tbuckley/cabot-search huggingface dataset:
Abstract 2377: Development and characterization of scFvs against TIP1/PDZ protein for cancer targeting
Authors: Abhay Singh, Vaishali Kapoor, Philipp Diebolder, Aaron Rhee, Buck Rogers, Dinesh Thotala, Dennis Hallahan
Journal: Cancer Research (2019)

Abstract We identified TIP1 as a potential target to treat various cancers. TIP1 is over-expressed in glioblastoma, lung, head and neck and breast cancer. It is also a radiation inducible neo-antigen. TIP1consists of a single PDZ domain that binds the c-terminus of various cellular proteins like β-catenin, Rho, FAS, etc. It plays an important role in cell signaling, cancer development, and progression. TIP-1’s involvement in various survival pathways makes it an attractive target for anticancer therapeutics. Cancer can be targeted by different agents like antibodies (monoclonal, scFv, bi-specific, diabodies), peptides and small molecules. We will be targeting TIP1 using single-chain variable fragment (scFv) antibodies. scFv is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a peptide linker. We generated a phage-displayed scFv library (WASHU 2) from patient samples. For library screening, we cloned and purified the recombinant TIP1 protein. We used the TIP1 protein as bait for biopanning to pulldown the TIP1-binding scFvs from the library. Three rounds of biopanning were performed to enrich the specific TIP1 binding scFvs. Phage ELISA was performed to confirm the binding of the identified clones to the TIP1 protein. Approximately fifty-one clones showing positive binding to TIP1 protein were identified.We have sequenced the identified clones to verify the full length of scFv sequence. Unique clones are being characterized and developed further as targeting agents of various cancers. We found cancer specific binding of our lead scFvs in mouse models of cancer. The lead scFvs will be expressed as scFv-Fc to enhance their biological activity. We will characterize the scFv-Fcs for their binding affinity to TIP1, cancer cell surface binding, in vivo tumor targeting and tissue cross-reactivity. The scFvs having the potential to internalize will be developed as immunotoxins. Citation Format: Abhay Singh, Vaishali Kapoor, Philipp Diebolder, Aaron Rhee, Buck Rogers, Dinesh Thotala, Dennis Hallahan. Development and characterization of scFvs against TIP1/PDZ protein for cancer targeting [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 2377.
Abstract 2820: Macrophages recruited to and function to promote activation of cancer stem cells in response to chemotherapy
Authors: Xi C. He, Linheng Li
Journal: Cancer Research (2019)

Abstract Failure of chemoradiotherapy for treating colorectal cancer (CRC) is often caused by the relapse of residual tumor cells that enrich cancer stem cells (CSCs). However, how CSCs are regulated by tumor microenvironment (TME), particularly myeloid derived cells (MDCs), remains unclear. Here, we used the APCMin/+ adenoma model to study the dynamic interaction between MDCs and CSCs in vivo following chemoradiotherapy. Using 3D scanning electronic microscopy, we observed that while proliferating tumor cells were dying following chemoradiotherapy, MDCs or its derivative tumor associated macrophages (TAMs) were recruited to the site where CSCs paired with necroptotic cells. TAMs functioned to promote activation of slow-cycling CSCs. Dissected with single cell RNA-seq, we observed that while proliferating tumor cells were declining following chemotherapy, an increase in MDCs was accompanied with a reduction of immune cells as well as an activation and short-term expansion of initially quiescent CSCs. Depletion of TAMs using a drugs or genetic means resulting in reduced CSCs and attenuated tumorigenesis. Mechanistically, we uncovered that TAM with secreted PGE2 activated Akt and Wnt signaling to promote activation of CSCs. Hence, targeting TAMs will benefit clinical treatment of CRC by reducing drug-resistant CSCs. Note: This abstract was not presented at the meeting. Citation Format: Xi C. He, Linheng Li. Macrophages recruited to and function to promote activation of cancer stem cells in response to chemotherapy [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 2820.
Serum Bcma May Interfere with Anti-Bcma-CAR-Transduced T Cells or Other Anti-Bcma Antibody-Based Immunotherapy in Multiple Myeloma
Authors: Haiming Chen, Mingjie Li, Eric Sanchez, Camilia Soof, Saurabh Patil, Kyle Udd, Mizi Zhou, Tara Hekmati, Emily Y Wang, Edward J Tanenbaum, Remy Schlossberg, Moryel A Yashar, Cathy S Wang, George Y Tang, James R Berenson
Journal: Blood (2017)
Abstract 4272: Suppression of epigenetic regulator NURF leads to autophagy mediated chemo-and immune sensitization of triple negative breast cancer
Authors: Liliya Tyutyunyk, David A. Gewirtz, Joseph Landry, Nga Dao
Journal: Cancer Research (2019)

Abstract Dysregulation of the epigenome is implicated in initiation and progression of variety of cancers and their acquired resistance to chemotherapy. As such, targeting epigenetic regulators has the potential to modulate tumor cell biology and reestablish tumor cell sensitivity to chemotherapy and/or radiation. Our studies demonstrate that silencing of the epigenetic regulator Nucleosome Remodeling Factor (NURF) sensitizes breast tumor cells to chemotherapy and enhances the anti-tumor immune response. Compared to controls, NURF KD 4T1 breast tumor cells exposed to doxorubicin (Dox) show increased DNA damage (gamma H2AX staining) and autophagy (acridine orange staining) in vitro and enhanced growth inhibition both in vitro and in vivo. NURF KD also sensitizes 4T1 cells to doxorubicin stimulated Natural Killer (NK) cell antitumor activity ex vivo, which is associated with a cytokine/chemokine secreted by doxorubicin exposed NURF KD cells; potential candidates are CCL5, TNFa and CCL2. The importance of NK cells for the enhanced growth control of doxorubicin treated NURF KD cells was confirmed using a mAb depletion approach. Autophagy may be instrumental in NK cell activation and elimination of tumor cell targets by mediating cytokine secretion. Sensitization of NURF KD 4T1 cells to doxorubicin, both increased autophagy and enhanced NK cell activity, were also observed using a small molecule inhibitor of NURF, suggesting that NURF can also be targeted pharmacologically. Our studies suggest that enhanced doxorubicin induced DNA damage and autophagy (cell autonomous effects) and NK cell cytotoxic activity (cell non-autonomous affects) may be primary contributors to immune sensitization in NURF KD cells. Increased cell autonomous antitumor effects by doxorubicin in concert with increased cell non-autonomous immunogenicity could help to achieve tumor regression, reduce metastasis, and possibly promote long term remission in breast cancer. Citation Format: Liliya Tyutyunyk, David A. Gewirtz, Joseph Landry, Nga Dao. Suppression of epigenetic regulator NURF leads to autophagy mediated chemo-and immune sensitization of triple negative breast 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 4272.
Abstract 2547: Management of Pericardial Effusion During and After Ablation for Atrial Fibrillation in Patients Undergoing the Procedure With Therapeutic INR
Authors: Luigi Di Biase, J. David Burkhardt, Rodney Horton, Javier Sanchez, G. Joseph Gallinghouse, Shane Bailey, Prasant Mohanty, Dimpi Patel, Robert A. Schweikert, Jennifer E. Cummings, Dhanunjay Lakkireddy, Atul Verma, Steven Hao, Richard Hongo, Salwa Beheiry, Amin Al-Ahamad, Paul Wang, Antonio Dello Russo, Gemma Pelargonio, Michela Casella, William R. Lewis, Aldo Bonso, Sakis Themistoclakis, Antonio Raviele, Ospedale Dell’Angelo, Andrea Natale
Journal: Circulation (2009)

Introduction: Pericardial effusion is a well known complication during and after catheter ablation of atrial fibrillation. The percentage reported in the literature is around 1.2%. The aim of this ...
Abstract 157: Functional and Structural Intermediate Vascular Phenotypes Relating to Long-Term Cardiovascular Risk in Kawasaki Disease
Authors: Katherine Y Chen, Nagib Dahdah, Roch L Maurice, Jessica Miller, Nigel Curtis, Michael Cheung, David Burgner
Journal: Circulation (2015)

Background: It is uncertain whether Kawasaki disease (KD) increases overall long term cardiovascular risk, especially in those without demonstrable coronary artery lesions. Data from non-invasive vascular assessment, extrapolated from studies of subclinical atherosclerosis, are conflicting. Methods: Patients at least 2 years post-KD and healthy controls had fasting plasma glucose, lipid profile, high sensitivity C-reactive protein, carotid-femoral pulse wave velocity (PWV), carotid intima-media thickness (cIMT), abdominal aorta intima-media thickness (aIMT), retinal vascular calibre, carotid and aortic elastography performed. Results: 37 controls and 45 patients with KD (21 with regressed or persistent coronary artery changes) were studied at mean ± sd of 10.5 ± 5.7 years following KD. Compared to controls, KD patients did not have increased traditional cardiovascular risk factors; blood pressure, body mass index, waist-to-hip ratio, glucose, cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride and smoking history. Of the cohort, 26 patients (age 15.38 ± 6.19 years) and 27 controls (age 18.7 ± 7.11 years) have had cIMT, aIMT and carotid elastography analysed. The maximum aIMT in KD patients was 0.65 ± 0.15 mm, compared to 0.63 ± 0.13 mm in controls, with the most marked difference in those with coronary artery changes at 0.68 ± 0.14 mm. After adjusting for age, sex, systolic blood pressure, aortic diastolic diameter and high sensitivity C- reactive protein, the average maximum aIMT in all KD patients was 0.071mm larger (95% CI -0.005, 0.147) than controls. Aortic elastography and Doppler pulse wave analysis are underway. Otherwise, there are no detectible differences in PWV, cIMT, carotid elastography, or retinal vascular calibre between KD patients and controls. Conclusion: Compared to carotid artery characteristics, changes in the abdominal aorta may be more discriminative markers of long-term cardiovascular risk in KD. Focus on large arteries in longitudinal KD vascular studies are warranted. Recruitment and analysis are ongoing and further results will be presented.
Abstract 1420: Novel expansion of CD8+PD1+ spleen cells for therapeutic intent in pancreatic adenocarcinoma cancer
Authors: Kathryn Cole, Quan P. Ly, Jesse L. Cox, Michael A. Hollingsworth, James C. Padussis, Jason M. Foster, Luciano M. Vargas, James E. Talmadge
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor prognosis and overall survival. In 2018 it is estimated that there will be 44,333 deaths making PDAC the 3rd cause of cancer related deaths. A distal pancreatomy for PDAC in the body/tail of the pancreas usually includes a splenectomy, with current practice to discard the spleen post-surgery. Spleens can provide a large number of lymphocytes, including CD8+ T-cells with potential to be utilized for adoptive cellular therapy. Our studies have focused on spleen from this patient population, which we posit (and show herein) provides a large number of CD8+PD1+ cells for expansion and the first clinical strategy to expand activated, tumor specific T-cells for subsequent infusion with therapeutic intent. In our studies we used Milteny magnetic bead isolation of CD8+PD1+ T-cells from the spleens of PDAC patients with disease in the distal pancreas. The purity of the cells was 98% with a yield of 79% providing 9x108 CD8+PD1+ cells from an idealized 160 gm spleen. CD8 expansion was undertaken with various growth factor cocktails incorporating combinations of three interleukins (IL); IL-7, IL-15, and IL-21 at varying concentrations. IL-7 supports T-cell survival and proliferation, IL-15 is a potent T-cell growth factor and promotes naïve and memory T-cell survival, and IL-21 limits T-cell exhaustion in response to chronic stimulation. The optimized cocktail incorporated IL-7, IL-15, and IL-21 at 40 ng/mL, which demonstrated maximum T-cell expansion, based on cellularity and cell viability. The predominant T-cell memory phenotype of the CD8+PD1+ cells following expansion was transitional memory (TTM) T-cells that increased from 35.6 ± 4.3 to 52 ± 3%. This memory T-cell phenotype has a high proliferative potential while retaining effector function. Following six days of culture with the three interleukins we observed a 10 fold increase in CD8+PD1+ cells such that 9x109 cells are obtained from the 160 gm spleen. These cells, based on ELISPOT analysis with autologous tumor lysate pulsed dendritic cells retained tumor specificity. In conclusion, CD8+PD1+ cells can be isolated from resected spleen, expanded with retention of tumor specificity and potentially used for adoptive cellular therapy. Citation Format: Kathryn Cole, Quan P. Ly, Jesse L. Cox, Michael A. Hollingsworth, James C. Padussis, Jason M. Foster, Luciano M. Vargas, James E. Talmadge. Novel expansion of CD8+PD1+ spleen cells for therapeutic intent in pancreatic adenocarcinoma 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 1420.
A phase I trial using CD19 CAR-T expressing PD-1/CD28 chimeric switch-receptor for refractory or relapsed B-cell lymphoma.
Authors: Hui Liu, Wen Lei, Chaoting Zhang, Chunmei Yang, Juying Wei, Qunyi Guo, Xiaojun Guo, Zhilu Chen, Ying Lu, Zheming Lu, Wenbin Qian
Journal: Journal of Clinical Oncology (2019)

7557 Background: The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has established efficacy in the treatment of refractory or relapsed (R/R) B-cell lymphoma. However, the existence of different immunosuppressive pathways such PD-1/PD-L1 pathway can restrict the full potential of CAR-T therapy. A recent study demonstrates that a novel PD-1/CD28 chimeric switch-receptor, comprising the extracellular domain of PD-1 and the transmembrane and cytoplasmic signaling domains of CD28, can be used a modality for augmenting antitumor activity of mesothelin- and prostate specific cancer antigen-specific CAR-T cells in either pleural mesothelioma or prostate cancer xenograft model. Here, we describe the first human trial of CD19-PD-1/CD28-CAR-T cells (a CD19-specific CAR-T expressing PD-1/CD28 chimeric switch-receptor) to evaluate safety and efficacy. Methods: This phase I, single-arm, open-label, multicenter trial enrolled patients (18-75 years) with R/R large B-cell lymphoma. PD-L1 expression was confirmed by immunohistochemistry using an anti-PD-L1 mAb (SP142), and confirmed by the review committee with a central evaluation. Seventeen patients received conditioning chemotherapy (cyclophosphamide [500 mg/m2] and fludarabine [30 mg/m2] on days -5, -4 and -3) and followed by CD19-PD-1/CD28-CART cells infusion at doses ranging 0.5 to 4 × 10 6 CAR + T cells/kg on day 0. Response was assessed by F-FDG PET/CT at month 3 after CAR-T infusion, according to the International Working Group Response Criteria for Malignant Lymphoma, and duration of response was evaluated by ultrasonic and computed tomography every three months from month 3 to month 12. Results: At data cutoff, 17 patients had received CD19-PD-1/CD28-CART cells. Overall PD-L1 positivity was 15/17 (88.2%) and the mean percentage of PD-L1 positivity was 19.7% (range, 5-50%). Fourteen patients (82.35%) developed cytokine release syndrome (grade ≤ 2) and four (23.53%) developed neurotoxicity (grade = 1), which was reversible in all. The overall response rate was 58.8% (10/17) and complete remission rate was 41.2% (7/17). At a median follow-up 5 months, median overall survival for all patients was not reached. Conclusions: This trial showed the feasibility, controllable toxicities, and effective activity of CD19-PD-1/CD28-CART cells for treating patients with R/R B-cell lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the PD-1/PD-L1 pathway in lymphoma in the clinical setting. Clinical trial information: NCT03258047.
Abstract 707: Emerging role of mitochondrial pathway in crosstalk between ferroptosis and apoptosis
Authors: Yong J. Lee
Journal: Cancer Research (2019)

Abstract Introduction: Several processes lead to cell death; ferroptosis, apoptosis, necrosis, and autophagy are the primary mechanisms. Each type of biological death has been believed to have a distinct biochemical and morphological fingerprint. However, emerging evidence suggests that these different types of cell death often share common pathways. In this study, we investigated whether mitochondrial signaling pathways play an important role in the intracellular communication between ferroptosis and apoptosis. Methods: The human colorectal carcinoma HCT116 cell line was used to evaluate the interplay between cell death pathways. Cells were treated with the apoptotic agent TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and ferroptotic agents such as artesunate and erastin. Cell death was determined by trypan blue exclusion assay. Apoptosis was measured by western blot. Ferroptosis was assessed using MDA assay. Bax oligomerization was performed by mitochondrial fractionation followed by SDS-PAGE under nondenaturing conditions. Results: We observed that the combinatorial treatment induced synergistic apoptosis, which was mediated through an increase in caspase activation. We also observed an increase in pro-apoptotic Bax oligomerization in the mitochondrial fraction. The combined treatment-induced apoptosis was suppressed in Bax-deficient HCT116 cells. Ferroptotic agents enhanced the intracellular level of anti-apoptotic Mcl-1. However, the combined treatment decreased the level of Mcl-1. Interestingly, the combined treatment-induced apoptosis was abolished in HCT116 cells with knockin of Mcl-1 phosphorylation site mutant (S121A/E125A/S159A/T163A). Conclusions: These data suggest a novel mechanism for the combined treatment of the apoptotic agent TRAIL and ferroptotic agent erastin/artesunate-induced synergistic apoptosis through the mitochondrial pathway. Citation Format: Yong J. Lee. Emerging role of mitochondrial pathway in crosstalk between ferroptosis and apoptosis [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 707.
Author Correction: End-to-end lung cancer screening with three-dimensional deep learning on low-dose chest computed tomography
Authors: Diego Ardila, Atilla P. Kiraly, Sujeeth Bharadwaj, Bokyung Choi, Joshua J. Reicher, Lily Peng, Daniel Tse, Mozziyar Etemadi, Wenxing Ye, Greg Corrado, David P. Naidich, Shravya Shetty
Journal: Nature Medicine (2019)
Endoscopic submucosal dissection as a diagnostic procedure for a giant submucosal “sausage” causing dysphagia
Authors: Martin Dahan, Anne Guyot, Aurelie Charissoux, Marion Schaefer, Romain Legros, Mathieu Pioche, Jérémie Jacques
Journal: Endoscopy (2019)

A 56-year-old woman was referred to our endoscopy unit for severe dysphagia with weight loss. A large sessile submucosal lesion was discovered during gastroscopy at 25 – 40 cm from the dental arches. Endoscopic ultrasonography (EUS) revealed a submucosal lesion not invading the muscular layer with a cystic component. The findings of EUS-guided fine needle aspiration (EUS-FNA) were inconclusive. Computed tomography (CT) confirmed a large hypodense lesion obstructing the middle and lower third of the esophagus ([Fig. 1]). Therefore, we chose a diagnostic endoscopic submucosal dissection (ESD) to avoid morbid surgery for a potentially benign lesion.
Survival and prognostic factors of localized gastric carcinomas (about 50 cases). Experience of the medical oncology department of Hassan II University of Fez
Authors: H. Erraichi, S. Berrad, L. Nouikh, K. Messoudi, K. Oualla, Z. Benbrahim, S. Arifi, N. Mellas
Journal: Annals of Oncology (2019)
Abstract 1992: Mesenchymal stem cell-derived interleukin-28 can drive the selection of apoptosis resistant bone metastatic prostate cancer
Authors: Jeremy J. Mcguire, Leah Cook, Jeremy Frieling, Ayaz Muhammad, Harshani Lawrence, Nicholas Lawrence, Conor Lynch
Journal: Cancer Research (2019)

Abstract Bone metastatic prostate cancer is painful and incurable. We believe that understanding the interactions of tumor cells and the surrounding stromal cells may provide new therapeutic options. Bone metastatic prostate cancer promotes mesenchymal stem cell (MSC) recruitment and differentiation into osteoblasts, leading to the clinically often-observed osteogenic phenotype. However, the reciprocal roles of bone- marrow derived MSCs on prostate cancer cells are less explored. Here, we discovered that MSCs significantly suppress prostate cancer growth in vitro and in vivo. Mechanistically, we show that MSC-derived interleukin-28 (IL-28) promotes prostate cancer cell apoptosis via the IL-28 receptor alpha (IL-28Rα). However, chronic exposure to MSCs yields prostate cancer cell populations that are resistant to IL-28 induced apoptosis and therapeutics such as docetaxel. In vivo, we observed that MSC selected prostate cancer cells rather than being suppressed, grow at a significantly enhanced rate in bone. The increase in apoptosis resistance is accompanied by a shift in downstream signaling of the IL-28Rα from STAT1 to STAT3. Reduction of STAT3 levels or pharmacological inhibition (STI-201) significantly reduces the growth of MSC selected prostate cancer cells in vitro and in vivo. Collectively, these data shed light on how MSCs in the bone marrow microenvironment initially protect against prostate cancer cell establishment but in doing so, help select for aggressive, apoptosis resistant bone metastatic prostate cancer cells that are more aggressive. Given that the majority of prostate to bone metastases are positive for STAT3 expression and activity, our data provide rationale for the therapeutic targeting of STAT3 in bone metastatic prostate cancer. Citation Format: Jeremy J. Mcguire, Leah Cook, Jeremy Frieling, Ayaz Muhammad, Harshani Lawrence, Nicholas Lawrence, Conor Lynch. Mesenchymal stem cell-derived interleukin-28 can drive the selection of apoptosis resistant bone metastatic 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 1992.