tbuckley/cabot-search huggingface dataset:
Abstract 948: A novel antibody-drug conjugate that induces long-term tumor regression and anticancer stem cell activity
Authors: Jay W. Harper, Chris Lloyd, Shenlan Mao, Xin Lin, Nazzareno Dimasi, Phil Howard, Ellen O'Connor, David Farkas, Christopher Barton, Jeff Smith, Helen Zhong, Tracy Chen, Mary Jane Hinrichs, Marlon Rebelatto, Xiang-Qing Yu, Susan Spitz, Andrew Pierce, Dominic Lai, Hurt Elaine, Lilian van Vlerken-Ysla, Jalla Sanjoo, Katy Miller, Karen McCullough, Priya Kannan, Simon Thompson, Parthiv Mahadevia, Chris Martin, Robert Hollingsworth, Adeela Kamal
Journal: Cancer Research (2015)

Abstract Antibody-drug conjugates (ADCs) selectively deliver cytotoxic agents to tumors and provide the potential for increased clinical benefit to cancer patients. We have developed an ADC consisting of an antibody against a target expressed on the surface of tumor cells that is site-specifically conjugated with a pyrrolobenzodiazepine (PBD) dimer payload (PBD-ADC). The tumor-associated antigen is overexpressed in many carcinomas, on both bulk tumor cells and cancer stem cells (CSCs), while normal tissue expression is limited, thus making it an ideal ADC target. The PBD payload was selected due to its picomolar potency and because, unlike tubulin inhibitors, it could be cytotoxic to CSCs as well as bulk tumor cells. The PBD-ADC is significantly efficacious in target-positive in vivo tumor models of gastric, breast and lung carcinomas, inducing long-term tumor regressions and demonstrates greater potency compared to ADCs conjugated with either tubulysin or auristatin payloads, both tubulin inhibitors. Additionally, the PBD-ADC significantly reduced the CSC population of tumors in vivo, unlike ADCs bearing tubulin inhibitor payloads. The PBD-ADC appears to be efficacious against tumors that have acquired resistance to a tubulysin-based ADC, however possible mechanisms of resistance to this PBD-ADC are being investigated. Collectively, this novel ADC represents a promising therapy that may deliver durable clinical responses in indications with unmet medical need. Citation Format: Jay W. Harper, Chris Lloyd, Shenlan Mao, Xin Lin, Nazzareno Dimasi, Phil Howard, Ellen O'Connor, David Farkas, Christopher Barton, Jeff Smith, Helen Zhong, Tracy Chen, Mary Jane Hinrichs, Marlon Rebelatto, Xiang-Qing Yu, Susan Spitz, Andrew Pierce, Dominic Lai, Hurt Elaine, Lilian van Vlerken-Ysla, Jalla Sanjoo, Katy Miller, Karen McCullough, Priya Kannan, Simon Thompson, Parthiv Mahadevia, Chris Martin, Robert Hollingsworth, Adeela Kamal. A novel antibody-drug conjugate that induces long-term tumor regression and anticancer stem cell activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 948. doi:10.1158/1538-7445.AM2015-948
Abstract 4588: Whole genome hypo- and hyper-methylation sequencing among Africa American patients with colorectal cancer
Authors: Hassan Ashktorab, Afnan Shakoori, Shatha Zarnogi, Xueguang Sun, Sudhir Varma, Edward Lee, Babak Shokrani, Adeinko O. Laiyemo, Kareem Washington, Hassan Brim
Journal: Cancer Research (2015)

Abstract Background: Colorectal cancer (CRC) involves epigenetic changes including DNA hypomethylation, a paradigm shift in the role of DNA methylation alterations in colorectal carcinogenesis. Aim: Here we performed Reduced Representation Bisulfite Sequencing (RRBS) on a normal, and a tumor patient's tissue DNA to elucidate hyper- and hypomethylaed target genes in colorectal cancer progression in this population. Methods: Genomic DNA was isolated from fresh frozen surgical tissues from a patient with normal colon, and from a carcinoma patient. RRBS was performed on these DNA samples for hyper- and hypomethylation targets identification. Alignment, mapping and CpG methylation analyses were performed. Preferential hypomethylated pathways were determined using Ingenuity Pathway Analysis (IPA). Results: We identified the hyper (6360 CpG sites) and hypo-methylation (4845 CpG sites) status of top genes in the CpG Island within promoter regions (19 and 18 genes respectively). Top hyper- and hypomethylated CpG Island outside promoter regions (16 and 18 genes, respectively) were also identified. Among these top genes, CDH4 and SOX21 were reported to be hypermethylated in CRC and SCUBE2 (112 methylated CpG) mapped by IPA to the Hedgehog, TGF-β, and VEGF Signaling pathways was reported to play a role in breast cancer. Among the top hypomethylated genes, ACOT9 (97 CpGI sites) and RIN2 (40 CpGI sites) might play a significant role in CRC in AAs, since IPA mapped these markers to the Wnt/β-catenin, VEGF and PTEN signaling pathways. ACOT9 was found to play a role in breast cancer. Conclusion: This work provides insight into differential CpG island hyper- and hypo-methylation profiles in CRC and provides a window into the more complex epigenetic events associated with CRC, including the hypomethylation of known and novel genes. Investigations into the possible roles of the novel gene targets in the context of early and prognostic methylation biomarkers are underway. Citation Format: Hassan Ashktorab, Afnan Shakoori, Shatha Zarnogi, Xueguang Sun, Sudhir Varma, Edward Lee, Babak Shokrani, Adeinko O. Laiyemo, Kareem Washington, Hassan Brim. Whole genome hypo- and hyper-methylation sequencing among Africa American patients with colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4588. doi:10.1158/1538-7445.AM2015-4588
Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop
Authors: Ting Li, Hanqing Guo, Xiaodi Zhao, Jiang Jin, Lifeng Zhang, Hong Li, Yuanyuan Lu, Yongzhan Nie, Kaichun Wu, Yongquan Shi, Daiming Fan
Journal: Cancer Research (2016)

Molecular links between inflammation and cancer remain obscure despite their great pathogenic significance. The JAK2/STAT3 pathway activated by IL6 and other proinflammatory cytokines has garnered attention as a pivotal link in cancer pathogenesis, but the basis for its activation in cancer cells is not understood. Here we report that an IL6-triggered feedback loop involving STAT3-mediated suppression of miR-520d-5p and upregulation of its downstream target cyclophilin B (CypB) regulate the growth and survival of gastric cancer cells. In clinical specimens of gastric cancer, we documented increased expression of CypB and activation of STAT3. Mechanistic investigations identified miR-520d-5p as a regulator of CypB mRNA levels. This signaling axis regulated gastric cancer growth by modulating phosphorylation of STAT3. Furthermore, miR-520d-5p was identified as a direct STAT3 target and IL6-mediated inhibition of miR-520d-5p relied upon STAT3 activity. Our findings define a positive feedback loop that drives gastric carcinogenesis as influenced by H. pylori infections that involve proinflammatory IL6 stimulation. Cancer Res; 77(5); 1227-40. ©2016 AACR.
Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis
Authors: Ting Feng, Lanfang Wang, Trenton R. Schoeb, Charles O. Elson, Yingzi Cong
Journal: The Journal of Experimental Medicine (2010)

The authors regret that in the original version of this article the lengths of some of the scale bars in Figs.1,5, and 6 were incorrect.In addition, the image depicting Rag-defi cient recipients of CBir1 and OTII T cells in Fig. 6 E was incorrect.
rAAV8-733-Mediated Gene Transfer of CHIP/Stub-1 Prevents Hippocampal Neuronal Death in Experimental Brain Ischemia
Authors: Felipe Cabral-Miranda, Elisa Nicoloso-Simões, Juliana Adão-Novaes, Vince Chiodo, William W. Hauswirth, Rafael Linden, Luciana Barreto Chiarini, Hilda Petrs-Silva
Journal: Molecular Therapy (2017)

Brain ischemia is a major cause of adult disability and death, and it represents a worldwide health problem with significant economic burden for modern society. The identification of the molecular pathways activated after brain ischemia, together with efficient technologies of gene delivery to the CNS, may lead to novel treatments based on gene therapy. Recombinant adeno-associated virus (rAAV) is an effective platform for gene transfer to the CNS. Here, we used a serotype 8 rAAV bearing the Y733F mutation (rAAV8-733) to overexpress co-chaperone E3 ligase CHIP (also known as Stub-1) in rat hippocampal neurons, both in an oxygen and glucose deprivation model in vitro and in a four-vessel occlusion model of ischemia in vivo. We show that CHIP overexpression prevented neuronal degeneration in both cases and led to a decrease of both eIF2α (serine 51) and AKT (serine 473) phosphorylation, as well as reduced amounts of ubiquitinated proteins following hypoxia or ischemia. These data add to current knowledge of ischemia-related signaling in the brain and suggest that gene therapy based on the role of CHIP in proteostasis may provide a new venue for brain ischemia treatment. Brain ischemia is a major cause of adult disability and death, and it represents a worldwide health problem with significant economic burden for modern society. The identification of the molecular pathways activated after brain ischemia, together with efficient technologies of gene delivery to the CNS, may lead to novel treatments based on gene therapy. Recombinant adeno-associated virus (rAAV) is an effective platform for gene transfer to the CNS. Here, we used a serotype 8 rAAV bearing the Y733F mutation (rAAV8-733) to overexpress co-chaperone E3 ligase CHIP (also known as Stub-1) in rat hippocampal neurons, both in an oxygen and glucose deprivation model in vitro and in a four-vessel occlusion model of ischemia in vivo. We show that CHIP overexpression prevented neuronal degeneration in both cases and led to a decrease of both eIF2α (serine 51) and AKT (serine 473) phosphorylation, as well as reduced amounts of ubiquitinated proteins following hypoxia or ischemia. These data add to current knowledge of ischemia-related signaling in the brain and suggest that gene therapy based on the role of CHIP in proteostasis may provide a new venue for brain ischemia treatment.
Abstract 527: Ectopic expression of truncated IFIT2 at C-terminal tetratricopeptide repeats enhances the migration activity of oral squamous cell carcinoma cells
Authors: Prabha Regmi, Te-Chang Lee
Journal: Cancer Research (2015)

Abstract Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) belongs to one of interferon-stimulated gene family that comprise of tetratricopeptide repeats (TPR). TPR repeats are thought to mediate protein-protein interaction. Our previous report suggests that depletion of IFIT2 enhances cell migration and metastatic activity in oral squamous cell carcinoma (OSCC) cells via activation of atypical PKC signaling. However, the exact mechanism by which IFIT2 depletion activates the aPKC signaling pathway also remains unknown. Since IFIT2 comprises of nine TPR repeats, this study aims to explore the role of TPR in functioning of IFIT2. To address the above questions, different stable cell lines of truncated forms of IFIT2 were subjected to cell migration assay. Interestingly, C-terminal depleted cells exhibited increased migration ability and also showed loss of cell polarity thus leading to random cell orientation. Furthermore, these depleted cells also showed altered expression of junction proteins such as Claudin-1 and E-cadherin in comparison to IFIT2 overexpressed cells. Taken together, C-terminal depleted cells exhibit features of loss of function of IFIT2 suggesting the possible role of terminal TPR domain in maintaining the functional role of IFIT2. To identify specific TPR domain, different mutation construct are generated and its functional role is under study. Citation Format: Prabha Regmi, Te-Chang Lee. Ectopic expression of truncated IFIT2 at C-terminal tetratricopeptide repeats enhances the migration activity of oral squamous cell carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 527. doi:10.1158/1538-7445.AM2015-527
694. Targeting KRAS in Pancreatic Cancer by Gene Silencing with U1 Adaptors
Authors: Ashley T. Tsang, Xin Yu, Rafal Goraczniak, Mark Brenneman, Samuel Gunderson, Darren R. Carpizo
Journal: Molecular Therapy (2015)

Activating mutations of the KRAS gene are key drivers of pancreatic cancer, but the KRAS protein has been refractory to small-molecule drugging. U1 Adaptors are oligonucleotides that enable the U1 small nuclear ribonucleoprotein complex to stably bind within the terminal exon of a specific pre-mRNA. This interferes with the obligatory polyadenylation step in mRNA maturation, causing selective destruction of the targeted mRNA in the nucleus. Unlike siRNA or antisense oligos, U1 Adaptors can be extensively modified for nuclease resistance or targeted delivery without loss of silencing activity, offering important advantages as therapeutic agents. We sought to translate U1 Adaptor technology to suppress KRAS in pancreatic cancer. A panel of U1 Adaptors targeting human KRAS (KRAS Adaptors) was screened in vitro using the human pancreatic cancer cell line MiaPaca-2 (KRAS G12D mutant). Candidate KRAS Adaptors reduced KRAS mRNA expression by up to 76%, as effectively as an siRNA control. Knockdown of KRAS protein expression was confirmed by western blot. Inhibition of cell growth in vitro was demonstrated for MiaPaca-2 and two additional pancreatic cancer cell lines, Panc1 (KRAS G12D mutant) and BXPC3 (KRAS wildtype). We evaluated KRAS Adaptors in mice bearing subcutaneous MiaPaca-2 xenograft tumors. For in-vivo delivery, the Adaptors were initially complexed with PAMAM dendrimers linked to a tumor-targeting, cyclic RGD peptide (cRGD), and administered by tail vein injection twice weekly for three weeks. Tumor growth was inhibited by as much as 68% compared to vehicle controls (p=0.0002). Excised tumors were analyzed by qPCR and IHC, which confirmed reductions of KRAS mRNA and protein. Although U1 Adaptors complexed with cRGD-dendrimers have been efficacious in this study and others, dendrimers have technical drawbacks and reported toxicities, and dendrimer-free formulations are preferable. As an alternative, we conjugated KRAS Adaptors directly to cRGD peptide or to internalizing RGD (iRGD), which is a variant RGD peptide that triggers permeabilization of tumor endothelium and internalization by cells through secondary binding to neuropilin. The cRGD- and iRGD-conjugated KRAS Adaptors were tested for efficacy against subcutaneous MiaPaca-2 xenografts, and tumor growth was inhibited to equal or greater extent as with the original cRGD-dendrimer system. iRGD may be of particular benefit for pancreatic adenocarcinomas, which have a densely fibrotic stroma that impedes drug delivery. Enhanced delivery of small- and large-molecule therapeutics into primary pancreatic adenocarcinomas in KPC mice has been achieved previously by conjugating or coinjecting iRGD peptide. We have shown that U1 Adaptors can successfully target human KRAS both in vitro and in vivo. These results support the continued development of U1 Adaptor technology as a strategy for therapeutic suppression of KRAS in pancreatic cancer.
Abstract 2627: Lapatinib promotes promoted the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes
Authors: Chunling Dai, Shaolin Ma, Zhesheng Chen, Kenneth To, Liwu Fu
Journal: Cancer Research (2015)

Abstract Purpose: Lapatinib has been used in combination with capecitabine or paclitaxel in treating patients with progressive HER2-overexpressing metastatic breast cancer. Unfortunately, an increased hepatotoxicity had been found in the combinational therapy. The aim of this study was to investigate the potential mechanism of the increased hepatotoxicity during the combination treatment of lapatinib and chemotherapeutic agent. Experimental design: The incidence of hepatotoxicity was analyzed in the patients and Swiss mice with combinational treatment of lapatinib and paclitaxel or doxorubicin. Pharmacokinetic studies of paclitaxel and doxorubicin were carried out in mice. The chemotherapeutic agent accumulation was performed in ABCB1 overexpressing hepatocellular cancer cells and normal liver tissues. Results:The patients received lapatinib and paclitaxel treatment showed a higher incidence of hepatobiliary system disorders than those received paclitaxel alone. The in vivo experiments showed that the subjects in group of lapatinib plus chemotherapeutic agent had significantly higher levels of alanine aminotransferase and serious hepatocyte injury compared with that in group of single drug. Pharmacokinetic studies revealed that lapatinib could increase the exposed level of paclitaxel and doxorubicin without inhibiting the activity of CYP 3A4. Further study demonstrated that lapatinib could increase the accumulation of doxorubicin in ABCB1-overexpressing hepatocellular cancer cells and normal liver tissues without altering the protein level of ABCB1. Conclusion: The higher incidence of hepatotoxicity during the treatment of lapatinib plus chemotherapeutic agent was due to the increased agent accumulation in liver cells via inhibiting the function of ABC transporters inhibited by lapatinib. This is important information direction for the design of combinational therapy in clinic. Citation Format: Chunling Dai, Shaolin Ma, Zhesheng Chen, Kenneth To, Liwu Fu. Lapatinib promotes promoted the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2627. doi:10.1158/1538-7445.AM2015-2627
X-Rays absorption evaluation in cancer patients submitted to cosmeceutical prophylaxis with smoothing emulsion and sun protecion factor cream during radiotherapy
Authors: C. Valsuani, A. Beatini, P. Pacetti, G. Marcozzi, S. Luxardo, V. Marchetti, R. Tartarini, M. Orlandi, A. Tofani, A. Tagliagambe, A. Mambrini
Journal: Annals of Oncology (2015)
Ultra-slow N-Acetyltransferase 2 Is Associated with Recurrence-free Time in Bladder Cancer Patients
Authors: Silvia Selinski, Holger Gerullis, Thomas Otto, Emanuel Roth, Frank Volkert, Daniel Ovsiannikov, Johannes Salem, Oliver Moormann, Berit Christine Geis, Hartmut Niedner, Meinolf Blaszkewicz, Jan G. Hengstler, Klaus Golka
Journal: European Urology (2016)
Bevacizumab beyond disease progression in advanced non-squamous NSCLC (WJOG 5910L): a randomized phase II trial
Authors: Takashi Seto, Masayuki Takeda, Hidetoshi Hayashi, Koichi Azuma, Morihito Okada, Shunichi Sugawara, Takeharu Yamanaka, Kazuhiko Nakagawa, Yoichi Nakanishi, Isamu Okamoto
Journal: Annals of Oncology (2015)
518. Artificial Mouse Model: An Animal-Free System for Assessment of CAR-T Cell Function
Authors: Pradip Bajgain, Usanarat Anurathapan, Ayumi Watanabe, John Wilson, Norihiro Watanabe, Sujita Sukumaran, Helen Heslop, Cliona Rooney, Malcolm Brenner, Ann Leen, Juan Vera
Journal: Molecular Therapy (2015)

Although numerous studies have sought to better understand tumor:T cell interactions, their experimental systems have primarily been restricted to the use of in vitro "two dimensional" assays or in vivo SCID mouse models. Both systems, however, have proved to be poor predictors of clinical T cell activity. In addition, SCID models are expensive, time consuming, and lack physiological relevance. Therefore, to study T cell function we have tested a novel, animal-free system called the Artificial-Mouse (Art Mouse) developed by Wilson Wolf Corporation. The Art Mouse is a gas permeable culture system that contains multiple chambers connected in series in order to allow the dynamic study of T cell migration, expansion and anti-tumor effects. These properties can be monitored by periodic bioluminescence imaging and flow cytometric analysis. We first explored the ability of the Art Mouse to generate a chemokine gradient. Seventy-two hours after adding 24μg of MCP1 in compartment 1 (C1), we detected the following concentrations: C1 (196.79ng/ml), C2 (78.52ng/ml), C3 (56.80ng/ml), C4 (9.79ng/ml), C5 (2.52ng/ml) and C6 (0.64ng/ml). To evaluate if these conditions would drive T cell migration, 24μg of MCP1 was added in C1 and 3 days later 20×106 CAR-PSCA T cells marked with firefly-luciferase GFP (FFluc-GFP) were placed in C6. After 5 days we observed an accumulation of CAR-PSCA Tcells in C1 (increase from 1.29×108 to 2.09×108 photons/second; p/s), with no accumulation observed in the control (no MCP1). Importantly, engraftment of the pancreatic tumor cell line CAPAN1 (which produces IL8 and CXCL1) in C1 also induced CAR-PSCA T cell migration (increase from 0.92×108 to 1.45×108 p/s). To assess the utility of this new tool in evaluating anti-tumor effects we established a 3D tumor model by seeding C1 with 1×106 FFLuc-GFP-marked CAPAN1 cells (PSCA+ve pancreatic tumor cell line). Subsequently, 20×106 CAR-PSCA T cells were added to C6. We then monitored the tumor signal by frequent bioluminescence imaging and observed a progressive decrease in the tumor signal (2.0±.32×108 to 1.4±.09×105 p/s, day 0 to day 30). In contrast, in the absence of T cells the tumor signal progressively increased (1.7±.59×108 to 1.3±.29×109 p/s, day 0 to day 30). Notably, this model resembles the growth kinetics and anti-tumor effects observed in SCID xenograft models but an important distinction between the two platforms is the substantially lower variability in the Art Mouse (Std Dev of 0.32×108 vs 3.31×108p/s, Art Mouse vs SCID mice). Thus, this preliminary data suggests that the Art Mouse can serve as an animal-free alternative to study dynamic T cell features including migration, expansion and anti-tumor effects.
Updates on PFS and safety results of a Phase I / II study (AF-001JP) of alectinib in ALK-rearranged advanced NSCLC
Authors: Toshiyuki Kozuki, Makoto Nishio, Katsuyuki Kiura, Takashi Seto, Kazuhiko Nakagawa, Makoto Maemondo, Akira Inoue, Toyoaki Hida, Tomohiro Tanaka, Tomohide Tamura
Journal: Annals of Oncology (2015)