tbuckley/cabot-search huggingface dataset:
Abstract 2955: Herceptarg, a novel heterodimeric biparatopic common light chain IgG1 antibody based on trastuzumab and pertuzumab, exerts potent anti-tumoral activity
Authors: Ekkehard Moessner, Thomas Hofer, Inja Waldhauer, Werner Scheuer, Ralf Hosse, Lydia Duerner, Mi He, Karlheinz Zick, Jens Fischer, Claudio Sustmann, Tina Weinzierl, Marina Bacac, Christian Gerdes, Pablo Umana, Christian Klein
Journal: Cancer Research (2016)

Abstract Introduction: Trastuzumab and pertuzumab are humanized antibodies recognizing different functional HER2 epitopes. Preclinical data demonstrated strong anti-tumoral efficacy when combining them (Scheuer et al., Canc Res, 2009). The CLEOPATRA trial showed that the addition of pertuzumab to trastuzumab + docetaxel strongly improves overall survival of HER2+ metastatic breast cancer patients (Swain et al., NEJM, 2015). Herceptarg is a novel heterodimeric 1+1 biparatopic common light chain IgG1 antibody based on trastuzumab and pertuzumab. Methods: Using consensus light chains, pertuzumab heavy chain affinity maturation via phage display and knob-into-holes technology, a heterodimeric biparatopic common light chain antibody based on trastuzumab and pertuzumab was generated (Figure 1A). This bispecific antibody was characterized in direct comparison to the respective parental antibodies and their combination in vitro by surface plasmon resonance, proliferation, ADCC and CDC assays and in vivo using the orthotopic KPL-4 breast cancer xenograft model. KPL-4 cells were provided by Prof. Kurebayashi (Kawasaki Medical School, Kurashiki, Japan). Results: In vitro, Herceptarg has the highest binding affinity for HER2 on cells, mediates potent ADCC activity, comparable or superior growth inhibition activity of breast and gastric cancer cells and CDC superior to the combination of pertuzumab and trastuzumab. In vivo, Herceptarg (10 mg/kg, q1w) mediates anti-tumoral efficacy in the orthotopic KPL-4 breast cancer xenograft model resulting in tumor regression comparable to the combination of trastuzumab and pertuzumab (10 mg/kg, q1w, each), and superior to the respective single agent therapies. Conclusions: Taken together, these data demonstrate that Herceptarg, as a single IgG1 bispecific antibody is superior (or at least comparable) to the combination of trastuzumab and pertuzumab in vitro and in vivo and may ultimately improve outcome of breast and gastric cancer patients. Citation Format: Ekkehard Moessner, Thomas Hofer, Inja Waldhauer, Werner Scheuer, Ralf Hosse, Lydia Duerner, Mi He, Karlheinz Zick, Jens Fischer, Claudio Sustmann, Tina Weinzierl, Marina Bacac, Christian Gerdes, Pablo Umana, Christian Klein. Herceptarg, a novel heterodimeric biparatopic common light chain IgG1 antibody based on trastuzumab and pertuzumab, exerts potent anti-tumoral 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 2955.
Abstract 4929: UbcH10 may represent a potential marker of gastric carcinoma
Authors: Mengxuan Yang, Yingying Qu, Gang Hu, Shiwei Tu, RL Shi, XB Wu, ZQ Hu, QM Zhang, SQ Liu, GF Pan, Ziping Zhang, He Zhou
Journal: Cancer Research (2016)

Abstract Gastric cancer is a fatal disease with limited early diagnostic methods available. There is an urgent need to find more effective targets for early diagnosis and therapeutics. UbcH10 is an ubiquitin-conjugating enzyme with a high expression reported in some cancers. Several gastric tumor cell lines with high or low expression of UbcH10 were exploited to study the role of UbcH10 in gastric cancer. Knocking down of UbcH10 expression using siRNA in high expressing gastric cancer cell lines resulted in reduced proliferation, increased cisplatin-induced apoptosis and reduced serum-induced ERK, Akt and p38 phosphorylation signaling. In agreement, overexpression of UbcH10 expression in low-expression gastric cancer cell lines led to enhanced cell proliferation, resistance to cisplatin-induced apoptosis. Most importantly, IHC analyses showed that the UbcH10 protein expressed at a high level in patient gastric cancer tissues, but not in adjacent mesenchyme tissues. These data suggest that UbcH10 may promote gastric cancer growth and can serve as a biomarker for diagnosis or target for new therapeutics in gastric cancer. Citation Format: Mengxuan Yang, Yingying Qu, Gang Hu, Shiwei Tu, RL Shi, XB Wu, ZQ Hu, QM Zhang, SQ Liu, GF Pan, Ziping Zhang, He Zhou. UbcH10 may represent a potential marker of gastric carcinoma. [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 4929.
Tau and β-Amyloid—The Malignant Duo
Authors: William Jagust
Journal: JAMA Neurology (2016)

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Blimp-1–mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis
Authors: SuJin Hwang, Dustin A. Cobb, Rajarshi Bhadra, Ben Youngblood, Imtiaz A. Khan
Journal: The Journal of Experimental Medicine (2016)

CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)–susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell–intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches.
A Novel CD16xCD33 Bispecific Killer Cell Engager (BiKE) Mediates a Double Hit For Natural Killer (NK) Cells To Target CD33+ Myelodysplastic Syndrome (MDS) Cells and Myeloid Derived Suppressor Cells (MDSCs) At All Disease Stages
Authors: Julie A. Ross, Troy C. Lund, Michael R. Verneris, Andres Wiernik, Erica D. Warlick, Stephen Spellman, Mbs, Michael D. Haagenson, Alexander J. Lenvik, Mark R. Litzow, Daniel J. Weisdorf, Daniel A. Vallera, Jeffrey S. Miller
Journal: Blood (2013)
Abstract 3667: Potential role of DUSP4 as a tumor suppressor in pancreatic cancer
Authors: Chandra K. Singh, Jasmine George, Minakshi Nihal, Nihal Ahmad
Journal: Cancer Research (2016)

Abstract Pancreatic cancer remains one of the most lethal of all human malignancies, with 48,960 expected new cases and 40,560 deaths predicted in the USA in the year 2015. In order to develop novel strategies for the management of pancreatic cancer, it is of utmost importance to intensify our efforts to dissect the molecular mechanisms involved in the pathophysiology of this fatal neoplasm. Dual-specificity phosphatase-4 (DUSP4), a family member of dual-specificity phosphatases, is capable of dephosphorylating both phosphotyrosine and phosphoserine/phosphothreonine residues and possesses activity against key signaling components of the MAPK pathway that plays an important role in cancer growth. DUSP4 has been shown to be widely expressed in different tissues and implicated in cancer development, differentiation, apoptosis and inflammation. In a recent study from our laboratory that was aimed at defining the molecular targets of the anti-cancer plant-based alkaloid sanguinarine in pancreatic cancer, we identified DUSP4 as a key protein modulated by sanguinarine. Specifically, based on proteomics data and validation by qRT-PCR and immunoblot analysis, we found that sanguinarine significantly increases DUSP4 in BxPC-3 and MIA PaCa-2 pancreatic cancer cells. Indeed, an association of DUSP4 loss with cancer progression has been shown in certain cancers. However, the role of DUSP4 in pancreatic cancer is not known. This study was designed to determine the role and importance of DUSP4 in pancreatic cancer. We determined the expression profile of DUSP4 in pancreatic cancer using immunohistochemical analysis of a tissue microarray containing a variety of pancreatic cancers and normal pancreatic tissues. The DUSP4-immunostaining was microscopically imaged followed by quantification of DUSP4 protein by multispectral Vectra™ system coupled with inForm software. We found a significant downregulation of DUSP4 in human pancreatic cancer tissues, when compared to normal pancreatic tissues. Further, to understand the importance of DUSP4 in pancreatic cancer, we determined the effect of a force overexpression of DUSP4 in MIA PaCa-2 pancreatic cancer cells. We found that DUSP4 overexpression in MIA PaCa-2 cells resulted in a significant i) decrease in cell growth and proliferation, ii) clonogenic survival, and iii) induction of apoptosis. These preliminary findings suggest a potential tumor suppressive function of DUSP4 in pancreatic cancer. Further detailed studies are ongoing in our laboratory to validate the role and functional significance of DUSP4 in pancreatic cancer. Citation Format: Chandra K. Singh, Jasmine George, Minakshi Nihal, Nihal Ahmad. Potential role of DUSP4 as a tumor suppressor in pancreatic cancer. [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 3667.
Adenosine monophosphate deaminase 3 activation shortens erythrocyte half-life and provides malaria resistance in mice
Authors: Elinor Hortle, Brunda Nijagal, Denis C. Bauer, Lora M. Jensen, Seong Beom Ahn, Ian A. Cockburn, Shelley Lampkin, Dedreia Tull, Malcolm J. McConville, Brendan J. McMorran, Simon J. Foote, Gaetan Burgio
Journal: Blood (2016)
Abstract 811: Mosaic chromosome Y loss is not associated with testicular germ cell tumor risk
Authors: Mitchell J. Machiela, Casey L. Dagnall, Anand Pathak, Jennifer T. Loud, Stephen J. Chanock, Mark H. Greene, Katherine A. McGlynn, Douglas R. Stewart
Journal: Cancer Research (2016)

Abstract Background Testicular germ cell tumors (TGCTs) affect approximately 6 in 100,000 men with peak incidence in men 15 to 40 years of age. Established risk factors include family history of disease, undescended testis, contralateral TGCT, impaired fertility, and 21 GWAS susceptibility loci. Recent evidence suggests a 1.6 Mb deletion in the AZFc region (“gr/gr” deletion) of chromosome Y previously associated with male infertility is also associated with two- and three-fold increased risks of sporadic and familial TGCT, respectively. Furthermore, population-based studies have suggested mosaic chromosome Y loss in blood-derived DNA may be associated with increased risk of various solid tumors. Our aim was to investigate if mosaic loss across the entire Y chromosome is a TGCT risk factor. Methods We obtained blood and buccal-derived DNA from two studies: the NCI Familial Testicular Cancer Study (FTC, Cases = 172, Controls = 163) and NCI's US Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study (STEED, Cases = 506, Controls = 611). We designed a quantitative polymerase chain reaction (qPCR) with 15 probes spanning the Y chromosome to assess Y loss. Samples were run in triplicate across three batches and normalized to a standard curve. We quantified probe signals as a target to reference (T/R) ratio, and averaged ratios across the 15 probes to yield an overall Y chromosome signal. Results On average, men with TGCT had slightly lower mean T/R ratios compared with control men lacking TGCT (1.02 vs. 1.03). Multivariate logistic regression models adjusted for study batch effects detected no significant relationship between mean Y chromosome T/R ratio and TGCT risk (OR = 0.34, 95% CI = 0.10-1.17, P = 0.09). A similar null relationship was observed when using a threshold of 1.5 standard deviations below the mean T/R ratio to dichotomize between mosaic Y loss and no mosaic Y loss (OR = 0.59, 95% CI = 0.21-1.63, P = 0.31). Conclusion Our study suggests that mosaic chromosome Y loss, as measured by 15 probes spanning the Y chromosome, is not associated with either sporadic or familial TGCT risk. Further studies aimed at investigating the AZFc region of the Y chromosome are needed to better assess whether this locus is directly associated with TGCT risk or is indirectly associated by means of a shared relationship with impaired fertility. Citation Format: Mitchell J. Machiela, Casey L. Dagnall, Anand Pathak, Jennifer T. Loud, Stephen J. Chanock, Mark H. Greene, Katherine A. McGlynn, Douglas R. Stewart. Mosaic chromosome Y loss is not associated with testicular germ cell tumor risk. [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 811.
MAESTRO: A randomized, double-blind phase III study of evofosfamide (Evo) in combination with gemcitabine (Gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC).
Authors: Eric Van Cutsem, Heinz-Josef Lenz, Junji Furuse, Josep Tabernero, Volker Heinemann, Tatsuya Ioka, Igor Bazin, Makoto Ueno, Tibor Csõszi, Harpreet Wasan, Bohuslav Melichar, Petr Karasek, Teresa Mercade Macarulla, Carmen Guillen, Ewa Kalinka-Warzocha, Zsolt Horvath, Hans Prenen, Michael Schlichting, Ayman Ibrahim, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2016)

4007 Background: Hypoxia in PDAC is associated with disease progression and poor prognosis. Evo is a hypoxia-activated prodrug of Br-IPM that is preferentially activated under hypoxic conditions. The addition of Evo to Gem significantly improved PFS in a randomized phase II trial in advanced PDAC (NCT01144455). Methods: MAESTRO was an international, randomized, double-blind, placebo-controlled phase III trial of Evo/Gem vs Placebo (Pbo)/Gem in pts with locally advanced unresectable or metastatic PDAC (NCT01746979). Evo 340 mg/m2 or matched Pbo and Gem 1,000 mg/m2 were administered IV on days 1, 8, and 15 of a 28-day cycle. Key eligibility criteria included ECOG PS 0/1. The primary endpoint was overall survival (OS). 660 patients were to be randomized 1:1 to obtain 508 events (deaths) to assure 90% power to detect a hazard ratio (HR) of 0.75 for OS with a two-sided α of 0.05. Secondary endpoints included PFS and objective response rate (ORR). Results: From Jan 2013 to Nov 2014, 693 pts were randomized (346 Evo/Gem, 347 Pbo/Gem). Baseline characteristics were balanced. Median OS was 8.7 mo with Evo/Gem vs 7.6 mo with Pbo/Gem; HR = 0.84 (95% CI: 0.71–1.01, p = 0.059). Median PFS was 5.5 mo with Evo/Gem vs 3.7 mo with Pbo/Gem; HR = 0.77 (95% CI: 0.65–0.92, p = 0.004). Best ORR was 20% with Evo/Gem vs 16% with Pbo/Gem; odds ratio (OR) = 1.32 (95% CI: 0.88–1.97, p = 0.17). Confirmed ORR was 15% with Evo/Gem vs 9% with Pbo/Gem; OR = 1.90 (95% CI: 1.16 – 3.12, p = 0.009). Most common non-hematologic AEs of nausea (47%), decreased appetite (35%) and vomiting (33%) were similar across arms. Hematologic AEs of neutropenia, thrombocytopenia and anemia were more frequent with Evo/Gem. AEs leading to death were 9% with Evo/Gem vs 11% with Pbo/Gem. AEs leading to treatment discontinuation were 17.9% on Evo/Gem and 15.6% on Pbo/Gem. Conclusions: The primary endpoint was not met as difference in OS time was not statistically significant. Evo/Gem showed signs of antitumor activity with longer PFS and higher ORR. The safety profile was similar to that previously reported. Clinical trial information: NCT01746979.
Underutilization of Coronary Artery Disease Testing Among Patients Hospitalized With New-Onset Heart Failure
Authors: Darshan Doshi, Ori Ben-Yehuda, Machaon Bonafede, Noam Josephy, Dimitri Karmpaliotis, Manish A. Parikh, Jeffrey W. Moses, Gregg W. Stone, Martin B. Leon, Allan Schwartz, Ajay J. Kirtane
Journal: Journal of the American College of Cardiology (2016)
Abstract 3685: Redox regulation of p53 stability is a function of inhibition of PP2A-mediated dephosphorylation at threonine 55
Authors: Stephen Chong, Shazib Pervaiz
Journal: Cancer Research (2016)

Abstract Protein Phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that has critical roles in numerous cellular pathways. The role of PP2A as an essential tumor suppressor in numerous death signaling pathways is well documented. In this regard, recent work from our laboratory has highlighted a novel mechanism of apoptosis inhibition via post-translational redox-modification of PP2A. Increase in intracellular superoxide, either by pharmacological inhibition or siRNA-mediated silencing of superoxide dismutase 1 (SOD1), results in the dissociation of PP2A-AC catalytic core from its B regulatory subunit. Dissociation of the PP2A heterotrimer is a result of the selective nitration [by peroxynitrite derived from the reaction of superoxide with nitric oxide] of a conserved tyrosine residue on B56δ which we identified as Y289 (B56δY289). Importantly, we showed in lymphoma cells that PP2A-AC catalytic core is typically targeted to Bcl-2 by its B56δ regulatory subunit. When O2- is elevated, it signals for the sustained phosphorylation of Bcl-2 at S70 by inducing the release of PP2A-AC catalytic core from B56δ-bound Bcl-2. This results in the sustained phospho-activation of anti-apoptotic Bcl-2 and resistance to apoptotic stimuli. Notably, Bcl-2 is not the only substrate of PP2A, nor is B56δ the only PP2A regulatory subunit susceptible to redox modification. Thus, implications from redox-modification of PP2A may extend beyond the phospho-activation of Bcl-2. In the context of carcinogenesis, another notable substrate of PP2A is the tumor suppressor, p53. p53 stability is negatively influenced by its phosphorylation status at threonine-55 (T55). Phosphorylation of T55, on the other hand, is countered by PP2A harboring the B56γ3 subunit. Here we provide evidence that the B56γ3 sub-unit of PP2A complexes with p53 and this complex is sustained upon an increase in intracellular superoxide. Importantly, redox-mediated inhibition of B56γ3-containing PP2A (PP2AB56γ3) prevents the dephosphorylation of p53 at T55, thereby negatively impacting the stability of p53 in tumor cells with elevated superoxide level. This, we hypothesize, may be a novel death inhibitory mechanism that renders tumor cells resistant to conventional DNA-damaging therapeutic agents that rely heavily on the activation of p53 for death induction. Citation Format: Stephen Chong, Shazib Pervaiz. Redox regulation of p53 stability is a function of inhibition of PP2A-mediated dephosphorylation at threonine 55. [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 3685.
Abstract 2626A: A lignan compound arctigenin inhibits prostate tumor growth in vitro and in vivo
Authors: Piwen Wang, Susanne M. Henning, Jaydutt V. Vadgama
Journal: Cancer Research (2016)

Abstract Arctigenin is a novel anti-inflammatory lignan derived mainly from the seeds of Arctium lappa, an herb widely used in traditional Chinese medicine to treat inflammation related diseases such as cough, cold and swelling of throat. The present study was designed to investigate whether arctigenin is a potent inhibitor of prostate cancer using both in vitro and xenograft mouse models. The treatments with arctigenin at lower doses (&amp;lt; 2μM) for 48h dose-dependently inhibited the proliferation of two androgen-sensitive prostate cancer cell lines, LNCaP and LAPC-4, by 40-50% compared to control. There was no cytotoxicity observed in normal prostate epithelial PrEC cells with arctigenin doses up to 10μM. An intervention study was then conducted in severe combined immunodeficiency (SCID) mice to confirm the tumor-inhibitory effect of arctigenin in vivo. Male SCID mice (n = 10 per group) were inoculated with 5×10⁁5 LAPC-4 cells subcutaneously. One week later when tumors were palpable the intervention started. Mice were administered with arctigenin at 50mg/kg (LD) or 100mg/kg (HD) or vehicle control daily for 6 weeks by oral gavage. After 4 weeks of intervention the tumor growth was significantly inhibited by both of the arctigenin doses. After 6 weeks of intervention, the tumor volumes were reduced by 48% (LD arctigenin) and 67% (HD arctigenin) compared to control. There was no significant difference in food or water consumption or body weight among groups. An ELISA assay of growth factors demonstrates that arctigenin treatments significantly decreased the concentrations of VEGF, EGF, NGF-β, TNF-α, and FGF-β in tumor tissues compared to control. Western blot analysis revealed a significantly reduced expression of galectin-4 in tumor tissues by arctigenin treatment. Previous studies have shown that strong expression of galectin-4 can be induced in different types of cancer, associated with tumor growth and progression. A microRNA PCR array assay was performed to measure the tumor concentrations of 84 microRNAs involved in prostate cancer development and progression. A panel of microRNAs including miR-126 and miR-135 were identified to be responsive to arctigenin treatment. Further mechanistic investigation using tissue microarray assay is ongoing to measure the protein markers of proliferation and apoptosis in tumor tissues. This study provides a promising non-toxic agent to enhance chemoprevention of prostate cancer. These results warrant future clinical trial studies to confirm the anti-carcinogenic effect of arctigenin in humans. Citation Format: Piwen Wang, Susanne M. Henning, Jaydutt V. Vadgama. A lignan compound arctigenin inhibits prostate tumor growth in vitro and in vivo. [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 2626A.