tbuckley/cabot-search huggingface dataset:
Abstract 356: Novel conditionally active biologic (CAB) antibody targeting EpCAM demonstrates anti-tumor efficacy in vivo
Authors: Cathy Chang, Gerhard Frey, Leslie Sharp, William (Bill) J. Boyle, Jing Wang, Charles Xing, Haizhen Liu, Christina Wheeler, Marlena Walls, Jay M. Short
Journal: Cancer Research (2019)

Abstract Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell-cell adhesion during cell signaling, migration, proliferation, and differentiation. EpCAM is expressed at high levels exclusively in epithelia and epithelial-derived neoplasms, making it a suitable target for many important solid tumor types and cancer stem cells. EpCam expression on normal tissues limits its utility as target for therapeutic antibodies and ADCs due to the potential effects on normal epithelial throughout the body. Conditionally Active Biologics (CAB) technology is a proprietary platform that selects antibodies that bind to target antigens in the context of diseased tissues, but not normal tissues, by taking advantage of the unique conditions in the tumor microenvironment. Using our CAB technology, we have developed CAB antibodies to EpCAM that reversibly bind to recombinant EpCAM and EpCAM expressing cells under select conditions that are present in the tumor microenvironment but not in normal tissues. In vitro and in vivo efficacy data for several anti-EpCAM antibodies and ADCs will be presented and suggest that conditionally active EpCam ADCs generated using the CAB technology will provide drug candidates that have an increased safety margin and therapeutic index in the clinic. Citation Format: Cathy Chang, Gerhard Frey, Leslie Sharp, William (Bill) J. Boyle, Jing Wang, Charles Xing, Haizhen Liu, Christina Wheeler, Marlena Walls, Jay M. Short. Novel conditionally active biologic (CAB) antibody targeting EpCAM demonstrates anti-tumor efficacy in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 356.
CD81 as target for B cell lymphomas
Authors: Ralf Küppers
Journal: The Journal of Experimental Medicine (2019)

In this issue of JEM, Vences-Catalán et al. (https://doi.org/10.1084/jem.20190186) demonstrate that a particular anti-CD81 antibody shows promising features as a novel immunotherapeutic tool to treat B cell lymphomas. Surprisingly, although CD81 is widely expressed, only minor side effects on other CD81+ immune cells analyzed were observed.
Abstract 15355: Primary Prevention for Sudden Cardiac Arrest With Ejection Fraction Less Than 45%, Not 40% is Beneficial in 40-Day Survivors After Acute Myocardial Infarction
Authors: Ki Hong Lee, Hyung Wook Park, Myung Ho Jeong, Dae Young Hyun, Jumin Won, Sung Sik Oh, Youngkeun Ahn, Jeong Gwan Cho
Journal: Circulation (2017)

Introduction: Primary prevention with implantable cardioverter defibrillator (ICD) is recommended in 40-day survivors after acute myocardial infarction (AMI) less than 40% of ejection fraction (EF)...
Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: A multicenter, open label, registration directed phase II study.
Authors: Nathan Hale Fowler, Felipe Samaniego, Wojciech Jurczak, Ewa Lech-Maranda, Nilanjan Ghosh, Piers Patten, James Andrew Reeves, Lori Ann Leslie, Julio C. Chavez, Paolo Ghia, Corrado Tarella, John M. Burke, Jeff Porter Sharman, Kathryn Kolibaba, Owen A. O'Connor, Chan Cheah, Hari P. Miskin, Peter Sportelli, Michael S. Weiss, Pier Luigi Zinzani
Journal: Journal of Clinical Oncology (2019)

7506 Background: Rituximab (RTX) alone or with chemo has substantially improved outcomes for patients (pts) with marginal zone lymphoma (MZL), but relapse is common and not all pts are candidates for or respond to current salvage therapies. Umbralisib is a novel, next-gen PI3Kδ inhibitor with unique inhibition of casein kinase-1ε (CK1ε) and a differentiated tolerability profile compared to earlier PI3Kδ inhibitors (Burris et al, 2018). This registration-directed study evaluates the efficacy and safety of umbralisib in pts with rel/ref (R/R) MZL. Methods: Pts had histologically confirmed MZL, ECOG PS ≤2, and ≥1 prior therapy including ≥1 anti-CD20 mAb-containing regimen. Pts received umbralisib 800 mg orally once daily until PD or unacceptable toxicity. The primary endpoint was overall response (ORR) as assessed by independent review (IRC) per 2007 IWG criteria. ORR by investigator assessment is reported here, and ORR by IRC is forthcoming. Secondary endpoints included duration of response (DOR), PFS, and safety. Results: 69 pts were enrolled; we report on the first 38 who are eligible for at least 6 months (mos) of follow-up as of the data cutoff. Among the 38 pts: extranodal (n = 23), nodal (n = 8), and splenic (n = 7). Median age was 67 years (range, 34-81). Median # of prior systemic therapies was 2 (range, 1-5). Seven pts (18%) had monotherapy RTX only, and 26 (68%) had at least one anti-CD20 mAb-containing chemoimmunotherapy. Median follow-up was 9.6 mos. ORR was 55% (4 CRs and 17 PRs). Eleven pts (29%) had stable disease (SD) of which 6 of these SD pts remain on study ranging from 7-12+ mos. The clinical benefit rate (CR+PR+SD) was 84%, and 91% of pts with at least 1 post-baseline assessment experienced tumor reductions. Median time to initial response was 2.7 mos, while median DOR was not reached (95% CI: 8.4-NR). The 12-month PFS was 71%. The most common all causality (≥20%) adverse events (AE) of any grade included: diarrhea (45%), nausea (29%), fatigue (26%), headache (26%), cough (24%), and decreased appetite (21%). The most common Grade 3/4 events were neutropenia (8%), febrile neutropenia (5%), and diarrhea (5%). As of the cutoff date 58% continue treatment. Conclusions: PI3Kδ inhibition with single-agent umbralisib is active and well tolerated in pts with R/R MZL, achieving durable responses with chemotherapy-free therapy. Clinical trial information: NCT02793583.
High Resolution Mapping of Human Lymphopoiesis Reveals a Common Lymphoid Progenitor (CLP) Population
Authors: Nivedita Shankar Saxena, Kara L. Davis, Matthew Arthur Inlay, Astraea Junger, Yujun Yang, Mark L. Krampf, Beruh Dejene, Garry P. Nolan, Irving L Weissman, Kenneth I. Weinberg
Journal: Blood (2016)
Prognostic value, clinicopathologic features and diagnostic accuracy of interleukin-8 in colorectal cancer: A prospective study in 60 patients in Tunisia
Authors: J. Ayari, S. Karrit, R. Guesmi, A. Zribi, S. Fendri, S. Ben Nasr, M. Balti, A. Haddaoui
Journal: Annals of Oncology (2019)
Comparative Effectiveness of Certolizumab Pegol, Abatacept, and Biosimilar Infliximab in Patients With Rheumatoid Arthritis Treated in Routine Care: Observational Data From the Danish <scp>DANBIO</scp> Registry Emulating a Randomized Trial
Authors: Kathrine L. Grøn, Bente Glintborg, Mette Nørgaard, Frank Mehnert, Mikkel Østergaard, Lene Dreyer, Niels S. Krogh, Jakob B. Bjørner, Merete L. Hetland
Journal: Arthritis & Rheumatology (2019)

Nationwide Danish guidelines regarding rheumatoid arthritis (RA) patients initiating biologic treatment (i.e., biologic disease-modifying antirheumatic drugs [DMARDs]) are issued on an approximately annual basis. For biologics-naive patients treated with concomitant methotrexate, mandatory medications included certolizumab pegol (CZP; year 2013-2014, recommended compliance 80%), abatacept (ABA; 2014-2015, 80%), and biosimilar infliximab (CT-P13; 2015-2016, 50%). We hypothesized that these guidelines could be perceived as a surrogate randomization tool in which calendar period rather than patient-specific factors defined the choice of the biologic DMARD. We undertook this study to assess compliance with guidelines (supporting the assumption of surrogate randomization) and to compare the effectiveness of CZP, ABA, and CT-P13 in patients treated according to guidelines.This was an observational cohort study emulating a randomized trial (using intent-to-treat analyses). RA patients compliant with the treatment guidelines were identified in DANBIO, and information on prior comorbidities was obtained by linking to national registries. Outcome measures included remission rates according to the Disease Activity Score in 28 joints (DAS28) (at 6 and 12 months) and treatment retention at 1 year, compared across treatment regimens. Comorbidity/confounder-adjusted multivariable logistic and Cox regression analyses were used.Seven hundred seventy-six patients were included in the study (336 receiving CZP, 215 receiving ABA, 225 receiving CT-P13). Compliance with treatment guidelines was high: 70%, 65%, and 59%, respectively. Six-month DAS28 remission rates were 35%, 33%, and 42%, and 12-month rates were 35%, 31%, and 35%, respectively. Compared to CZP, adjusted odds ratios for 6- and 12-month DAS28 remission rates were 0.96 (95% confidence interval [95% CI] 0.63-1.47) and 0.74 (95% CI 0.47-1.15) for ABA and 1.38 (95% CI 0.91-2.09) and 0.96 (95% CI 0.62-1.49) for CT-P13, respectively. Adjusted hazard ratios for withdrawal (during days 0-90 and days 91-365) were 0.70 (95% CI 0.39-1.27) and 1.16 (95% CI 0.84-1.60) for ABA and 0.58 (95% CI 0.33-1.10) and 0.83 (95% CI 0.59-1.17) for CT-P13, respectively, compared to CZP.The surrogate randomization procedure enabled head-to-head comparisons of CZP, ABA, and CT-P13. Although some differences in estimated effectiveness were observed across drugs, confidence intervals were wide and statistical significance was not reached.
Abstract 11879: Control of Fibroblast Function by Adrenergic/EPAC System and Potential Role in Atrial Remodeling
Authors: Sirirat Surinkaew, Mona Aflaki, Xiao- Y Qi, Yiguo Sun, Stanley Nattel
Journal: Circulation (2015)

Introduction: Heart failure (HF) produces left atrial (LA)-selective fibrosis and atrial fibrillation. HF also causes adrenergic activation, which contributes to remodeling via a variety of pathways mediated by altered signaling molecules, including the exchange protein activated by cAMP (Epac). Hypothesis: To evaluate the effects of adrenergic receptor (AR) and Epac1 signaling on LA fibroblast (FB) function and its potential role in HF-induced atrial remodeling. Methods: HF was induced in dogs by ventricular tachypacing (VTP, 240 bpm) for various periods. mRNA and protein expression were measured in freshly isolated LA FBs by qPCR and immunoblot, respectively. Results: Epac1 expression decreased in LA FBs within 12 hrs (-3.9 fold) of VTP onset (Fig. A). The selective Epac activator, 8-pCPT (33 μM) reduced, whereas the Epac blocker ESI-09 (1 μM) enhanced, LA FB collagen expression (Fig. B). Norepinephrine (NE, 1 μM) decreased Epac1 expression, an effect blocked by prazosin, and increased FB collagen protein production (Fig. C). Isoproterenol (ISO) increased Epac1 expression (Fig. D), an effect antagonized by ICI (β2-AR antagonist, 2 μM), but not CGP (β1-AR antagonist, 2 μM). β2-AR activation with ISO decreased collagen expression (Fig. E), an effect mimicked by salbutamol (10 μM) and blocked by ICI but not CGP. Transforming growth factor (TGF) β1 (10 ng/ml), known to be activated in HF, suppressed Epac1 expression, an effect blocked by the Smad3 inhibitor SIS3 (Fig. F). Conclusions: AR activation has complex effects on FBs, with NE/α-AR-activation suppressing Epac1 and increasing collagen expression, and β2-ARs having opposite effects. HF reduces LA FB Epac1 expression, likely via increased NE release from adrenergic nerve endings, along with TGF β1 activation. Epac1 signaling reduces FB collagen expression, so Epac1 downregulation in HF contributes to the atrial profibrotic milieu and may be a novel target for prevention of profibrillatory atrial remodeling.
Abstract 5196: Vorinostat exhibits anticancer effects through modulation of nuclear receptors and tumor suppressor genes in sub-types of triple negative breast cancer cells
Authors: Fatemeh NouriEmamzadeh, Beverly Word, Ebony Cotton, Kai Littlejohn, Gustavo Miranda-Carboni, Beverly Lyn-Cook
Journal: Cancer Research (2019)

Abstract Aberrantly expression of histone deacetylases (HDAC) play a critical role in tumorigenesis. The expression of individual HDACs has been shown to correlate to decreases in both, disease-free and overall survival, thus targeting HDACs is emerging as a new therapy for cancer. Histone acetylation is associated with elevated transcription, while deacetylation is associated with gene repression. Emerging evidence suggests their role in triple negative breast cancer (TNBC) progression. TNBC is an aggressive type of cancer that has poor prognosis and molecular studies have shown several subtypes within TNBC. These cancers lack targeted treatments and several options used such as, PARP inhibitors, angiogenesis inhibitors, androgen receptor inhibitors and others have shown limited efficacy, however histone deacetylase inhibitors are showing promising results in clinical trials. Vorinostat, a histone deacetylase inhibitor, also known as suberanilohydroxane acid (SAHA) was approved by the FDA for treatment of cutaneous T cell lymphoma. In this study, vorinostat was investigated in subtypes of TNBC cell lines, MB231(MSL) and two basal-like 2 TNBC cell lines, HCC70 and HCC1806. Cells were treated with vorinostat for 24 hrs. Vorinostat significantly up-regulated the tumor suppressor gene NR4A1 by 20 fold, NR4A3 by 10 fold and AR5A by 5 fold. RORα gene had the highest up-regulation, 60 fold, whereas PPARγ 4.5 fold. Estrogen related receptor A, ESRRA was also up-regulated in HCC70 cells. A decrease in expression was noted in DDX5, which is known to be elevated in basal-like tumors. A different profile was noted in the MB231 TNBC cells. Vorinostat also decreased growth and cell invasion, which shows its functional effects on these aggressive TNBC cell lines These changes suggest that vorinostat, which is currently in clinical trials for TNBC may be exerting its effect through modulation of orphan nuclear receptors and reactivation of tumor suppressor genes through epigenetic mechanisms. Further studies are needed to determine other signaling pathways modulated by this HDAC inhibitor. Citation Format: Fatemeh NouriEmamzadeh, Beverly Word, Ebony Cotton, Kai Littlejohn, Gustavo Miranda-Carboni, Beverly Lyn-Cook. Vorinostat exhibits anticancer effects through modulation of nuclear receptors and tumor suppressor genes in sub-types of triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5196.
Abstract 2958: Evaluating the therapeutic effects of methylene blue against prostate cancer
Authors: Priyadarshini Thiruvalluvan Shanthi, Abigail Foes, Gnanasekar Munirathinam
Journal: Cancer Research (2019)

Abstract Prostate cancer (PCa) is the second most commonly occurring cancer among men and the fourth most commonly occurring cancer overall. According to American Cancer Society, in the year 2018, it was estimated that there will be 164,690 new cases and 29,430 deaths from PCa. The treatment options currently available for PCa are found to be ineffective with varied side effects and complications associated with the development of resistance among patients. Therefore, there is an unmet need to find a safe and potent agent to treat PCa. In our study, we focused on studying the anticancer potential of Methylene Blue (MB) which belongs to the class of phenothiazinium salt. MB has been widely used to treat the condition of methemoglobinemia, emerging studies have shown that it has been effectively used as a photosensitizer in the treatment of cancer by means of photodynamic therapy (PDT). Our initial analysis showed that MB effectively reduced the viability of androgen-dependent (LNCaP) and androgen-independent (PC3 and DU145) PCa cells. Further experimental evaluations showed that MB inhibited the colony forming ability of PCa cells in-vitro suggesting its tumor suppressive potential. In addition, our studies showed that MB treatment disrupted the migration potential of PCa cells in a wound healing assay indicating the anti-metastatic function of MB. Moreover, confocal and FACS analysis using Annexin V FITC and propidium iodide staining revealed that MB effectively targeted the PCa cell lines by inducing apoptotic cell death. To delineate the underlying anticancer mechanism of MB, apoptosis protein array was performed employing LNCaP cells, and the results of which showed that key apoptotic molecules such as Bax, TRAIL R2/D5, and phospho p53 (Serine 15, Serine 46, Serine 392) were robustly upregulated in LNCaP cells following MB treatment. In conclusion, our findings suggest that MB induces apoptosis in PCa cells and thus could serve as a potential anticancer agent for treating both hormone-dependent and -independent PCa. Citation Format: Priyadarshini Thiruvalluvan Shanthi, Abigail Foes, Gnanasekar Munirathinam. Evaluating the therapeutic effects of methylene blue against prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2958.
Abstract 502: Aldo-keto reductase 1B8 (AKR1B8) deficiency causes intestinal immune deficiency
Authors: Xin Wang, Deliang Cao
Journal: Cancer Research (2019)

Abstract Background: Intestinal epithelial cells (IECs) are crucial mediators of intestinal immunity. IECs defects may disrupt development and maturation of intestinal immunity. Aldo-keto reductase 1B10 (AKR1B10) is a regulator of de novo fatty acids synthesis and lipid synthesis by mediating acetyl-CoA carboxylase-α (ACCA) stability. Aldo-keto reductase 1B8 (AKR1B8) is an ortholog in mice of human AKR1B10, which has similar regulatory function in fatty acid/lipid synthesis. AKR1B8 deficiency causes IECs defects in proliferation and self-renewal, which may lead to dysregulation of intestinal immunity. Methods: AKR1B8 -/- mice mouse stain was produced by homozygous recombination. Immune cells were isolated from colonic lamina propria (cLP) and mesenteric lymph nodes (MLN). Flow cytometry and immunofluorescence staining were applied for immune cell sorting and measurements. Microbiota composition were quantified by next generation sequencing. Results: AKR1B8 deficiency causes infiltration of neutrophils, mast cells and basophils in the colon. Also, AKR1B8 deficiency causes impaired γδT cells and T helper cells (Th cells) immunity, such as IFNγ, IL17, IL4 or IL22 production, in colon and mesenteric lymph nodes, while enhances distinct arm of CD8 activity and Treg cells. These alterations may be due to the changes of MHCII+ DCs and CD103+ DCs in AKR1B8 deficient mice. Meanwhile, AKR1B8 inhibits the phosphorylation of p-AKT (T308 and S473) and p-ERK (1/2) in IECs, and suppresses the regulation IKKα/NF-κB signaling cascades. Furthermore, AKR1B8 deficiency induces gut microbiota shifts with higher ratio of Firmicutes/Bacteroidetes. Conclusions: AKR1B8 is a critical mediators for IECs signaling and immune homeostasis. Loss of AKR1B8 in IECs induces Th cells immune deficiency. This study identified a new compensatory mechanism under IECs defects for maintaining intestinal immune homeostasis. Citation Format: Xin Wang, Deliang Cao. Aldo-keto reductase 1B8 (AKR1B8) deficiency causes intestinal immune deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 502.
Abstract 259: Interplay between Bcl-2 and cFLIP in lymphoma disease progression is a function of an altered redox milieu
Authors: Jayshree L. Hirpara, Shazib Pervaiz
Journal: Cancer Research (2019)

Abstract Bcl-2 is associated with chemoresistance and despite the preponderance of evidence linking its anti-apoptotic function to hematologic cancers, it’s now emerging that overexpression of Bcl-2 is a feature shared by a host of cancers. Canonically, the death inhibitory activity of Bcl-2 is associated with its ability to prevent mitochondrial outer membrane permeabilization. However, recent evidence has highlighted a novel facet in the biology of Bcl-2, whereby enforced expression of Bcl-2 resulted in an increase in mitochondrial oxygen consumption and elevated levels of the reactive oxygen species (ROS), superoxide (O2-.). Alleviating the levels of intracellular O2-. sensitized Bcl-2 overexpressing cells to death receptor induced apoptosis via a robust increase in upstream caspase 8 activation. Using a variety of functional mutants of the NOX-activating small GTPase Rac1, we show a clear link between Bcl-2 induced apoptosis resistance and intracellular O2-.. In the search for the molecular target of this inhibitory signal, we now show that Bcl-2 overexpression is associated with an increase in the transcription and protein levels of the receptor inhibitory protein, cFLIP. We employed pharmacological and genetic approaches to modulated intracellular O2-. and present evidence cFLIP is transcriptionally regulated by O2-.; increase in cFLIP promoter activity and mRNA levels. Interestingly, inhibiting glycolysis also resulted in downregulation of cFLIP in a ROS-dependent manner. Notably, primary cells derived from patients with lymphoma also showed a significant downregulation of cFLIP when subjected to conditions that decrease O2-. and elicited enhanced sensitivity to TRAIL-induced apoptosis. Importantly, TCGA and Affy meta-cohorts’ analyses revealed consistent correlation trend: Bcl-2 and cFLIP (CFLAR) were positively correlated; Bcl-2 and SOD1 (superoxide dismutase 1) were negatively correlated. A strong negative correlation was also observed between CFLAR and SOD1. Furthermore, Kaplan-Meier analyses of overall survival (OS) were performed in the in-house High expression of either Bcl-2 or CFLAR conferred poor OS outcome. When stratified by CFLAR and Bcl-2 expressions, cases with higher expression of the two genes had the worst prognosis with the shortest median survival. Notably, DLBCL with high Bcl-2 and low SOD1 had the worst OS outcome, compared against expression levels of Bcl-2 and SOD1. Together, these findings point to a concordance between cFLIP and Bcl-2, which negatively correlates with SOD1 in driving lymphoma progression. Citation Format: Jayshree L. Hirpara, Shazib Pervaiz. Interplay between Bcl-2 and cFLIP in lymphoma disease progression is a function of an altered redox milieu [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 259.
Abstract 16010: Abnormal Aortic Flow in Children With Pulmonary Arterial Hypertension is Associated With Non-Uniform Wall Shear Stress Distribution
Authors: Michal Schafer, Dunbar Ivy, Steven Abman, Lorna Browne, Brian Fonseca, Michael DiMaria, Alex Barker, Max Mitchell, Uyen Truong
Journal: Circulation (2018)

Introduction: Children with pulmonary arterial hypertension (PAH) have been shown to have abnormal aortic distensibility associated with main pulmonary artery (MPA) dilation and left ventricular dy...