tbuckley/cabot-search huggingface dataset:
Abstract 4812: 9-ING-41, a novel inhibitor of glycogen synthase kinase-3beta (GSK-3β), is active as a single agent and within combination therapies in bladder cancer cell lines
Authors: Hiroo Kuroki, Tsutomu Anraku, Vladimir Bilim, Masayuki Tasaki, Daniel Schmitt, Andrew Mazer, Francis J. Giles, Andrey Ugolkov, Yoshihiko Tomita
Journal: Cancer Research (2019)

Abstract Glycogen synthase kinase-3beta (GSK-3β) is a serine/threonine protein kinase that has been established as a therapeutic target in a broad spectrum of human malignancies. We have previously identified aberrant GSK-3β nuclear expression in bladder cancer (BC), and demonstrated that GSK-3β positively regulated BC cell survival and proliferation. Our objective was to evaluate the antitumor effects of the clinically viable agent 9-ING-41, a maleimide-based ATP-competitive GSK-3 inhibitor, which has broad spectrum antitumor activity and marked activity in reversing chemoresistance in a variety of pre-clinical models of human cancers. We used flow cytometry, Western immunoblotting, quantitative RT-PCR, BrDU incorporation and MTS assays to examine antitumor activity of 9-ING-41 in BC (T24, HT1376, RT4 cell lines). Additionally, we studied combination therapy of 9-ING-41 with gemcitabine and cisplatin, standard agents used for the treatment of patients with advanced BC, with cabozantinib, a multi kinase inhibitor, and with chloroquine, an autophagy inhibitor. A dose-dependent decrease in cancer cell proliferation was observed by MTS assay and BrdU incorporation assay with GI50 0.7μM (T24), 4.7 μM(HT1376), 2.2μM(RT4). Treatment with 9-ING-41 induced prominent cell cycle arrest (predominantly G2 arrest) in BC cells. Expression of cell cycle related proteins, including Cyclin D, and anti-apoptotic proteins, such as XIAP and Bcl-2, were significantly decreased as detected by Western immunoblotting and real time RT-PCR. Treatment with 9-ING-41 significantly potentiated the growth inhibitory effect of cisplatin and gemcitabine in cultured cells. In addition, combination therapy with 9-ING-41 and cabozantinib or chloroquine, significantly potentiated the effect of either single agent. Our data proved that a single treatment using 9-ING-41 is effective in BC cells. Combination treatment of 9-ING-41 with standard chemotherapeutic drugs or novel agents may provide a new therapeutic approaches in BC. These data provide a rational for the inclusion of patients with advanced BC in clinical studies of 9-ING-41. Citation Format: Hiroo Kuroki, Tsutomu Anraku, Vladimir Bilim, Masayuki Tasaki, Daniel Schmitt, Andrew Mazer, Francis J. Giles, Andrey Ugolkov, Yoshihiko Tomita. 9-ING-41, a novel inhibitor of glycogen synthase kinase-3beta (GSK-3β), is active as a single agent and within combination therapies in bladder cancer cell lines [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 4812.
Altered Cellular White Matter But Not Extracellular Free Water on Diffusion MRI in Individuals at Clinical High Risk for Psychosis
Authors: Yingying Tang, Ofer Pasternak, Marek Kubicki, Yogesh Rathi, Tianhong Zhang, Junjie Wang, Huijun Li, Kristen A. Woodberry, Lihua Xu, Zhenying Qian, Anni Zhu, Susan Whitfield-Gabrieli, Matcheri S. Keshavan, Margaret Niznikiewicz, William S. Stone, Robert W. McCarley, Martha E. Shenton, Jijun Wang, Larry J. Seidman
Journal: American Journal of Psychiatry (2019)

Detecting brain abnormalities in clinical high-risk populations before the onset of psychosis is important for tracking pathological pathways and for identifying possible intervention strategies that may impede or prevent the onset of psychotic disorders. Co-occurring cellular and extracellular white matter alterations have previously been implicated after a first psychotic episode. The authors investigated whether or not cellular and extracellular alterations are already present in a predominantly medication-naive cohort of clinical high-risk individuals experiencing attenuated psychotic symptoms.Fifty individuals at clinical high risk, of whom 40 were never medicated, were compared with 50 healthy control subjects, group-matched for age, gender, and parental socioeconomic status. 3-T multishell diffusion MRI data were obtained to estimate free-water imaging white matter measures, including fractional anisotropy of cellular tissue (FAT) and the volume fraction of extracellular free water (FW).Significantly lower FAT was observed in the clinical high-risk group compared with the healthy control group, but no statistically significant FW alterations were observed between groups. Lower FAT in the clinical high-risk group was significantly associated with a decline in Global Assessment of Functioning Scale (GAF) score compared with highest GAF score in the previous 12 months.Cellular but not extracellular alterations characterized the clinical high-risk group, especially in those who experienced a decline in functioning. These cellular changes suggest an early deficit that possibly reflects a predisposition to develop attenuated psychotic symptoms. In contrast, extracellular alterations were not observed in this clinical high-risk sample, suggesting that previously reported extracellular abnormalities may reflect an acute response to psychosis, which plays a more prominent role closer to or at onset of psychosis.
Image Gallery: Benign lymphangiomatous papules of the skin after radiotherapy
Authors: C. Liu, M.‐J. Ko
Journal: British Journal of Dermatology (2019)

DEAR EDITOR, Benign lymphangiomatous papules are benign lymphatic proliferations that occur after radiation therapy.A 52-year-old woman presented with multiple asymptomatic, approximately 4-mm, purpuric papules on the bilateral breasts for 1 year (a, b).Four years earlier she had received bilateral lumpectomy for ductal carcinoma in situ, followed by tamoxifen and postoperative radiation therapy.Dermoscopy revealed yellow lacunae surrounded by septa with focally mottled reddish areas (c).A skin biopsy revealed dilated vascular spaces in the upper dermis.Endothelial cells were strongly positive for CD31 (d) and focally positive for D2-40.Careful differentiation from irradiation-induced malignant vascular tumour is critical.
Association of Carpal Tunnel Syndrome With Amyloidosis, Heart Failure, and Adverse Cardiovascular Outcomes
Authors: Emil L. Fosbøl, Rasmus Rørth, Birgitte Pernille Leicht, Morten Schou, Mathew S. Maurer, Søren Lund Kristensen, Lars Kober, Finn Gustafsson
Journal: Journal of the American College of Cardiology (2019)
Resolution of a large infradiaphragmatic leak with endoscopic vacuum therapy after total gastrectomy
Authors: Oriol Sendino, Gerhard Jung, Dulce Momblan, Antonio Maria de Lacy
Journal: Endoscopy (2019)

Anastomotic insufficiency with leakage is a life-threatening complication after radical gastrectomy. Surgical reintervention may be associated with high rates of recurrence and increased morbidity [1]. Placement of a fully covered self-expandable metal stent is commonly performed as a first line conservative treatment. However, success rates after endoscopic stenting range between 63 % and 91 % [2]. Endoscopic vacuum therapy is a novel technique that allows continuous drainage of the leak, control of infection, and secondary wound healing process, and has shown high clinical success rates [3] [4] [5].
Heterogeneity of HDAC3 expression and its modulation by valproic acid in glioblastoma cells.
Authors: Herbert H. Engelhard, Yi Lu, Corbin Rayfield, Lili Yue, Sajani Lakka, Nadim Mahmud
Journal: Journal of Clinical Oncology (2013)

e13038 Background: Glioblastoma (gbm) is a devastating malignancy and a therapeutic challenge. Our group and others have observed long-term gbm survivors treated with valproic acid (VPA), a histone deacetylase (HDAC) inhibitor. While in vitro studies of HDAC inhibitors have been promising, clinical trials and retrospective analyses have been disappointing. We hypothesize that HDAC3 may be a more specific target or treatment marker for gbm. Since limited data is available pertaining to HDAC3 and its modulation in gbm, our goals were to: 1) develop methods for determining HDAC3 expression and localization in gbm cells, 2) study HDAC3 heterogeneity among different gbm cell lines, including one in low passage, and 3) test the effect of VPA treatment on HDAC3 expression of gbm cells in vitro. Methods: Three established gbm cell lines (U-87, U-251 and E297), were cultured using standard technique. HeLa cells were used as the positive HDAC3 control. Cells were stained using 2 different antibodies, and analyzed using immunofluoresence microscopy (IFM), and Western blotting (with β-actin standards). IgG was used for negative isotype controls. Cell counts, viability, and H&amp;E staining for changes in morphology were also recorded. Lysates for Western blots were made from whole cells, nuclei, and cytoplasmic preparations. Band quantification was performed using the ImageJ software. Cells in exponential growth were treated for 48 hours with 10 mM VPA, and compared to untreated cells. Results: Untreated cells studied for HDAC3 using IFM showed nuclear and some cytoplasmic staining in all 4 lines, which varied according to cell type and morphology. Western blot analysis confirmed the variability of HDAC3 expression seen by IFM. The effect of VPA treatment on gbm HDAC3 expression (cytoplasmic and nuclear) was seen to be highly variable, ranging from marked down-modulation in some gbm cells, to minimal effect in others. Conclusions: These data provide the groundwork for studying HDAC3 levels in patients undergoing therapy with HDAC inhibitors. The effect of VPA on the HDAC3 expression of gbm cells is heterogeneous; individualized assessment of such effect will be necessary in delineating any subset of patients that may respond to VPA treatment.
Abstract 254: Discovery of dual inhibitors of NQO1 and GSTP1 for malignant glioblastoma treatment
Authors: Kecheng Lei, Shilin Luo, Lingjing Jin, Keqiang Ye
Journal: Cancer Research (2019)

Abstract Glioblastoma (GBM) is a highly aggressive form of neoplasia due to its frequently overexpressed or mutant epidermal growth factor receptor (EGFR). NADPH quinone Oxydoreductase1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 are enzymes with dual roles that decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and GBM cell proliferation. To search for a small molecule that blocks the malignant cancer proliferation, we conducted a high-throughput Screening (HTS) and identified a small molecule inhibitor (5-methyl-N-(nitro-1,3-thiazol-2-yl)-3-phenylisoxazole-4-carboxamide) as “HIT” that binds to both NQO1 and GSTP1 with high affinity and selectivity. The “HIT” blocks NQO1 and GSTP1 enzyme activity and mediates apoptosis in GBM via caspase activation. Inactivation of NQO1 and GSTP1 with siRNA or HIT resulted in imbalanced redox homeostasis, leading to mitigated cancer cell proliferation in vitro and in vivo. Thus, optimization of “HIT”, the dual NQO1 and GSTP1 inhibitor, may provide a novel strategy to antagonizing GBM. Citation Format: Kecheng Lei, Shilin Luo, Lingjing Jin, Keqiang Ye. Discovery of dual inhibitors of NQO1 and GSTP1 for malignant glioblastoma treatment [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 254.
Abstract 18704: Late Blockade of Wnt/frizzled Signaling Pathway with UM206 Halts Further Dilatation of the Left Ventricle Following Myocardial Infarction
Authors: Evangelos P Daskalopoulos, Kevin C Hermans, Ben J Janssen, W. M Blankesteijn
Journal: Circulation (2012)

Purpose: Current pharmacotherapy cannot stop left ventricular (LV) dilatation that occurs after myocardial infarction (MI). Recently we have shown that in the MI mouse model, LV dilatation can be prevented by pharmacological blockade of Wnt/frizzled signaling with UM206. In these studies UM206 treatment was started immediately after induction of MI. The subject of the current study was to investigate if similar beneficial effects could be obtained with UM206 when treatment was started 3 weeks after the MI induction, when adverse LV dilatation has become manifest. Methods: Swiss male mice were subjected to MI by occlusion of the left anterior descending artery. At 3 weeks post-MI, UM206 administration (Alzet osmotic minipump, 6µg/kg/day) was initiated and animals were sacrificed at 8 weeks post-MI. The results were compared with vehicle (saline)-treated animals (treatment between weeks 3-8) that were also sacrificed at weeks 8 post-MI. Cardiac geometry and function parameters were obtained using 3D-echocardiography (Vevo 2100, Visualsonics, Toronto, Canada). Results: UM206 late treatment had a beneficial effect on both End diastolic volume (EDV, saline: 278 ± 24 mm3, UM206: 202 ± 13 mm3; p&lt;0.01) and End systolic volume (ESV, saline: 250 ± 27 mm3, UM206: 151 ± 15 mm3; p&lt;0.01). Ejection Fraction (EF) was also improved in UM206-treated animals (saline: 11.0 ± 3.2 %, UM206: 23.2 ± 2.6 %; p&lt;0.05), while increased lung weights (an indication of heart failure development) were found in the saline-treated animals only (saline: 319 ± 42 mg, UM206: 214 ± 6 mg, p&lt;0.01). Conclusion: In the MI mouse model, administration of UM206 starting at week 3 post-MI, halts further increases in EDV and ESV while preserving the EF, resulting in improved overall cardiac function and prevention of heart failure development. The results show that pharmacotherapy targeting the Wnt/frizzled signaling can be beneficial in preventing heart failure after MI, even after adverse LV remodeling has been initiated.
Abstract CT078: Cyfi: Results from a Phase Ib expansion cohort of anti-hepatocyte growth factor and cytarabine in relapsed and refractory AML
Authors: Victoria E. Wang, Charalambos Andreadis
Journal: Cancer Research (2019)

Abstract Objective: Patients with AML who are refractory to induction therapy or relapse within 1 year have poor outcomes. Elevated serum hepatocyte growth factor (HGF) level is an adverse prognostic factor. Pre-clinical models have shown that myeloid blasts produce HGF in an autocrine fashion and pharmacologic blockade of the HGF/c-Met axis sensitizes blasts to cell death. We initiated a Phase Ib study with dose expansion cohort study to assess the safety and tolerability of the anti-HGF antibody ficlatuzumab with cytarabine in AML patients who are refractory to 7+3 or have relapsed within 1 year of induction. Methodology: The 3 x 3 design was used for the Phase I with an expansion cohort of an additional 13 patients accrued and treated at the MTD. Ficlatuzumab was administered in escalated dosing of 10, 15, or 20 mg/Kg for 4 doses every 2 weeks starting on day 1. 20 mg/Kg dose was used for the expansion cohort. Cytarabine was administered at a fIxed dose of 2 g/m2 on days 2-7. PBMCs were collected at defined time points. Differential expression from multiplexed single cell RNA sequencing (scRNAseq) was used to assess biomarkers predictive of response. Results: Of the total 18 patients accrued thus far, 16 are evaluable. 5 had progressive disease, and 11 responded, all complete responses. Most frequent grade 3/4 TEAEs were febrile neutropenia, LFT abnormalities, and electrolyte disturbance. There was 1 death from sepsis and multi-organ failure on day 23, following ANC recovery, from the disease, and 1 patient who withdrew from the study due to grade 4 gastrointestinal bleed, likely ficlatuzumab related, both prior to response assessment. scRNA sequencing identified a TNF alpha and IFN gamma inflammatory signature that correlates with response to ficlatuzumab at count recovery. Conclusion: Cytarabine and ficlatuzumab is a safe combination with promising efficacy in high risk relapsed and refractory AML. This combination is warranted in further Phase II studies. scRNAseq may be used to identify biomarkers of response. Citation Format: Victoria E. Wang, Charalambos Andreadis. Cyfi: Results from a Phase Ib expansion cohort of anti-hepatocyte growth factor and cytarabine in relapsed and refractory AML [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 CT078.
Efficacy and safety of FOLFIRI/Aflibercept (FA) in an elderly population with metastatic colorectal cancer (mCRC) after the failure of an oxaliplatin-based regimen
Authors: N. Martínez-Lago, M. Carmona Campos, P. Gonzalez Villarroel, M. Salgado Fernandez, J. De la Cámara Gómez, C. Romero Reinoso, A. Cousillas Castiñeiras, J. Méndez Méndez, Y. Vidal Insua, C. Reboredo Rendo, M. Covela Rúa, G. Quintero Aldana, B. Graña Suarez, A. Carral Maseda, M. Jorge Fernandez, M. Pellón Augusto, C. Grande Ventura, E. Gallardo Martin, A. Fernández Montes, M. Reboredo-Lopez
Journal: Annals of Oncology (2019)
Abstract 3673: The BMI1/Sp1/IGF1R pathway mediates pemetrexed resistance in non-small cell lung cancer cells
Authors: Wen-Ling Wang, Peng-Ju Chien, Wen-Wei Chang, Bing-Yen Wang
Journal: Cancer Research (2019)

Abstract Background: Lung cancer is the leading cause of cancer death in Taiwan and worldwide and non-small cell lung cancers (NSCLCs) account for more than 85% of lung cancers. Pemetrexed is approved for several steps of nonsquamous NSCLC therapy but drug resistance often occurs in long-term treatment. Cancer stem cells (CSCs) are considered as the rare subpopulation of cancer cells with the features of tumor initiation, drug resistance, and metastatic capability. The signaling pathway and potential targets contribute to the maintenance of pemetrexed-resistant cancer stem cell remain unknown. Methods: To investigate the mechanism of pemetrexed resistance in lung cancers, the pemetrexed-resistant A549 cells were established (A400). The sphere-formation assay, western blot analysis and real-time qPCR were employed to identify cancer stem cells and study their properties. Result: We first discovered that the pemetrexed-resistant A549 cells (called A400) contained more CSC activity than the parental A549 cells including the increased number of tumorspheres and the upregulation of BMI1, c-Myc, Sox2 and p-IGF1Rtyr1165/1166 expression. The treatment of PTC-209, a BMI1 inhibitor, displayed a greater inhibitory effect in cell proliferation in A400 than A549 cells and it suppressed tumorsphere formation capability of A400 cells. In addition, PTC-209 treatment downregulated the expression of IGF1R, p-IGF1Rtyr1165/1166, and Sp1, a positive regulatory transcriptional factor in IGF1R expression, in A400 cells. We also found that Sp1 was increased in A400 when compared to parental A549 cells. With the treatment of Sp1 inhibitor in A400 cells, the expression of IGF1R was suppressed without changing BMI1 level. Finally, we examined the therapeutic effect of BMI1 inhibition in vivo and resulted found that intraperitoneal administration of PTC-209 enhanced the pemetrexed efficacy in NOD/SCID mice harboring A400 xenograft tumors. Conclusion: Our data reveal that BMI1/Sp1/IGF1R pathway is upregulated in pemetrexed resistant NSCLCs and targeting BMI1 could be a therapeutic strategy in NSCLCs when pemetrexed resistance occurs. Citation Format: Wen-Ling Wang, Peng-Ju Chien, Wen-Wei Chang, Bing-Yen Wang. The BMI1/Sp1/IGF1R pathway mediates pemetrexed resistance in non-small cell lung 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 3673.
Optimizing treatment with anti-epidermal growth factor receptor drugs for patients with metastatic colorectal cancer: novel mechanisms of resistance beyond RAS
Authors: C. Cardone, B. Blauensteiner, V. Moreno-Viedma, M. Paul, G. Martini, T. Troiani, P. Vitiello, D. Ciardiello, L. Poliero, C. Borrelli, A. Rachiglio, D. Rizzi, E. Maiello, T. Latiano, N. Normanno, M. Sibilia, F. Ciardiello, E. Martinelli
Journal: Annals of Oncology (2019)
Abstract 343: A potent and selective cfms inhibitor EI-1071 inhibits CSF1R signaling and regulates the tumor-associated macrophages
Authors: Hung-Kai Chen, Huey-Wen Hsiao, Li-Ming Lu, Chih-Lun Hsiao, Yin-Ping Wang, Jing-Yi Huang, Chu-Bin Liao, Shao-Zheng Peng, Daw-Tsun Shih
Journal: Cancer Research (2019)

Abstract We have found that tumor-associated macrophages (TAMs) isolated from metastatic tumors displayed a predominant M2 phenotype. Preclinical studies show that M2-polarized TAMs forge an immunosuppressive microenvironment at metastatic niches to facilitate colonization. Colony-stimulating factor 1 receptor (CSF-1R) signaling is known to regulate the survival and maintenance of M2 TAMs, suggesting targeting CSF-1R might have therapeutic potential in halting cancer progression. To this end, we developed an orally active and selective small-molecule CSF-1R inhibitor EI-1071. Experimental procedures: EI-1071 was evaluated in kinase and cell-based bioassays, including macrophage proliferation and osteoclast differentiation. In vivo activity was verified using murine syngeneic models of colorectal cancer and breast cancer. EI-1071 was administered individually or in combination with an anti-PD1 antibody. Tumor infiltrating leucocytes were profiled using flow cytometric analysis. Results: EI-1071 exhibited nanomolar potency for inhibition of CSF-1R but not other 453 kinases tested. In cell-based bioassays, EI-1071 inhibited CSF-1R activity in human monocytes/macrophages, AML-5 leukemia, MNFS-60 leukemia, and human osteoclasts. In preclinical studies, EI-1071 displayed a favorable ADME properties, including hepatocyte stability, high Caco-2 permeability, and pharmacokinetic profiles. Oral administration of EI-1071 reduced TAM infiltration in the MC38 colorectal cancer and EMT6 breast cancer models. Moreover, EI-1071 dosed with an anti-PD-1 antibody showed further enhanced antitumor activity in vivo . Conclusions: Preclinical characterization of EI-1071 demonstrated that it is a potent and selective CSF-1R inhibitor and has a favorable drug like properties for further clinical evaluation. Therefore, EI-1071 is undergoing IND-enabling activities for the First-In-Human (FIH) Phase 1 study. Citation Format: Hung-Kai Chen, Huey-Wen Hsiao, Li-Ming Lu, Chih-Lun Hsiao, Yin-Ping Wang, Jing-Yi Huang, Chu-Bin Liao, Shao-Zheng Peng, Daw-Tsun Shih. A potent and selective cfms inhibitor EI-1071 inhibits CSF1R signaling and regulates the tumor-associated macrophages [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 343.