A. Henderson, T John Martin, Enes Makalic, Miroslaw K. Kapuscinski, Daniel Schmidt, John Hopper. Epistasis analysis of the PTHLH region in European subjects of the iCOGS breast cancer GWAS suggest multiple genes may be implicated in its role in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1098. doi:10.1158/1538-7445.AM2015-1098
Therapeutic strategy for resectable pancreatic cancer patients with thromboembolic risks
Authors: Takahisa Fujikawa, Yasunori Yoshimoto, Yuichiro Kawamura, Hidekazu Hayashi, Teruo Iwata, Seiichiro Tada, Tomohiro Noda, Keita Fukuyama, Akira Tanaka
Journal: Annals of Oncology (2015)
Mtss1 Suppresses BCR-ABL Induced Cell Migration and Is Downregulated in CML Stem Cells.
Authors: Mirle Schemionek, Shuchi Agrawal, Martin Stehling, Daniel G. Tenen, Ashley Hamilton, Tessa Holyoake, Ulrich Steidl, Wolfgang E. Berdel, Albrecht Schwab, Carsten Müller-Tidow, Steffen Koschmieder
Journal: Blood (2008)
Abstract 3247: Primary tumor cell lines generated from patient-derived-xenograft models are useful tools for study tumor biology, drug efficacy
Authors: Gang Hu, Yong Huang, Fubo Xie, Xuzhen Tang, Xueyan Yang, Kunyan Liu, Yixin Zhang, Weikang Tao, He Zhou
Journal: Cancer Research (2015)

Abstract Patient-derived-xenograft (PDX) models have been widely used in the biomedical research. They recapitulate the genomic diversity/heterogeneity of patient tumors, maintain a lot of the characteristics of the original tumors and showed much better correlation with clinical outcome comparing to traditional cell line derived xenograft models. However, the relatively low throughput and time-consuming nature of PDX studies prevent them from being used in large scale screening or mechanistic studies. To address this, different cancer cell lines have been developed in our laboratory from the PDX tumors. We performed STR analyses to validate their identity. Whole exome sequencing, RNA-seq, SNP array 6.0 were performed on selected cell lines. When we compared 5 of these cell lines with their parental PDX tumors, over 93% of the CNVs identified in the cell lines were also found in the corresponding PDX models. Copy number analyses also revealed similar focal amplifications both on the cell lines and the original PDX models. More importantly, efficacy studies using different compounds showed similar drug responses using in vitro cell culture, xenografts using these cell lines and original PDX models. Our data demonstrated the high fidelity of these cell lines to their parental PDX models. In addition, we generated cell lines from progressed tumors upon exposure to long term drug treatment. The pair of treatment sensitive and resistant tumor cell lines facilitated the research on development of drug resistance. Overall, while maintaining the genetic background and phenotypic characteristics of the PDX models, these primary tumor cell lines serve as a bridge between the high-throughput drug screening and highly clinical relevant PDX models. They represent useful tools in biomedical research. Citation Format: Gang Hu, Yong Huang, Fubo Xie, Xuzhen Tang, Xueyan Yang, Kunyan Liu, Yixin Zhang, Weikang Tao, He Zhou. Primary tumor cell lines generated from patient-derived-xenograft models are useful tools for study tumor biology, drug efficacy. [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 3247. doi:10.1158/1538-7445.AM2015-3247
Novel View on Unwanted Side Effects of Radio-Chemotherapy on Bone Marrow (BM) Microenvironment - Radio-Chemotherapy Upregulates BM-Level of Bioactive Lipids, Sphingosine-1- Phosphate (S1P) and Ceramide-1-Phosphate (C1P), That Chemoattract Metastasizing Cancer Cells
Authors: Gabriela Schneider, Bryndza Ewa, Chihwa Kim, Janina Ratajczak, Magda Kucia, Mariusz Z Ratajczak
Journal: Blood (2011)
Personalized Treatment with low doses of Lenalidomide and Dexamethasone for Relapsed Multiple Myeloma in frail or Elderly Patients
Authors: Angel Ruedas, Pablo Guisado, Beatriz Aguado, Ricardo Perez, Joaquin Martinez, J Valentin Garcia-Gutierrez, M. Jesús Blanchard, Pilar Bravo, Carlos Montalban
Journal: Blood (2012)
A phase I trial of imatinib (IM) plus mFOLFOX-bevacizumab in patients with advanced colorectal cancer.
Authors: M. Michael, N. C. Tebbutt, P. Gibbs, L. R. Lipton, M. Jefford, A. Milner, M. Gouillou, A. Hatzimihalis, G. A. McArthur, J. R. Zalcberg
Journal: Journal of Clinical Oncology (2011)

e14119 Background: PDGFR inhibition by reducing tumoral interstitial fluid pressure may increase chemotherapy penetration and efficacy. Imatinib (IM) has anti-PDGFR activity at standard doses. The aims of this phase I study were to assess the MTD of IM in combination with mFOLFOX-bevacizumab (Bev) in patients (pts) with advanced colorectal cancer (CRC), identify potential PK interactions, toxicities and efficacy. Methods: Eligible pts had measurable disease, 0-1 prior regimens, ECOG 0-1, adequate organ function. On day -14, pts commenced IM p.o daily + Bev (5mg/kg/2 weekly). On day 1, (14 days post), pts commenced mFOLFOX-Bev (oxaliplatin 85mg/m2/2hrs, leucovorin 200mg/m2, 5FU bolus 400mg/m2 day 1, 5FU CI 2.4g/m2/46hrs). Bloods were taken for IM steady state PK analysis from day -14 to day 14; and for oxaliplatin and 5FU PK in cycle 1, days 1 to 3. DLTs were defined, in the first 6 weeks, as: grade (Gr) 4 neutropenia >7 days, Gr4 thrombocytopenia/Gr3 with bleeding, febrile neutropenia, drug-related Gr3/4 non-haematological toxicity, delay in the start of next cycle >2 weeks. Dose escalation was standard with 3 pt cohorts. IM planned dose levels (DL): DL1; 400mg, DL2; 600mg, DL3; 800mg po daily. Pts restaged on day 1 cycles 1 and 2 and then every 8 weeks. Results: 10 pts enrolled, M:F = 7:3, 1 pt had prior chemotherapy. DL1; 3 pts, DL2; 7 pts (1 replaced due to early progression). DLTs observed in 3 of 6 pts in DL2 (600mg): febrile neutropenia (2); Gr3 infection and Gr4 neutropenia (1). Worst drug-related AEs: DL1 (3); Gr3 thromboembolism (1), Gr3 hypertension (1), Gr4 neutropenia (1). DL2 (7); febrile neutropenia (2), Gr4 dehydration (1), Gr3 (4) and Gr4 (1) neutropenia. Median number of cycles: DL1 = 12, DL2 = 6 (range 1-12). Overall response rate: DL1 = 1/3 (SD 2/3), DL2 = 0/6 (SD 5/7). Steady state PK parameters for IM were not impacted by mFOLFOX-Bev. Oxaliplatin and 5FU PK parameters were not impacted by IM exposure. Conclusions: 400mg p.o. daily of IM was the MTD with mFOLFOX-Bev. Dose escalation of IM an inhibitor of PDGFR, ABL and KIT was limited by neutropenia. Further study is warranted as IM can be delivered at levels that inhibit PDGFR.
Plasma Cell Folate Receptor Overexpression Differentiates Multiple Myeloma from Monoclonal Gammopathy of Undetermined Significance and Smoldering Myeloma.
Authors: Patricia Greipp, Greg Cascino, Teresa Kimlinger, Vincent Rajkumar, Franklyn G. Prendergast, Rafael Fonseca, P. Leif Bergsagel, Philip S. Low, Philip R. Greipp
Journal: Blood (2004)
AllergoOncology – the impact of allergy in oncology: <scp>EAACI</scp> position paper
Authors: E. Jensen‐Jarolim, H. J. Bax, R. Bianchini, M. Capron, C. Corrigan, M. Castells, D. Dombrowicz, T. R. Daniels‐Wells, J. Fazekas, E. Fiebiger, S. Gatault, H. J. Gould, J. Janda, D. H. Josephs, P. Karagiannis, F. Levi‐Schaffer, A. Meshcheryakova, D. Mechtcheriakova, Y. Mekori, F. Mungenast, E. A. Nigro, M. L. Penichet, F. Redegeld, L. Saul, J. Singer, J. F. Spicer, A. G. Siccardi, E. Spillner, M. C. Turner, E. Untersmayr, L. Vangelista, S. N. Karagiannis
Journal: Allergy (2016)

Abstract Th2 immunity and allergic immune surveillance play critical roles in host responses to pathogens, parasites and allergens. Numerous studies have reported significant links between Th2 responses and cancer, including insights into the functions of IgE antibodies and associated effector cells in both antitumour immune surveillance and therapy. The interdisciplinary field of AllergoOncology was given Task Force status by the European Academy of Allergy and Clinical Immunology in 2014. Affiliated expert groups focus on the interface between allergic responses and cancer, applied to immune surveillance, immunomodulation and the functions of IgE‐mediated immune responses against cancer, to derive novel insights into more effective treatments. Coincident with rapid expansion in clinical application of cancer immunotherapies, here we review the current state‐of‐the‐art and future translational opportunities, as well as challenges in this relatively new field. Recent developments include improved understanding of Th2 antibodies, intratumoral innate allergy effector cells and mediators, IgE‐mediated tumour antigen cross‐presentation by dendritic cells, as well as immunotherapeutic strategies such as vaccines and recombinant antibodies, and finally, the management of allergy in daily clinical oncology. Shedding light on the crosstalk between allergic response and cancer is paving the way for new avenues of treatment.
In Memoriam: Milton Alter, MD, PhD (1929-2016)
Authors: Amos D. Korczyn, Philip B. Gorelick
Journal: JAMA Neurology (2016)

On February 4, 2016, the neurological community lost a founding father of neuroepidemiology, Milton (Meir) Alter. For those of us who had the privilege to work with him, he is remembered as an elegant and scholarly man, a devoted colleague, and family man.
Using the hyperinsulinemic euglycemic clamp to assess insulin sensitivity at 3 months following Roux-en-Y gastric bypass surgery in type 2 diabetes patients with BMI &lt;35 kg/m2 in China
Authors: Lei Zhao, Liyong Zhu, Zhihong Su, Yong Liu, Pengzhou Li, Xiangwu Yang, Weizheng Li, Lingjie Tan, Xulong Sun, Shaihong Zhu
Journal: International Journal of Surgery (2016)
Pericardial Effusion Is a Marker of Increased Mortality in Thalassemia Major Patients
Authors: Antonella Meloni, Patrizia Toia, Leonardo Sardella, Giuseppe Serra, Roberta Chiari, Alfonso D'Ambrosio, Lucia De Franceschi, Maria Giovanna Neri, Maria Chiara Resta, Paolo Preziosi, Vincenzo Positano, Monica Benni, Alessia Pepe
Journal: Blood (2014)
Abstract 3466: Regulation of iodine uptake by SENP2 in thyroid cancer
Authors: Eun Kyung Lee, Min Ji Park, You Jin Lee
Journal: Cancer Research (2015)

Abstract Background: About 10∼20% of thyroid cancer patients does not respond to radioactive iodine(RAI) therapy, since the expression or membrane trafficking of sodium iodine symporter(NIS) was ameliorated. We investigated whether iodine uptake and expression of NIS were regulated by the balance of SUMOylation in thyroid cancer. Methods: We analyzed the expression of NIS mRNA using fresh frozen tissues of papillary thyroid cancer. After overexpression of desumoylating enzyme SENP2 in human anaplastic thyroid cancer cell line (FRO) and silencing SENP2 in human NIS-overexpressed HeLa cell line (HeLa-hNIS), we evaluated the expression of NIS mRNA and iodine uptake. We selected 30 patients of different expression level of SENP2 (low and normal SENP2) and constructed tissue microarray for immunohistochemistry stain. And the patients’ clinico-pathologic features were reviewed using medical records. Results: Twenty six percent of papillary thyroid cancer tissue showed reduced expression of SENP2 and NIS mRNA. Silencing SENP2 in HeLa-hNIS, NIS mRNA and iodine uptake was reduced. By co-immunoprecipitation, the interaction between SUMO2/3 and C/EBPβ was detected. After overexpression of SENP2, NIS mRNA and iodine uptake was restored. By comparison of response of RAI among two groups, reduction of serum thyroglobulin level after RAI was blunted in the group of low SENP2, compared to that in the group of normal SENP2. Conclusion: Overexpression of SENP2 can induce NIS expression and iodine uptake. This may be a novel therapeutic target for RAI-refractory thyroid cancer patients. Citation Format: Eun Kyung Lee, Min Ji Park, You Jin Lee. Regulation of iodine uptake by SENP2 in thyroid cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3466. doi:10.1158/1538-7445.AM2015-3466