tbuckley/cabot-search huggingface dataset:
Abstract 688: Anti-CNTN4 antibody, GENA-104A07 suppresses tumor growth in murine syngeneic tumor models by regulating T cell function
Authors: Mi Young Cha, Youn Kyung Houh, Yun Yeon Kim, Hyunuk Kim, Joo-Yeon Chung, Kyung Mi Park, Hansoo Park
Journal: Cancer Research (2021)

Abstract Vast improvements in tumor treatment have been achieved with immune checkpoint inhibitors. They have been approved for use in monotherapy or combinations for patients with different types of cancer. However, the treatments often yield limited benefits and strong responses are observed only in a minority of treated patients. For this reason, enormous efforts have been made to explore primary or acquired resistance mechanisms to improve the available current therapies. CNTN4 (contactin 4, alias BIG-2) is a neuronal cell adhesion molecule, which is mainly expressed in the human brain and functions in axonal growth and guidance. Some genetic evidence has indicated that CNTN4 may be associated with non-neurological disorders such as cancer and cardiovascular conditions as well as neurodevelopmental disorders. Recently we identified CNTN4 as a novel immunomodulatory protein, which is expressed on tumors. In this study, we investigate the potential of CNTN4 as a cancer immunotherapeutic target, using GENA-104A07 to target it. GENA-104A07 is a humanized IgG4 monoclonal antibody that specifically binds to human and mouse CNTN4 with sub-nanomolar binding affinity by ELISA assay, not to any other related proteins having similar sequences. This molecule competitively interferes with the binding of CNTN4 and its receptor protein. The in vitro functional effect showed that the treatment of GENA-104A07 alleviates the immune suppressive effect induced by CNTN4 on T cells. Consequently, the administration of GENA-104A07 induces significant suppression of the tumor growth as monotherapy in syngeneic mouse models with a high expression level of CNTN4. GENA-104A07 treatment increases the expression of activation markers and pro-inflammatory cytokines on T cells. Taken together with in vitro and in vivo studies, the efficacy of GENA-104A07 demonstrated that CNTN4 blockage with monoclonal antibody may provide an immunotherapeutic strategy for human cancer. Currently, the preliminary safety study is ongoing in mice, and IND enabling studies will be initiated early next year with the optimized antibody. Citation Format: Mi Young Cha, Youn Kyung Houh, Yun Yeon Kim, Hyunuk Kim, Joo-Yeon Chung, Kyung Mi Park, Hansoo Park. Anti-CNTN4 antibody, GENA-104A07 suppresses tumor growth in murine syngeneic tumor models by regulating T cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 688.
Abstract 3057: Development of radiation-triggered phosphor platform for localized activation in combinatory cancer treatment
Authors: Rao V. Papineni, Sunil Krishnan, Ajayan Pulickel, Onur Sahin
Journal: Cancer Research (2021)

Abstract A defined spatial and temporal control of induction of toxicity in response to external ionizing radiation such as X-rays has unique clinical benefits over conventional systems such as passive drug delivery or its activation. Here, we have combined X-rays with well characterized nanoscintilators emitting light that activates paired photosensitizers in photodynamic therapy (PDT) that improves the prowess of PDT to deep seated tumor treatment. Yttrium oxide nanoparticle construct doped with Europium (YOE) and coated with a silica layer entrapping methylene blue (MB) as the photosensitizer was fabricated. The nanoconstruct (YSM, for YOE, silica, MB) was decorated with polyethylene glycol (PEG) to make it biocompatible and characterized extensively for physicochemically parameters. Transmission electron microscopy (TEM) revealed a resultant average nanoparticle diameter of 24.1 ± 5.7 nm, and dynamic light scattering (DLS) a hydrodynamic diameter of 135.3 ± 17.9 nm. This nanoconstruct was evaluated for its ability to generate singlet oxygen reactive oxygen species upon irradiation using singlet oxygen sensor green (SOSG) fluorescence assay. Further, demonstrated that this nanoconstruct was taken up by cancer cells in vitro and by tumors in vivo. The uptake of YSM particles by Panc02 murine pancreatic cancer cells was tested by inductively coupled plasma – mass spectrometry. This demonstrated robust uptake in cells after 24hr incubation. No noticeable cell death occurred with doses of 0 Gy and 4 Gy, cell viability decreased significantly after a dose of 8 Gy irradiation in cells cultured with YSM when compared to controls. Since 8 Gy is within the range of a clinically applicable dose used routinely in stereotactic radiotherapy regimens, these results verified the potential of YSM to be used as scintillator-photosensitizer complexes for x-ray activated photodynamic therapy. Finally the biodistribution of YSM nanoconstructs in vivo in C57BL6 mice harboring subcutaneous Panc02 tumors show YSM accumulation in tumors. A versatile, biocompatible Yttrium oxide scintillator-photosensitizer complex (YSM) that can generate x-ray induced cytotoxic reactive oxygen species is fabricated. This is capable of facilitating x-ray activated photodynamic therapy (XPDT (external beam) and/or iXPDT (internal x-ray source)). It shows promise in maximizing the efficacy of the combinatory treatment and enhanced improvement of the quality of life and overall survival of cancer patients. Citation Format: Rao V. Papineni, Sunil Krishnan, Ajayan Pulickel, Onur Sahin. Development of radiation-triggered phosphor platform for localized activation in combinatory cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3057.
Protein farnesyltransferase: Flexible docking studies on inhibitors using computational modeling
Authors: Wayne C. Guida, Andrew D. Hamilton, Justin W. Crotty, Said M. Sebti
Journal: Cancer Research (2005)

3959  Using MacroModel, peptide, peptidomimetic and non-peptidomimetic inhibitors of the zinc metalloenzyme, farnesyltransferase, were docked into the enzyme binding site. In addition to CVFM and CVIM, as well as our own inhibitors FTI-276 and FTI-2148, we have docked other FTIs including Zarnestra which presently is in advanced clinical trials. The AMBER* force field was employed augmented with parameters that were derived for zinc. The single binding site model that was derived from the crystal structure for CVFM was used for these studies and it incorporated farnesyl pyrophosphate. In cases where the crystal structure of the ternary complex is known, the docking results, using the global minimum energy structure or one of the lowest energy structures, were in excellent agreement with the x-ray structures. Among the most important findings of this study is that numerous alternative conformations for the methionine side chain can be accommodated by the enzyme indicating that the methionine pocket can tolerate groups larger than methionine at the C-terminus of the tetrapeptide.
Gastrointestinal Sequelae 3 and 6 Months After Hospitalization for Coronavirus Disease 2019
Authors: Anam Rizvi, Zankhesh Patel, Yan Liu, Sanjaya K. Satapathy, Keith Sultan, Arvind J. Trindade
Journal: Clinical Gastroenterology and Hepatology (2021)

Gastrointestinal (GI) symptoms are highly prevalent in coronavirus disease 2019 (COVID-19) ranging from 17.6 % to 53 %.
Abstract 2868: A cell based phenotypic assay platform for cancer metastasis drug discovery and diagnostics
Authors: Arnab Roy Chowdhury, Debabani Roy Chowdhury, Manoj Pandre, Samrat Roy, Sundarajan Kannan, John W. Ellingboe
Journal: Cancer Research (2021)

Abstract Metastatic cancers are difficult to treat and are the cause of about 90% of cancer related deaths. Furthermore, predictive diagnostics are not readily available, and lack of good translational assays has impaired drug discovery. Mestastop has developed a platform of cell based functional assays that aims to address these drug discovery and diagnostic gaps. The platform is comprised of a set of 14 cell based phenotypic assays that capture multiple aspects of the complex process of metastasis, including characterization of the plasticity ratios (EMT, MET) and stemness of cells, invasion, intravasation, circulation, extravasation, and survival in secondary tissues (e.g metabolic shift, exosome secretion). Wild type tumor cells (initially a set of colon tumor cell lines) are utilized in the platform. Non-metastatic wild type cells (e.g. HT-29) that have been engineered into metastatic cells are also utilized to further elucidate metastatic processes, thereby creating two baseline data sets for each assay; one for the normal growing tumor and the other for the select metastatic population. Patient derived tumors are now being analyzed in the platform to help build a translational model. Preclinical animal models are being jointly developed with Immunobiome Inc. (South Korea). As the data from all these assays present a multivariate problem, we are developing a machine learning algorithm, METSCANTM, to analyze the results. The platform will be applied to the screening of novel compounds for drug discovery and of approved drugs for repurposing. Analysis of patient derived tumors may allow for the early detection of patients with high metastatic potential. Four colon cancer cell lines and several standard chemotherapy drugs have been used to validate the platform. A group of triple negative breast cancer cell lines is now being tested. Preliminary data for a set of approved, marketed drugs has further validated the potential of the platform for drug discovery and repurposing. The Mestastop proprietary assay platform will empower biopharma in the discovery of novel drug candidates and repurposing of approved drugs for the treatment of metastasis, and the early diagnosis of cancers with high metastatic potential, thereby addressing the unmet need in the area of cancer metastasis. Citation Format: Arnab Roy Chowdhury, Debabani Roy Chowdhury, Manoj Pandre, Samrat Roy, Sundarajan Kannan, John W. Ellingboe. A cell based phenotypic assay platform for cancer metastasis drug discovery and diagnostics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2868.
Abstract 1887: Anti-CD38/CD28xCD3 trispecific T cell engager induces proliferation of primary T cells and mediates potent killing of primary malignant plasma cells isolated from Multiple Myeloma bone marrow aspirates
Authors: Nizar El-Murr, Sahar Kassem, Nadège Carrié, Christophe Henry, Angela Virone-Oddos, Zhi-yong Yang, Dmitri Wiederschain, Helgi Van de Velde, Marielle Chiron, Ludovic Martinet
Journal: Cancer Research (2021)

Abstract Despite recent breakthrough in the treatment of multiple myeloma (MM) relapses are frequent, highlighting the need for novel approaches. Here we describe a novel anti-CD38/CD28xCD3 trispecific T cell engager (TCE) that targets CD38 expressed by malignant plasma cells and activates T cells by engaging CD3 and CD28 (1). Using bone marrow (BM) aspirates from MM patients, we confirmed that binding to malignant plasmocytes is primarily driven by the expression of CD38 and showed ex vivo that CD38/CD28xCD3 TCE induces a dose-dependent proliferation of CD4+ and CD8+ effector T cells. We also showed that MM patients' primary T cells were stimulated by CD38/CD28xCD3 TCE resulting in RPMI 8226 MM cell line lysis in co-culture assays. Killing of tumor cells was accompanied by MM effector CD8+ T cell degranulation and immunostimulatory cytokine production (IFN-γ and TNF-α). Finally, using MM patients' total BM cells, we showed that CD38/CD28xCD3 TCE induced the activation and cytokine production by cytotoxic CD8+ T cells and the CD38-dependent depletion of autologous primary malignant plasmocytes. Importantly, treatment of total BM cells with CD38/CD28xCD3 TCE also led to a CD38-dependent depletion of immunosuppressive myeloid derived suppressor cells (MDSC) that express CD38. Overall, these data show that CD38/CD28xCD3 trispecific TCE is active against primary myeloma cells and support the current evaluation of this next generation anti-CD38 multi-specific antibody in phase I clinical trial in patients with relapsed/refractory MM. (1) Wu, L., Seung, E., Xu, L. et al. Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Nat Cancer 1, 86-98 (2020). Citation Format: Nizar El-Murr, Sahar Kassem, Nadège Carrié, Christophe Henry, Angela Virone-Oddos, Zhi-yong Yang, Dmitri Wiederschain, Helgi Van de Velde, Marielle Chiron, Ludovic Martinet. Anti-CD38/CD28xCD3 trispecific T cell engager induces proliferation of primary T cells and mediates potent killing of primary malignant plasma cells isolated from Multiple Myeloma bone marrow aspirates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1887.
Abstract 9659: Combination Therapy with Olmesartan and Azelnidipine Exerts Anti-Atherogenic Effects in Diabetic Apolipoprotein E-Deficient Mice
Authors: Kazuki Noda, Maki Hosoya, Sota Nakajima, Junko Ohashi, Hiroaki Shimokawa
Journal: Circulation (2011)

Background: We have recently demonstrated that combination therapy with olmesartan (OLM), an angiotensin type 1 receptor blocker, and azelnidipine (AZL), an L-type Ca channel blocker, improves endothelial function more than each monotherapy in diabetic Apolipoprotein-deficient (ApoE -/- ) mice. In this study, we further examined whether this also is the case for atherosclrosis. Method and Results: We used male C57BL/6N (control) and streptozocin-induced diabetic ApoE -/- mice. The diabetic ApoE -/- mice were administered oral vehicle (untreated), OLM (30 mg/kg/day, PO), AZL (10 mg/kg/day, PO), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) for 5 weeks (n=8 each). Blood pressure was significantly elevated in the untreated group but was normalized by OLM+AZL or HYD. At 5 weeks, the extent of oil-red O staining in the aorta was markedly increased in the untreated group and was significantly ameliorated in the OLM+AZL group (P&lt;0.05). In the HYD group, despite the normalization of blood pressure, the extent of atherosclrosis in the aorta was comparable with that in the untreated group. Similarly, both perivascular fibrosis and medial thickness of the epicardial coronary arteries were increased in the untreated group, both of which were ameliorated only in the OLM+AZL group (both P&lt;0.05). In addition, cross-sectional area of cardiomyocyte was significantly increased in the untreated group and was significantly ameliorated only in the OLM+AZL group (P&lt;0.05). To examine the mechanisms involved, dihydroethidium staining was performed, which showed that aortic ROS production was significantly increased in the untreated group and was significantly inhibited only in the OLM+AZL group (both P&lt;0.05). Furthermore, both eNOS expression and activity (as examined by its phosphorylation at serine 1177) were increased only in the OLM+AZL group (P&lt;0.05). The expression of RAGE (receptor for advanced glycation end-products) also tended to decrease in the AZL and OLM+AZL groups compared with the untreated group (both P=0.05). Conclusion: These results indicate that the combination therapy with OLM and AZL exerts anti-atherogenic effects more than each monotherapy in ApoE -/- mice in vivo, for which reduction of oxidative stress may be involved.
Perioperative safety and short-term oncological outcomes of minimally invasive retroperitoneal lymph node dissection
Authors: C.D. Fankhauser, L. Afferi, S.P. Stroup, N.R.. Rocco, K. Olson, A. Bagrodia, W. Cazzaniga, E. Mayer, D. Nicol, E. Islamoglu, S. De Vergie, S. Ragheed, S.E. Eggener, S. Nazzani, N. Nicolai, L. Hugar, W.J. Sexton, D-V. Matei, T. Hermanns, R.J. Hamilton, A. Hiester, P. Albers, N. Clarke, A. Mattei
Journal: European Urology (2021)
Abstract 2953: Humanized IL6/hIL6R mouse model supports the evaluation of therapeutic drug candidates targeting to human IL6 and IL6 receptor
Authors: Lei Zhao, Yang Mao, Linlin Wang, Yichao Chen, Leila Kokabee, Qingcong Lin
Journal: Cancer Research (2021)

Abstract Interleukin 6 (IL-6) gene encodes a cytokine that functions in inflammation and the maturation of B cells and is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in the immune response Evidence of recent research shows blockade of IL-6 and IL-6 receptor interaction can offer a broader therapeutic strategy for various diseases included in acute systemic and chronic inflammatory diseases. The development of humanized mouse model can greatly support preclinical evaluation of human IL6 and IL6 receptor therapeutic drugs. To evaluate the efficacy of IL-6 and IL-6R therapeutic drug candidates, Biocytogen has generated a double humanized B-hIL6/hIL6R mouse model. In this model, the mouse IL6 gene that encodes the full length was replaced with the corresponding human sequences and the CDS of human IL6R gene was inserted into the IL6RA gene in B-hIL6/hIL6R mice. Human IL6 or IL6R protein expression was detected in homozygous B-hIL6/hIL6R mice by species-specific IL6 ELISA kit, also evaluated by flow cytometry. In efficacy study of anti-human IL6 antibodies in B-hIL6/hIL6R mice with collagen induced arthritis (CIA) , the IL6 antibody treatment reversed the disease progression by decreasing the total clinical score compared to the control group. The efficacy suggests that the B-hIL6/hIL6R mouse model is an effective tool for in vivo efficacy study in the development of IL6 and IL6R antibodies which provide a promising potential in future human clinical trials. Citation Format: Lei Zhao, Yang Mao, Linlin Wang, Yichao Chen, Leila Kokabee, Qingcong Lin. Humanized IL6/hIL6R mouse model supports the evaluation of therapeutic drug candidates targeting to human IL6 and IL6 receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2953.
Prognostic significance of cell-free DNA and androgen receptor amplification in castration-resistant prostate cancer
Authors: Y.K. Kubota, S.H Hatakeyama, T.O Okamoto, H.Y Yamamoto, T.Y Yoneyama, T.Y Yoneyama, Y.H Hashimoto, C.O Ohyama
Journal: European Urology (2021)
Abstract 1332: Antiretroviral agent inhibits proliferation and motility of BT-20 cells through inhibition of human endogenous retrovirus type K
Authors: John Lin, Mason Farris, Lauren Robbins, Matthew Lee, Serratt Nong, Yingguang Liu
Journal: Cancer Research (2021)

Abstract The purpose of the study was to establish the role of human endogenous retrovirus K (HERV-K) in cancer development and to explore the possibility of repurposing antiretroviral agents for cancer treatment. We screened different categories of antiretroviral agents and several breast cancer cell lines to study the ability of antiretroviral agents to inhibit cancer cell proliferation and to inhibit the natural expression of HERV-K in cancer cells. Cells were transduced with exogenous HERV-K genes or with HERV-K knockdown plasmids to investigate the relationship between cytotoxic effect of antiretroviral agents and HERV expression. We found that an integrase strand-transfer inhibitor, dolutegravir, inhibited HERV-K expression on both the RNA and protein levels in BT-20 cells. Transduction with both HERV-K env and pol genes rendered the cell line more resistant to dolutegravir. Knockdown of HERV-K with shRNA also increased resistance to dolutegravir compared to cells transduced with random double-stranded RNA. The cytotoxic effect of dolutegravir correlated with enhanced expression of E-cadherin and a reduction in cell motility. Interestingly, an HERV-K knockdown cell line also exhibited enhanced expression of E-cadherin and reduced motility. As a potential carcinogenic role of HERVs has raised interest in using antiretroviral agents as a new approach to treat cancer, we provide the first evidence that one antiretroviral agent actually inhibits the proliferation and motility of a cancer cell line through inhibiting an HERV. Citation Format: John Lin, Mason Farris, Lauren Robbins, Matthew Lee, Serratt Nong, Yingguang Liu. Antiretroviral agent inhibits proliferation and motility of BT-20 cells through inhibition of human endogenous retrovirus type K [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1332.
Comparison of early surgical outcomes of laparoscopic partial nephrectomy between T1a and T1b renal tumors with the incorporation of EAUiaiC in the “trifecta” – a retrospective study reported according to EAU standardized quality criteria
Authors: S. Kumar, S. Nagasubramanian, A. Jacob Philip George, N. Thampi John, A. Devasia, M. Joy
Journal: European Urology (2021)
Potential New Blood Biomarker for Myocarditis Detection
Authors: Jennifer Abbasi
Journal: JAMA (2021)

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