tbuckley/cabot-search huggingface dataset:
Abstract LB-197: Bispecific T-cell engagers: evaluation of circulating tumor-associated antigen levels and pharmacokinetics
Authors: Amy E. Gilbert, Ariel Avilion, David Doherty, Shyun Li, Julie Bailis, Dan Rock
Journal: Cancer Research (2016)

Abstract Immunotherapeutic approaches to activate patient T cells against cancer have emerged as a promising clinical strategy for many cancer types. One critical consideration for immune activating therapies is to establish efficacious and tolerable dosing limits. The conveyed estimate of the predicted therapeutic window could be impacted by presence of circulating tumor associated antigen. Here we evaluate a Bi-specific T cell Engager (BiTE®) directed against CD3 and CDH19, a type II cadherin overexpressed &amp;gt;60% of melanomas. Because, to our knowledge, the shedding of CDH19 was unknown we developed an immunoassay to detect soluble CDH19 (sCDH19) in the serum of human donors and patients with metastatic melanoma. Utilizing our immunoassay to detect sCDH19, we measured elevated levels of sCDH19 in the serum of metastatic patients relative to normal donors. Additionally, the potency of this BiTE® using T-cell dependent cellular cytotoxity assays was measured. We next incorporated the range of sCDH19 amounts in patients along with BiTE® potency and present desired pharmacokinetic profiles of this therapeutic. In sum, we report that sCDH19 is present in the circulation of patients with metastatic melanoma and evaluate the impact of sCDH19 on BiTE® pharmacokinetics and human dose projections. Citation Format: Amy E. Gilbert, Ariel Avilion, David Doherty, Shyun Li, Julie Bailis, Dan Rock. Bispecific T-cell engagers: evaluation of circulating tumor-associated antigen levels and pharmacokinetics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-197.
Downregulation Of SPINT2 Expression In Stromal Cells From Myelodysplastic Syndrome Patients Increases HGF and SDF-1 Secretion and Promotes Cell-Cell Adhesion By Alteration In Integrin Expression
Authors: Fernanda Marconi Roversi, Matheus Rodrigues Lopes, João Agostinho Machado-Neto, Ana Leda Longhini, Adriana da Silva Santos Duarte, Bruna Palodetto, Flavia Adolfo Corrocher, Paula de Melo Campos, Mariana Ozello Baratti, Fernando V Pericole, Patricia Favaro, Fabiola Traina, Sara Teresinha Saad
Journal: Blood (2013)
Abstract 3999: Altering the balance between immune activation versus regulation in the skin to promote CD8 T-cell activity within epithelial cancers
Authors: Jennifer A. Bridge, Nana H. Overgaard, Raymond J. Steptoe, Ian H. Frazer, James W. Wells
Journal: Cancer Research (2016)

Abstract The Human Papilloma Virus (HPV) 16 is a high-risk HPV known to be a causative agent in numerous cancers including cervical cancer. While prophylactic vaccines exist to combat the spread of HPV16, successful therapeutic vaccines to combat established HPV16-associcated disease remain elusive. The expression, in a mouse model (“E7”), of the HPV16 E7 gene in keratinocytes under the control of the K14 promoter, leads to a local immune suppressive environment, as evidenced by the lack of graft rejection when E7 skin grafts are placed on WT recipient mice. Furthermore, well healed (&amp;gt;30 days) E7 skin grafts are not rejected when mice are immunised with E7 peptide in combination with Quil A- or CASAC-based adjuvants. This is despite a substantial increase in E7 peptide/H-2Db pentamer staining in the blood, and marked killing of E7-peptide expressing TC-1 cells when injected i.v., confirming that CD8 T-cells respond to vaccination and differentiate into CTL capable of killing E7-expressing target cells. We hypothesised that the removal of regulatory T-cells (T-reg) might lead to E7 graft rejection in immunised mice. The co-administration of an anti-CD4-depeting antibody at the time of immunisation led to rejection of ∼50% of grafts. To confirm a role for T-reg, E7-grafted T-reg-deficient Rag1-/- mice received purified donor CD8 T-cells from E7-vaccinated WT mice. FACS staining of Rag1-/- lymph nodes 30 days post CD8+ T-cell transfer confirmed the absence of classical CD4+FoxP3+ Treg, however the E7 grafts did not reject. As in the WT mice however, rejection could be induced through the co-administration of an anti-CD4 antibody. The data suggest that the removal of a CD4+, non T-reg cell, leads to CD8+ T-cell activity in the skin as evidenced by E7 skin graft destruction. Citation Format: Jennifer A. Bridge, Nana H. Overgaard, Raymond J. Steptoe, Ian H. Frazer, James W. Wells. Altering the balance between immune activation versus regulation in the skin to promote CD8 T-cell activity within epithelial cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3999.
Caspase-Dependent Anti-Tumor Effects of ONC201/TIC10 on Acute Myeloid Leukemia (AML) and Multiple Myeloma (MM)
Authors: Amriti R. Lulla, Christina Leah B Kline, Liz J. Hernandez-Borrero, Varun Vijay Prabhu, Jessica M Wagner, David T. Dicker, Nathan G. Dolloff, Brian M Barth, Jeffrey J Pu, David F. Claxton, Joshua E. Allen, Wafik S. El-Deiry
Journal: Blood (2014)
Annual clinical updates in hematological malignancies: a continuing medical education series
Journal: American Journal of Hematology (2017)

Disease overview: Waldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy. Diagnosis: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. Risk stratification: Age, hemoglobin level, platelet count, β 2 -microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. Risk adapted therapy: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analogue, or both. The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem cell transplantation should be considered in induction therapy selection. Management of refractory disease: Bortezomib, thalidomide, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials.
Abstract 2396: Heterogeneity of colorectal cancers and multiple liver metastases by mutation and copy number profiling
Authors: Sharmini Alagaratnam, Tuva Høst Brunsell, Stine Aske Danielsen, Anita Sveen, Mette Eknæs, Merete Hektoen, Bård Røsok, Bjørn Atle Bjørnbeth, Arild Nesbakken, Ragnhild Lothe
Journal: Cancer Research (2016)

Abstract To investigate genetic and genomic heterogeneity in liver metastases of colorectal cancer, multiple tumor foci in the liver per patient were identified on the basis of radiological images and samples from these systematically biobanked. For a total of 67 patients, 258 metastatic tumor samples were collected (minimum of 2 and maximum of 9 samples per patient, median of 4 samples per patient). Additionally, for n = 14 patients, tumor samples from the corresponding primary colorectal cancer were also available. DNA isolated from these samples was subjected to mutation profiling by Sanger sequencing for the genes BRAF, KRAS, PIK3CA and TP53, as well as allele-specific copy number profiling by CytoscanHD SNP array. For the four genes investigated for mutations, 39/67 (58%) of the patients were homogeneous in their mutation profile, while 21/67 (32%) were heterogeneous (one or more samples had mutations not detected in all samples). For 7/67 patients (10%), no mutations were detected in any of these four genes. For 9/14 patients with matching primary tumors, there was complete concordance between the primary tumor and all liver metastases profiled for mutations, while the remaining 5/14 patients showed discordance in mutation profile between the primary tumor and at least one of the liver metastases profiled. High resolution copy number profiles of this cohort detected many of the aberrations previously described in primary colorectal cancer, specifically gain of chromosomes 7, 8q, 13q and 20q, and loss of chromosomes 5q, 8p, 15q, 17p and 18q. The extent of heterogeneity observed in patient-wise mutation profiles was largely mirrored in the copy number profiles of the same tumors. 16/27 (60%) of the patients for which both mutation and copy number profiles were available showed concordance in the degree of heterogeneity per patient. In summary, intra-individual heterogeneity varied from patient to patient, with results from the genetic and genomic data types largely concurring. Citation Format: Sharmini Alagaratnam, Tuva Høst Brunsell, Stine Aske Danielsen, Anita Sveen, Mette Eknæs, Merete Hektoen, Bård Røsok, Bjørn Atle Bjørnbeth, Arild Nesbakken, Ragnhild Lothe. Heterogeneity of colorectal cancers and multiple liver metastases by mutation and copy number profiling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2396.
5-Hydroxymethylcytosine Is Correlated with TET2 or IDH1/2 Mutations However, May Not be a Prognostic Value to Predict the Survivals in Normal Karyotype AML
Authors: Jae-Sook Ahn, Hyeoung-Joon Kim, Yeo-Kyeoung Kim, Seung-Shin Lee, Sung-Hoon Jung, Deok-Hwan Yang, Je-Jung Lee, Park Hee Jeong, Seung Hyun Choi, Chul Won Jung, Jun-Ho Jang, Heeje Kim, Joon Ho Moon, Sang Kyun Sohn, Sung-Hyun Kim, Dennis Dong Hwan Kim
Journal: Blood (2015)
Abstract 2718: Synthesis and characterization of novel benzylpyrazole-based BUB1 kinase inhibitors with anti-tumor activity
Authors: Marion Hitchcock, Gerhard Siemeister, Hans Briem, Amaury Ernest Fernandez-Montalvan, Simon Holton, Anne Mengel, Ursula Mönning, Michael Brands, Karl Ziegelbauer, Dominik Mumberg, Franz von Nussbaum.
Journal: Cancer Research (2016)

Abstract BUB1 (budding uninhibited by benzimidazoles 1) is a serine/threonine protein kinase. The protein is bound to kinetochores and plays a key role in the establishment of the mitotic spindle checkpoint and chromosome congression prior to anaphase. Inhibition of BUB1 kinase represents a novel approach for cancer treatment: whereas cell cycle arrest is the predominant mode of action of a number of antimitotic cancer drugs (e.g. taxanes and vinca alkaloids), BUB1 inhibition results in aneuploidy and cell death by driving cells through mitosis irrespective of DNA damage and misattached chromosomes. Here, we report the characterization of a novel benzylpyrazole lead-structure series inhibiting BUB1 exemplified by BAY-320, a novel, first-in-class small molecule inhibitor of BUB1 kinase. This structure class was initially discovered as a single hit in a high-throughput screen, and resulted in a lead compound by chemical optimization. Benzylpyrazole BAY-320 is highly selective for BUB1 with single digit nanomolar biochemical potency and single-digit micromolar cellular potency (HeLa proliferation assay). Synergistic effects can be observed when BUB1 inhibitor BAY-320 is combined with low doses of paclitaxel affecting chromosome segregation and cell proliferation. X-ray data of benzylpyrazoles allowed for a better understanding the binding mode for rational property design. Further data on structure-activity relationship including pharmacokinetic, drug metabolism and the synthesis of BAY-320 and analogues will be presented. These results validate the benzylpyrazoles as novel selective BUB1 inhibitors and BUB1 as a promising approach for cancer treatment. Citation Format: Marion Hitchcock, Gerhard Siemeister, Hans Briem, Amaury Ernest Fernandez-Montalvan, Simon Holton, Anne Mengel, Ursula Mönning, Michael Brands, Karl Ziegelbauer, Dominik Mumberg, Franz von Nussbaum. Synthesis and characterization of novel benzylpyrazole-based BUB1 kinase inhibitors with anti-tumor activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2718.
Le Service d’Investigation Epidémique aux Etats-Unis
Authors: Stephen M. Ostroff
Journal: Eurosurveillance (2001)

Le Service d’investigations epidemiques (Epidemic Intelligence Service, EIS) correspond au programme americain de formation a l’epidemiologie appliquee. D’une duree de deux ans, il est organise par les Centres de Controle et de Prevention des Maladies (Centers for Disease Control and Prevention, CDC). L’EIS celebrera son 50eme anniversaire en 2001. Ce programme a ete mis en place pendant la guerre de Coree, cinq ans seulement apres la creation du CDC pour combler l’insuffisance d’epidemiologistes de terrain confirmes, si des armes biologiques venaient a etre utilisees contre la population americaine. Il etait clair pour Alexander Langmuir, directeur de la section epidemiologie au CDC et fondateur de l’EIS, que ses stagiaires seraient egalement impliques dans de nombreuses activites et qu’ils contribueraient a combler le manque d’epidemiologistes qualifies, ayant une experience pratique de terrain pour l’investigation et le controle d’epidemies de survenue naturelle aux Etats-Unis.
Abstract 4718: ABBV-075, a novel BET family bromodomain inhibitor, represents a promising therapeutic agent for a broad spectrum of cancer indications
Authors: Aparna Sarthy, Leiming Li, Daniel H. Albert, Xiaoyu Lin, Warder Scott, Emily Faivre, Mai H. Bui, Xiaoli Huang, Denise M. Wilcox, Terry Magoc, Fritz G. Buchanan, Paul Tapang, George S. Sheppard, Le Wang, Steve D. Fidanze, John Pratt, Dachun Liu, Lisa Hasvold, Paul Hessler, Tamar Uziel, Lloyd Lam, Ganesh Rajaraman, Guowei Fang, Steven W. Elmore, Saul H. Rosenberg, Keith McDaniel, Warren Kati, Yu Shen
Journal: Cancer Research (2016)

Abstract Small molecule inhibitors of the bromodomain and extraterminal domain (BET) proteins have emerged as a promising option for cancer therapy. ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered Phase 1 clinical trials. It binds bromodomains of BRD2/4/T with similar affinities (Ki of 1-2.2 nM), but exhibits roughly 10-fold weaker potency towards BRD3 (Ki of 12.2 nM). ABBV-075 is highly selective for 18 bromodomain proteins tested (Kd &amp;gt; 1 μM; more than 600-fold selectivity vs. BRD4) and has moderate activity towards CREBBP (Kd = 87 μM; 54-fold selectivity vs. BRD4). ABBV-075 exhibited robust single agent activity in cell viability assays across cancer cell lines derived from solid tumors, leukemia and lymphomas. Further characterization of cancer cell responses to ABBV-075 indicated that ABBV-075 manifested diverse mechanisms of action in different cancer settings. These include 1): disruption of cell cycle control leading to G1 arrest followed by senescence, 2) inhibition of oncogenesis drivers leading to apoptosis and 3) potentially targeting tumor microenvironment to provide additional therapeutic benefit. Consistent with its broad spectrum of activities in vitro, ABBV-075 has comparable or superior efficacies to standard of care agents in flank xenograft mouse models of non-small-cell and small cell lung cancers, pancreatic, breast, prostate, head &amp; neck cancers, multiple myeloma, diffuse large B cell lymphoma and leukemia. These results support the development of ABBV-075 in diverse hematological malignancies and solid tumor indications. Citation Format: Aparna Sarthy, Leiming Li, Daniel H. Albert, Xiaoyu Lin, Warder Scott, Emily Faivre, Mai H. Bui, Xiaoli Huang, Denise M. Wilcox, Terry Magoc, Fritz G. Buchanan, Paul Tapang, George S. Sheppard, Le Wang, Steve D. Fidanze, John Pratt, Dachun Liu, Lisa Hasvold, Paul Hessler, Tamar Uziel, Lloyd Lam, Ganesh Rajaraman, Guowei Fang, Steven W. Elmore, Saul H. Rosenberg, Keith McDaniel, Warren Kati, Yu Shen. ABBV-075, a novel BET family bromodomain inhibitor, represents a promising therapeutic agent for a broad spectrum of cancer indications. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4718.
Composition of Cellular Subsets by Flow Cytometry Identifies Differences Between MDS Subtypes and Aplastic Anemia but No Differences Are Identified Between Cases with and without Monosomy 7.
Authors: Ester Mejstrikova, Vendula Pelkova, Michaela Reiterová, Martina Sukova, Zuzana Zemanova, Elena Vodickova, Vit Campr, Kyra Michalova, Marie Jarosova, Renata Formankova, Petr Smisek, Petr Sedlacek, Dagmar Pospisilova, Vladimir Mihal, Jiri Hak, Yahia Jabali, Jaroslav Sterba, Jan Blatny, Ondrej Zapletal, Zdenka Cerna, Tomas Votava, Daniela Prochazkova, Jan Trka, Jan Stary, Ondrej Hrusak
Journal: Blood (2009)
Abstract 3120: B-Catenin gene expression and its mutations: promising and key component in the pathogenesis of acute myeloid leukemia (AML)
Authors: Mohsin Maqbool, Sobuhi Iqbal, Atul Sharma, Sameer Bakhshi, Sreenivas Vishnubhatla, Ashish Datt Upadhyay, Lalit Kumar
Journal: Cancer Research (2016)

Abstract INTRODUCTION AND AIM: Wnt signaling pathway plays a critical role in stem cell self-renewal and proliferation of leukemic stem cells and its association with the pathogenesis of acute myeloid leukemia (AML) has also been described. Beta-Catenin, a key regulator of Wnt signaling is highly expressed in cancers. Its role has been recently documented in AML however its prognostic significance in AML is not clear. The present study was carried to determine the potential prognostic implications of B-catenin expression and mutations in de novo AML patients. METHODS: We performed the gene expression of B-Catenin and its mutations analysis in exon 3. We investigated the expression of B-Catenin gene in bone marrow and/or blood samples by quantitative PCR using SYBR-Green chemistry and analysis was done by ΔΔCT Method. 18S RNA and B2M genes were used as reference genes. B-Catenin mutations analysis was by done direct DNA Sanger sequencing. RESULTS: Total 117 de novo non M3 AML patients and 40 healthy controls were included for the gene expression and analyzed for their clinicopathologic and prognostic significance. Median age for entire cohort (n = 117) was 17.0 years (Range 1-60 years) with male:female ratio of (1.8:1). FLT3-ITD mutation was positive in 11 (9.5%) patients. Only 4% of AML patients showed genetic alterations in exon 3 of B-catenin and no significant correlation with base line characteristics. B-catenin showed a significantly increased mRNA expression with a 5 fold rise as compared to healthy controls (p&amp;lt;0.05). B-catenin over expression was significantly associated with poor survival at median followup of 17 months and having less CR rates (p = 0.03). There was no significant correlation of B-catenin over expression vs baseline clinical characteristics like Hb, TLC, Platelets, Cyto group (p = 0.11), blast percentage (p = 0.28), Flt3-itd mutations (p = 0.42). CONCLUSION: These results provide the evidence for WNT signaling activation existence in AML patients and suggest that B-Catenin could be the key component in the pathogenesis and can be prognostically important marker in AML. However B-catenin expression in larger cohort of samples and with longer follow-up is required to confirm our findings. Citation Format: Mohsin Maqbool, Sobuhi Iqbal, Atul Sharma, Sameer Bakhshi, Sreenivas Vishnubhatla, Ashish Datt Upadhyay, Lalit Kumar. B-Catenin gene expression and its mutations: promising and key component in the pathogenesis of acute myeloid leukemia (AML). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3120.
Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function
Authors: Carlo Albera, Ulrich Costabel, Elizabeth A. Fagan, Marilyn K. Glassberg, Eduard Gorina, Lisa Lancaster, David J. Lederer, Steven D. Nathan, Dominique Spirig, Jeff J. Swigris
Journal: European Respiratory Journal (2016)

This post hoc analysis examined the differences in idiopathic pulmonary fibrosis disease progression and the effects of pirfenidone in patients stratified by more preserved versus less preserved baseline lung function status using forced vital capacity (FVC) or GAP (gender, age and physiology) index stage. Efficacy outcomes, i.e. FVC, 6-min walking distance (6MWD) and dyspnoea (University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)), were analysed at 12 months in patients randomised to pirfenidone 2403 mg·day −1 or placebo in the pooled phase 3 CAPACITY/ASCEND population (n=1247), with subgroups stratified by baseline FVC ≥80% versus &lt;80% or GAP stage I versus II–III. Treatment-by-subgroup interaction was tested based on a rank ANCOVA model; factors in the model included study, region, treatment, subgroup and treatment-by-subgroup interaction term. Patients with both more preserved (FVC ≥80% or GAP stage I) and less preserved (FVC &lt;80% or GAP stage II–III) lung function at baseline demonstrated clinically significant disease progression at 12 months in terms of categorical decline in FVC, 6MWD and UCSD SOBQ. The magnitude of pirfenidone treatment effect was comparable between subgroups, regardless of whether lung function was classified using FVC or GAP index stage. These findings support the initiation of treatment with pirfenidone, irrespective of stage of baseline lung function in this patient population.
A novel nanogel delivery of poly-α, β-polyasparthydrazide by reverse microemulsion and its redox-responsive release of 5-Fluorouridine
Authors: Jingwen Guo, Yan Wang, Jing Wang, Xin Zheng, Di Chang, Siling Wang, Tongying Jiang
Journal: Asian Journal of Pharmaceutical Sciences (2016)

To achieve GSH-responsive 5-Fluorouridine (5-FU) delivery, a novel family of nanogel drug carriers has been successfully prepared. The new class of PAHy-based nanogels was prepared by the crossing-link reaction of poly-α, β-polyasparthydrazide (PAHy) chains and 3,3′-dithiodipropionic acid (DTDPA) consisting of a redox-responsive chain network. This particle highlights recent efforts in introducing a disulfide bond to drug delivery nanogel by DTDPA, and the increased release properties of complex nanogels produced excellent glutathione (GSH)-sensitivity and significant anti-tumor therapeutic efficacy. The PAHy-based nanogels were characterized by Fourier transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS) (nano-particle size ~200 nm), UV–vis spectrometry, X-ray diffraction (XRD) and differential scanning calorimetric (DSC). PAHy-based nanogels are promising controlled-release carriers for the tumor-targeting delivery of the anticancer agent 5-Fluorouridine.