tbuckley/cabot-search huggingface dataset:
Lymph node density and response to induction TPF in patients with HPV-related head and neck cancer.
Authors: H. C. Agbahiwe, S. Marur, A. A. Forastiere, G. Sanguineti
Journal: Journal of Clinical Oncology (2011)

5576 Background: Response to induction chemotherapy is being investigated for selection of patients with HPV-related squamous cell carcinoma (SCC) of the head and neck for dose de-escalated radiation therapy. This study aims to provide a detailed analysis and find predictors of lymph node response to induction taxotere, cisplatin, and 5-fluoruracil (TPF). Methods: Beginning in October 2007, patients at Johns Hopkins with HPV-related SCC of the oropoharynx and treated with induction TPF were analyzed. CT simulation was obtained before and after chemotherapy. All pathologic nodes (>1 cm in largest axial diameter) were contoured and the nodal volume was computed. The volumetric change was then reported as the percent change over baseline. Nodal density was estimated using Pinnacle planning software as the percent hypodense compared to the sternocleidomastoid muscle. Nodes were then categorized as either solid or cystic based on the median density. Results: 34 lymph nodes were identified among 13 patients. Before TPF, median nodal diameter and volume were 2.0 (1.0-6.0) cm and 3.8 (0.7-77.7) cc, respectively. Median nodal density was 29.5% (0-98%) and the median number of cycles of TPF was 2 (1-2). Median volumetric change was -57.2% (-91.7/+383.7%). Seven nodes (20.6%) increased in volume after induction while 25 (73.5%) and 20 (58.8%) nodes showed a decrease of at least 30% and 50% over baseline, respectively. Percent change was significantly different between solid (median: -68.7%) and cystic (-41.9%) nodes (Mann-Whitney U test, p=0.013). Of note, none of the solid nodes as opposed to 7/17 (41.1%) of the cystic nodes increased in volume during induction TPF (Fisher’s exact test, p=0.004). No correlation was found between initial nodal volume, number of cycles of TPF and response. Conclusions: On average, HPV-related lymph nodes decreased by greater than 50% of their initial volume following induction TPF and initial nodal density was found to be a significant predictor of response. While the implications of nodal density on disease control are unknown and will require longer follow up, tumor response as a criterion for treatment modification of HPV-related SCC of the oropharynx may need to account for these differences.
Association of IDH1 mutations in normal karyotype acute myeloid leukemia samples with higher HIF-1α and VEGF-A expression.
Authors: M. Smonskey, P. Starostik, G. Deeb, K. Demock, R. Vargas, D. Lal, S. N. Sait, M. Wetzler, E. S. Wang
Journal: Journal of Clinical Oncology (2011)

6530 Background: Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes have been reported in normal karyotype (NK) acute myeloid leukemia in association with poor prognosis. Glioma-derived IDH1 mutations have been shown to dominantly inhibit IDH1 catalytic activity, resulting in increased conversion of 2-hydroglutarate (2-HG) from α-ketoglutarate and higher HIF-1α levels. We have previously shown that increased HIF-1α expression in NK-AML samples predicted for poor clinical outcome (Deeb et al Leukemia Research Dec 2010 Epub). Here we examined the IDH1 and IDH2 mutational status of 81 adult NK-AML marrow samples previously characterized for expression of HIF-1α and its downstream target VEGF-A. Methods: Genomic DNA was extracted from marrow mononuclear cells from diagnostic AML samples. High-throughput DNA sequence analysis (PyroMark Q24 Pyrosequencer, Qiagen) performed with custom-designed primers for IDH1 R132 and IDH2 R140 and R172 mutations was used. HIF-1α and VEGF-A expression in AML cells was determined by immunohistochemistry (see Deeb et al, Leukemia Research online 2010) and RQ-PCR analysis. Results: Among these 81 NK-AML samples, 6 (7.4%) contained IDH1-mutations, most in R132H (n=4). Eleven samples (13.6%) contained IDH2-mutations, all in R140Q. IDH1-mutated AML samples expressed higher mean ± SEM levels of HIF-1α (30±18% vs. 10±2.7%) and VEGF-A (62±14 vs. 28±3.5%) protein expression and higher HIF-1α gene (6.9±3.5 vs. 4.0±0.5 fold) expression than IDH1 wildtype samples. In contrast, IDH2-mutated AML samples expressed no detectable HIF-1α protein and lower VEGF-A protein and HIF-1α gene levels than IDH2 wildtype samples. No differences in age, survival, presenting white blood cell count, or marrow blasts was noted based on IDH1/2 status. Conclusions: Our data suggest a potential association between IDH1 mutations and higher HIF-1α and VEGF-A protein expression in AML cells as compared with IDH1 wild-type cells. These results imply that HIF-1α mediated effects may play a role in the leukemogenic effects of IDH1 (but not IDH2) mutations. How HIF-1α expression impacts on metabolic or oxidative stress responses in IDH1-mutated AML warrants further exploration.
Prognostic Factors and Survival of Patients with Primary Mediastinal Large B-Cell Lymphoma.
Authors: Grzegorz S. Nowakowski, Prabhjot Kaur, William R. Macon, Thomas M. Habermann, Kay Ristow, Stephen M. Ansell, Thomas E. Witzig, Svetomir N. Markovic, Luis F. Porrata, Ivana N. Micallef, Patrick B. Johnston, Joseph P. Colgan, David J. Inwards
Journal: Blood (2005)
Cytogenetic/Molecular Findings and Treatment Outcome of Childhood Acute Megakaryoblastic Leukemia. Possible Favorable Effect of High Dose Cytarabine and Stem Cell Transplantation.
Authors: Keisuke Kato, Ayako Tagusagawa, Chie Kobayashi, Kazutoshi Koike, Masahiro Tsuchida
Journal: Blood (2007)
A Comparison of Hepatotoxicity and Neutropenia in Children Given Oral Mercaptopurine on a Twice-Daily Versus Once-Daily Dosing Schedule for Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study.
Authors: R. Chesley, B. A. Bell, M. Devidas, B. Bostrom, G. Erdmann, S. Sterikoff, B. Camitta
Journal: Blood (2004)
515. Targeting Hypoglycosylation with a Chimeric Antigen Receptor
Authors: Avery D. Posey, Robert D. Schwab, Alina Boestaneau, Laura A. Johnson, Carl H. June
Journal: Molecular Therapy (2015)

Genetically-engineering human T cells to target endogenously-expressed cell markers associated with both normal and malignant cells, whether upregulated or not, has shown tremendous efficacy in targeting CD 19-expressing leukemia and lymphoma cells and will undoubtedly demonstrate promise in other hematological malignancies. However, many of the tumor-associated antigens in epithelial malignancies are upregulated in malignant tissue but also expressed at lower-levels in normal tissue. As observed by the targeting of Her2 with CAR-T cells, targeting these antigens can present on-target, off-site toxicity and emphasizes the need for cancer cell-specific epitopes in CAR T cell therapy. Here, we have taken advantage of the disrupted glycosylation program that occurs during cancer transformation, which exposes cancer-specific glycoantigens that can be attractive targets for CAR development. Mucin-1 (Muc1) is a tumor-associated oncogene that is highly upregulated in many cancers and has been the target of many vaccine studies; less frequently targeted are the glycosylation changes of Muc1 that occurs during cancer transformation. Muc1 is heavily O- and N-glycosylated and transformed cells often fail to construct the complex oligosaccharide chains, exposing hypoglycosylated epitopes such as an O-linked GalNac (Tn antigen). We developed a CAR using the scFv sequence derived from the 5E5 mAb, which was developed against the Tn antigen of Mucin-1 (Muc1), and also using the endodomains of CD3zeta and 4- 1BB that promote T cell activation and co-stimulation, respectively. The resultant Muc1 Tn-antigen specific CAR (5E5CAR) was expressed in a lentiviral vector and we transduced normal human T cells. We showed that the 5E5 mAb and the 5E5CAR are specific to the hypoglycosylated epitope of Muc1, but not normal Muc1. In addition, we developed a safety profile of the 5E5 mAb against normal pediatric and adult human tissue. We demonstrate that human T cells expressing the 5E5CAR rapidly clear established Jurkat and Hs766T tumors in vitro and in NSG mouse xenograft models, as assessed by serial bioluminescence imaging and prolonged survival compared to mice expressing control CD19-specific CAR T cells (P<0.005). Restoring expression of wildtype Cosmc in Jurkat T cells abolishes the expression of the hypoglycosylated form of Muc1 and also abrogrates the cytotoxicity exhibited by 5E5CAR T cells, further highlighting the specificity of the 5E5CAR for the O-linked GalNac. In addition to the T cell leukemia and pancreatic cancer xenograft models, we also demonstrate that the 5E5CAR T cells are responsive to ovarian, breast, and lung cancers, among others. These results demonstrate that the 5E5CAR is specific for the Muc1 Tn antigen and provides a potent and safe cancer-specific immunotherapy for the targeting of malignancies.
P08.01 Mathematical modeling of pseudopalisades evolution in glioblastoma
Authors: C. Kong, W. Guo
Journal: Neuro-Oncology (2016)

Glioblastoma, a rapidly progressive high-grade astrocytoma, often characterizes an inner necrotic area surrounded by hypercellular regions known as “pseudopalisades” originated by local tumor vaso-occlusion caused by intravascular thrombosis. This leads to a tumor cell population actively migrating away from the central hypoxic region, which is believed to be instrumental to its accelerated growth. To quantitatively mimic the underlying dynamics of tumor cells in pseudopalisades development, we present a mathematical model that integrate tumor cell growth and motility, the effect of energy (oxygen) concentration on cell state, and the corresponding energy consumption. Cell motility and proliferation was designed to consume energy and thus linked to the cell’s energy budget. This model could simulate the histologic patterns of pseudopalisades, and generated a coarse-grained framework that could capture the essential features of the pseudopalisade formation as a traveling wave of tumor cells. The simulations may help us understand the dynamical complexity of pseudopalisades evolution.
Randomized, double-blinded, phase II trial of a WT1 peptide vaccine as adjuvant therapy in patients with malignant pleural mesothelioma (MPM).
Authors: L. M. Krug, A. S. Tsao, S. Kass, V. W. Rusch, W. D. Travis, K. Panageas, P. S. Adusumili, M. G. Kris, P. G. Maslak, D. A. Scheinberg
Journal: Journal of Clinical Oncology (2011)

TPS139 Background: The transcription factor, WT1, is commonly over-expressed in MPM and immunohistochemical tests for WT1 are used diagnostically. Certain WT1 peptides are processed and presented to the immune system and are thus an attractive target for T cell based immunotherapy. Using computer prediction analysis we designed analog peptides derived from WT1 sequences by substituting amino acids at key HLA-A0201 binding positions. We tested the safety and immunogenicity of a WT1 vaccine comprised of four peptides in patients with thoracic neoplasms expressing WT1 (Krug et al, Cancer Immunol Immunother, 2010). Six out of nine patients tested demonstrated CD4 T-cell proliferation to WT1 specific peptides, and all five HLA-A0201 patients tested mounted a CD8 T-cell response. One patient remains without progression >30 months after the start of the study. The median survival (measured from the date of the first vaccinations) was 13 months. Based on this pilot trial, we proposed a randomized phase II trial in a MPM patient population with minimal disease burden. Methods: Eligible patients will have MPM-expressing WT1 treated with combined modality therapy including surgery. Patients will be randomized to receive WT1 peptides plus Montanide adjuvant and GM-CSF, or Montanide and GM-CSF alone. The primary endpoint is progression free survival (PFS). 39 patients will be enrolled in each arm, which will provide 90% power to detect an improvement in PFS at one year from 50% to 70%. Immune responses will be evaluated using T cell proliferation assays, MHC tetramer staining and interferon-γ ELISPOT. Supported by grants from the Department of Defense (PR093640), NIH (Ca 23766,) and the Meso Foundation (MARF).
<i>Diabetes Care</i>: “Taking It to the Limit One More Time”
Authors: William T. Cefalu, Andrew J.M. Boulton, William V. Tamborlane, Robert G. Moses, Derek LeRoith, Eddie L. Greene, Frank B. Hu, George Bakris, Judith Wylie-Rosett, Julio Rosenstock, Steven E. Kahn, Katie Weinger, Lawrence Blonde, Mary de Groot, Stephen Rich, David D’Alessio, Lyn Reynolds, Matthew C. Riddle
Journal: Diabetes Care (2016)

With this January 2017 issue, our editorial team celebrates its 5-year anniversary at the helm of Diabetes Care . In 2012, when we accepted the assignment to oversee the scientific aspects of the journal, we envisioned that the editorial for this January 2017 issue would be our opportunity to thank the American Diabetes Association (ADA) for allowing us to lead this effort, to thank our reviewers and associate editors for their tireless efforts, and to thank the readers for their valuable suggestions and ideas. However, we are now writing to inform you that those plans have been put on hold. Our editorial team has been given the opportunity to continue to guide Diabetes Care for another 2-year period. We have accepted the invitation primarily because our “team” (including the editorial committee, editorial office, and publications staff) feels we still have creative ideas to make the journal better and considerable energy to bring these ideas to fruition. Therefore, suffice it to say, we remain honored to continue to lead Diabetes Care for this extended period.

It has been our custom to summarize our productivity and achievements in both the January and June issues of each year. This year we believe the trajectory of quality continues to rise. We hope you will also agree when reading the summary presented in this narrative. We feel each year’s monthly issues have surpassed the prior year’s work, and year 2016 is no exception! As we described in July of 2016, we aim to provide the readers with lagniappe—“a little something extra”! (1).

This past year the editorial team took our initiative to another level devoting several monthly issues to specific clinical or research topics. A current summary of all thematic monthly issues can be found in our Diabetes Care Online Collections (http://care.diabetesjournals.org/content/diabetes-care-online-collections). In the …
Abstract 1843: Novel actions of next-generation taxanes benefit advanced stages of prostate cancer
Authors: Renee de Leeuw, Lisa Berman-Booty, Matthew Schiewer, Stephen Ciment, Robert Den, Adam Dicker, William Kelly, Edouard Trabulsi, Costas Lallas, Leonard Gomella, Karen Knudsen
Journal: Cancer Research (2015)

Abstract Purpose: To improve the outcomes of patients with castrate resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individual specific treatments for patients with CRPC. The current studies compared the novel taxane, cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond. Experimental design: Cabazitaxel (CBTX) and docetaxel (DCTX) were compared via in vitro modeling to determine molecular mechanism, biochemical and cell biological impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro, and in xenograft tumors for cabazitaxel response. Results: The data herein show that i. CBTX exerts stronger cytostatic and cytotoxic response compared to DCTX, especially in CRPC; ii. CBTX induces aberrant mitosis, leading to pyknotic and multinucleated cells; iii. taxanes do not act through the androgen receptor (AR); iv. Gene expression profiling reveals distinct molecular actions for CBTX v. tumors that have progressed to castration resistance via loss of RB show enhanced sensitivity to CBTX. Conclusions: CBTX not only induces improved cytostatic and cytotoxic effects, but also impacts distinct molecular pathways, compared to DCTX, which could underlie its efficacy after DCTX treatment has failed in CRPC patients. Finally, RB is identified as the first potential biomarker that could define the therapeutic response to taxanes in metastatic CRPC. This would suggest that loss of RB function induces sensitization taxanes, which could benefit up to 50% of CRPC cases. Citation Format: Renee de Leeuw, Lisa Berman-Booty, Matthew Schiewer, Stephen Ciment, Robert Den, Adam Dicker, William Kelly, Edouard Trabulsi, Costas Lallas, Leonard Gomella, Karen Knudsen. Novel actions of next-generation taxanes benefit advanced stages of prostate 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 1843. doi:10.1158/1538-7445.AM2015-1843
Abstract B17: BET inhibitors block pancreatic stellate cell collagen production and attenuate fibrosis in vivo
Authors: Krishan Kumar, Brian DeCant, Hattaway Z. Hattaway, Paul J. Grippo, David J. Bentrem, Kazumi Ebine, Hidayatullah G. Munshi
Journal: Cancer Research (2016)

Abstract The fibrotic reaction, which can account for over 70% of the tumor mass, is a characteristic feature of the majority of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen production and fibrosis in vivo. In this report we show that bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) family of proteins, is expressed in activated PSCs in human PDAC tumors. We also show that BET inhibitors and specific targeting of BRD4, in contrast to targeting of BRD2 and BRD3, decrease collagen production by primary PSCs isolated from human PDAC tumors. While BET inhibitors do not induce apoptosis of primary PSCs or affect α-SMA expression, BET inhibitors disrupt α-SMA filament organization in stellate cells. Additionally, BET inhibitors attenuate stellate cell activation, fibrosis and collagen production in vivo in a Kras mouse model of pancreatic tumorigenesis. Our results demonstrate that BET inhibitors regulate fibrosis partly by modulating PSC activation and function. Citation Format: Krishan Kumar, Brian DeCant, Hattaway Z. Hattaway, Paul J. Grippo, David J. Bentrem, Kazumi Ebine, Hidayatullah G. Munshi.{Authors}. BET inhibitors block pancreatic stellate cell collagen production and attenuate fibrosis in vivo. [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 B17.
132. Targeting the BTK Locus in Primary Human Hematopoietic Cells with TALENs and AAV Donor Template
Authors: Courtnee Clough, Yupeng Wang, Iram F. Khan, Swati Singh, King Hung, David J. Rawlings
Journal: Molecular Therapy (2016)

X-linked agammaglobulinemia (XLA), a rare immunodeficiency, is caused by mutations in the Bruton's Tyrosine Kinase (BTK) gene. BTK is required for B-cell maturation, activation and BCR-mediated signaling. Patients lacking functional BTK have predominantly immature B-cells with near absence of mature B cells, minimal antibody production and are prone to recurrent and life-threatening bacterial infections. Available treatments are limited to intravenous immunoglobulin therapy, which lessens the severity of these infections and judicious use of antibiotic therapy. BTK is an ideal target for gene editing as BTK-expressing B cells exhibit a marked selective advantage in vivo, and even a small number of corrected HSC or B cell progenitors rescues B cell development and function in murine models and is expected to rescue the B cell compartment in XLA patients. Here we outline a strategy to edit the endogenous BTK locus in primary human cells, targeting a codon-optimized BTK cDNA into the first coding exon of BTK using BTK specific DNA nucleases and donor template. Four pairs of transcription activator-like effector nucleases (TALENs) cleaving within introns 1 or 2 of BTK were constructed and their cleavage efficiency in primary human T cells evaluated. Using the T7 Endonuclease assay, we determined that disruption (indel) rates of ~75% were obtained using the TALENs. Next, utilizing co-delivery of TALEN mRNA and an AAV donor template (consisting of an MND promoter-GFP cDNA expression cassette flanked by 1.0 kb BTK homology arms), we achieved up to 25% homology directed repair (HDR) in primary T cells. The translation of this gene editing strategy to human mobilized peripheral CD34+ cells is currently being optimized. If successful, this targeting approach will be used to test expression levels of the targeted cDNA as regulated by the endogenous BTK promoter.
Quantitation of truncated HER2 in formalin-fixed paraffin-embedded breast carcinoma tissues.
Authors: T. A. Hembrough, W. Liao, S. Thyparambil, D. Krizman, M. Darfler, J. Burrows
Journal: Journal of Clinical Oncology (2011)

e11130 Background: Trastuzumab treatment of Her2+ breast cancer is the benchmark success story for targeted cancer therapy, however, a significant number of patients are either non-responsive or experience disease progression. A novel mechanism of resistance in some patients is the expression of truncated Her2 (p95Her2), formed by proteolytic cleavage of the HER2 molecule. Truncated p95Her2 loses its extracellular trastuzumab binding epitope, but retains a constitutively active kinase domain predicted to be sensitive to kinase inhibitors, like lapatinib and neratinib. At present there are no diagnostic assays for this p95Her2. Methods: Using the Liquid Tissue-SRM (selective reaction monitoring) platform we have developed multiple mass spectrometric assays to quantify specific cytoplasmic or extracellular domain (ECD) peptides from Her2 directly from formalin fixed paraffin embedded (FFPE) clinical tissue. Results: We validated these assays using recombinant human Her2, where we saw equivalent intracellular and extracellular Her2 levels. In formalin fixed SkBr3 breast carcinoma cells, we also detected equivalent levels of the Her2 peptides, as expected. We initiated clinical validation of this assay by analyzing a dozen FFPE human breast carcinoma tumors where Her2 expression and gene amplification levels had been determined. In 9 of 12 tumors (IHC: 1+ to 3+) we measured equivalent levels of intracellular and ECD peptides. Most interesting, 3 tumors showed dramatic differences in the levels of Her2 peptides detected. In two 3+ tumors, the intracellular peptide was 50% higher than the ECD peptide and in the last tumor more than twice the expression of the ECD Her2 peptide. These data suggest that in these 3 human tumors Her2 is missing a significant percent of the ECD, and is truncated. Continuing our clinical validation work we are analyzing larger numbers of Her2 positive breast tumors from clinical cohorts capable of confirming the clinical usefulness of the p95Her2 assay. Conclusions: Measuring Her2 truncation in Her2 positive breast tumors will benefit patients by enabling clinicians to select patient more likely to benefit to TKI (lapatinib, neratinib) therapy and will help physicians to make earlier informed therapeutic decisions.