tbuckley/cabot-search huggingface dataset:
Challenges and opportunities for checkpoint blockade in T-cell lymphoproliferative disorders
Authors: Tycel Phillips, Sumana Devata, Ryan A. Wilcox
Journal: Journal for ImmunoTherapy of Cancer (2016)

The T-cell lymphoproliferative disorders are a heterogeneous group of non-Hodgkin's lymphomas (NHL) for which current therapeutic strategies are inadequate, as most patients afflicted with these NHL will succumb to disease progression within 2 years of diagnosis. Appreciation of the genetic and immunologic landscape of these aggressive NHL, including PD-L1 (B7-H1, CD274) expression by malignant T cells and within the tumor microenvironment, provides a strong rationale for therapeutic targeting this immune checkpoint. While further studies are needed, the available data suggests that responses with PD-1 checkpoint blockade alone will unlikely approach those achieved in other lymphoproliferative disorders. Herein, we review the unique challenges posed by the T-cell lymphoproliferative disorders and discuss potential strategies to optimize checkpoint blockade in these T-cell derived malignancies.
Abstract 4641: Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the Cheliensisin A (Chel A) inhibition of cell transformation
Authors: Chuanshu Huang, Junlan Zhu, Jingxia Li
Journal: Cancer Research (2015)

Abstract Cheliensisin A (Chel A), as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been demonstrated to have an inhibition of EGF-induced Cl41 cell transformation via stabilizing p53 protein in a Chk1-dependent manner, suggesting its chemopreventive activity in our previous studies. However, its underlying molecular mechanisms have not been fully characterized yet. In the present study, we found that Chel A treatment could increase c-Jun protein phosphorylation and activation, whereas the inhibition of c-Jun phosphorylation, by ectopic expression of a dominant-negative mutant of c-Jun, TAM67, reversed the Chel A inhibition of EGF-induced cell transformation and impaired Chel A induction of p53 protein and apoptosis. Moreover, our results indicated that Chel A treatment led to a PHLPP down-regulation by promoting PHLPP protein degradation. We also found that PHLPP could interact with and bind to c-Jun protein, whereas ectopic PHLPP expression blocked c-Jun activation, p53 protein and apoptotic induction by Chel A and further reversed the Chel A inhibition of EGF-induced cell transformation. With the findings, we have demonstrated that Chel A treatment promotes a PHLPP protein degradation, which can bind to c-Jun and mediates c-Jun phosphorylation, and further leading to p53 protein induction, apoptotic responses, subsequently resulting in cell transformation inhibition and chemopreventive activity of Chel A. Citation Format: Chuanshu Huang, Junlan Zhu, Jingxia Li. Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the Cheliensisin A (Chel A) inhibition of cell transformation. [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 4641. doi:10.1158/1538-7445.AM2015-4641
Adenoid cystic carcinoma of the head and neck (ACCHN) incidence and survival trends.
Authors: C. L. Ellington, S. A. Kono, T. K. Owonikoko, S. S. Ramalingam, F. R. Khuri, D. M. Shin, N. F. Saba
Journal: Journal of Clinical Oncology (2011)

5580 Background: Adenoid cystic carcinoma (ACC) is a rare tumor of minor salivary, parotid, and submandibular glands. The biological behavior of the disease is poorly understood, and treatment strategies have yet to be standardized. The 10-year survival is under 60%. Population-based studies examining ACC are scarce. We aimed to analyze incidence rates and survival outcomes for patients diagnosed with ACCHN using a national population-based data. Methods: Data were obtained from the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Newly diagnosed ACC cases of the HN reported to SEER from 1973 through 2007 were categorized according to the patient’s sex, age, and year of diagnosis, marital status, and stage. The incidence and survival of ACCHN were then examined and compared across different demographic and disease-related categories. Results: 3026 patients with ACC HN were identified between 1973 and 2007. The mean age at diagnosis was 57.4 years (range: 11–99 years). There was a noted decrease in incidence of ACCHN with a decline from about 3/1000,000 in 1973 to 1. /1000,000 in 2007 with an annual percent change (APC) of -1.9 (p <0.001). This change was noted across genders and races. The overall 5, 10 and 15-year survival outcomes for ACCHN were 90.3%, 79.9%, and 69.2% respectively. Female patients with localized disease, and younger patients had a significantly better survival across all time periods (all comparison-specific log rank p <0.001). By contrast, no associations between survival and marital status or race were found. Conclusions: The overall incidence of ACCHN seems to be declining. The reason for the noted differences in survival between genders remains unclear. While earlier detection in women may be a contributing factor, further investigation to clarify this difference is needed. Survival outcomes based on other parameters such as age or stage will be further described.
Abstract 507: Ionizing radiation regulates mutant p53-mediated cancer cell invasiveness through targeting cyclin D1
Authors: Shin-Hee Lee, Phillip Craigmile, Shiyong Wu
Journal: Cancer Research (2015)

Abstract Ionizing radiation (IR) is widely used as a main treatment for solid tumors, however, its potential influence and its role in the invasion and metastasis of cancer still remain unknown. In this study, we found that IR showed an inhibitory effect on the invasion of mutant p53 expressing cancer cells through targeting cyclin D1, which has been known as implicated in invasion and metastasis. Our data showed that gamma-irradiation (5 Gy) decreased trans-well migration of mutant p53 expressing cancer cells. It has been reported that following exposure to IR cyclin D1 is rapidly degraded via the ubiquitin pathway. We showed that IR-induced cyclin D1 degradation is restored after 24 hr in H1299 p53 negative cells. In contrast, cyclin D1 depletion was not recovered in H1299 mutant p53 cells, suggesting its inhibiting effect on cyclin D1 regulation. In addition, the levels of matrix metalloproteinase 9 were decreased in mutant p53 expressing cancer cells, indicating the reduction of cell migration and invasion. These data indicate that IR suppresses the restoration of cyclin D1 via the mutant p53, thus inhibiting the invasion of cancer cells expressing mutant p53. Citation Format: Shin-Hee Lee, Phillip Craigmile, Shiyong Wu. Ionizing radiation regulates mutant p53-mediated cancer cell invasiveness through targeting cyclin D1. [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 507. doi:10.1158/1538-7445.AM2015-507
760. Optimized AAV-Mediated Human Factor VIII Gene Therapy in Hemophilia A Mice and Cynomolgus Macaques
Authors: Jenny A. Greig, Qiang Wang, Amanda L. Reicherter, Erin Bote, Deirdre McMenamin, Christine Draper, Shu-Jen Chen, Alexandra L. Hanlon, Tamara Goode, K. Reed Clark, Samuel Wadsworth, Lili Wang, James M. Wilson
Journal: Molecular Therapy (2016)

In an effort to optimize expression of human coagulation VIII (hFVIII) for the treatment of hemophilia A, an extensive study was performed combining liver-specific promoter and enhancer elements with a codon-optimized human B-domain-deleted hFVIII transgene. Due to the large size of the FVIII coding sequence, there is a strong requirement for gene expression control elements to be as short as possible while retaining hepatocyte-restricted transcription. Several strong liver-specific promoters were shortened and combined, with combinations of up to three liver-specific enhancer sequences, to generate 42 enhancer/promoter combinations. These 42 liver regulatory gene cassettes were packaged into the AAVrh10 capsid and were tested in FVIII KO mice. Following intravenous (IV) administration of 1010 genome copies (GC), mice were bled every two weeks to follow hFVIII activity and antibody generation to the transgene. At week 2 post-injection, mice showed a range in hFVIII activity from 0.12-2.12 IU/ml. FVIII KO mice developed antibodies to hFVIII at week 4, and by week 8, mice in most of the 42 vector groups had detectable anti-hFVIII IgG levels. Based on the FVIII KO mouse studies and a small pilot rhesus macaque study, two of the original 42 enhancer/promoter combinations were selected for further evaluation in cynomolgus macaques, using two different Clade E capsids for expression. Each of the four vector combinations were administered IV at a dose of 1.2×1013 GC/kg into five macaques per group. With one capsid plus enhancer/promoter combination, peak expression of 37% of normal FVIII levels was seen at week 2 post-vector administration, which then plateaued at 20% of normal. While antibodies to the hFVIII were detected in the majority of macaques by week 8, antibodies remained undetectable in two animals at week 30 post-vector administration.
Difficulty of Achieving Clear Margins in Nonpalpable Ductal Carcinoma of the Breast
Authors: Cheng-Har Yip
Journal: JAMA Surgery (2016)

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385. Inhibiting the Myostatin Signaling Pathway using CRISPR/Cas9-Based Repressors
Authors: Pratiksha I. Thakore, Nishkala K. Shivakumar, Charles A. Gersbach
Journal: Molecular Therapy (2016)

Inhibition of myostatin signaling is a potential method to enhance skeletal muscle growth and has been proposed as a strategy to treat muscle weakness associated with sarcopenia, cachexia, and muscular dystrophies. Current approaches under clinical investigation for inhibiting the myostatin pathway rely on systemic administration of soluble factors, including myostatin blocking antibodies and soluble myostatin receptors. Treatment with these protein-based inhibitors has led to enhanced muscle mass in mouse models of muscular dystrophy and cachexia, but has demonstrated limited efficacy and some adverse side effects in subsequent clinical trials. We hypothesized that a targeted gene regulation strategy to localize inhibition of the myostatin pathway to skeletal muscle fibers may increase the effectiveness and safety of this therapy. The RNA-guided CRISPR/Cas9 system has emerged as a promising platform for targeted gene regulation. Fusion of catalytically inactive, "dead" Cas9 (dCas9) to the Kruppel-associated box (KRAB) domain generates a synthetic repressor capable of highly specific silencing of target genes. dCas9-KRAB repressors can be employed in gene therapy to silence detrimental gene products, repress oncogenes, inhibit viral replication, and treat dominant negative diseases. However, gene delivery of dCas9-KRAB to skeletal muscle in vivo is challenging because the size of the S. pyogenes dCas9 and KRAB domain fusion exceeds the packaging limit of standard AAV vectors. Recently, a smaller Cas9 protein derived from S. aureus was described for AAV delivery and in vivo gene editing. We generated a S. aureus dCas9-KRAB fusion and targeted the myostatin receptor, Acvr2b, for silencing. In cultured mouse myoblasts, S. aureus dCas9-KRAB potently repressed Acvr2b expression by qPCR and resulted in reduced myotube formation following differentiation compared to controls. The S. aureus dCas9-KRAB repressor was packaged into AAV vectors and expressed efficiently in vitro in cultured myoblasts and in vivo following direct injection into the mouse tibialis anterior muscle. Ongoing studies will determine the effects of transcriptional silencing of Acvr2b on myotube diameter in vitro and the efficiency of Acvr2b silencing achieved by engineered dCas9-KRAB repressors in vivo. These studies establish how transcriptional modulation with the CRISPR/Cas9 system can be used to investigate potential therapeutic gene targets for treating neuromuscular disorders.
Abstract 749: Both amplification and protein expression are required to predict FGFR tyrosine kinase inhibitor sensitivity in lung cancer
Authors: Hiromichi Ebi, Hiroshi Kotani, Seiji Yano
Journal: Cancer Research (2015)

Abstract FGFR1 amplification has been suggested to be a driver oncogene in squamous and small cell lung carcinoma. However, early clinical trials show that response rate of FGFR tyrosine kinase inhibitors (FGFR-TKIs) is 20-30% in patients with FGFR1 amplified lung cancer. To elucidate the reason for de novo resistance to FGFR-TKI, six FGFR1 amplified lung cancer cell lines (NCI-H1581, DMS-114, NCI-H520, NCI-H1703, HCC95, and Calu-3) were analyzed. These cells were confirmed to have FGFR1 amplification by FISH analysis. Cell viability assay showed only 2 of six cell lines, NCI-H1581 and DMS-114, are sensitive to a FGFR-TKI, BGJ-398. Among BGJ-398 insensitive cells, NCI-H1703, HCC95, and Calu-3 cells express low mRNA and protein level of FGFR1 even in the presence of FGFR1 amplification. In addition, while BGJ-398 downregulates ERK phosphorylation in FGFR1 protein expressing cells, the drug had no effect on ERK signaling in BGJ-398 resistant cells with low FGFR1 protein expression. Importantly, other driver oncogenes were found in these BGJ-398 insensitive cell lines. PDGFRa amplification in H1703 cells and HER2 amplification in Calu-3 cells were reported previously. In this study, we have also found ERBB3 ligand NRG1 was overexpressed in HCC95 cells. Knockdown of NRG1 suppressed cell growth and combination of lapatinib with BGJ-398 led to cell death. To further determine whether FGFR1 protein expression is enough for the sensitivity to FGFR-TKIs, lung cancer cell lines were screened to FGFR-TKIs, BGJ-398 and PD-173034. This screen identified that all FGFR-TKI sensitive cell lines harbor FGFR1 amplification with high protein expression. These results suggest FGFR-TKIs should be used to patients harboring both FGFR1 amplification and protein expression. In case tumors with FGFR1 amplification, but expressing low FGFR1 protein, another driver oncogene may coexist and targeting both FGFR1 and these coexisting driver oncogenes are required to treat these tumors. Citation Format: Hiromichi Ebi, Hiroshi Kotani, Seiji Yano. Both amplification and protein expression are required to predict FGFR tyrosine kinase inhibitor sensitivity in lung 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 749. doi:10.1158/1538-7445.AM2015-749
Abstract 4070: Prolonged silencing of diacylglycerol acyltransferase-1 induces a dedifferentiated phenotype in human liver cells
Authors: Soyoung Chang, Pil Soo Sung, Jungsul Lee, Junseong Park, Eui-Cheol Shin, Chulhee Choi
Journal: Cancer Research (2015)

Abstract Diacylglycerol acyltransferase-1 (DGAT1), a key enzyme in triglyceride (TG) biogenesis, is highly associated with metabolic abnormalities, such as obesity and type 2 diabetes. However, the effects of DGAT1 sliencing in the human liver have not been elucidated. To investigate the effects of DGAT1 silencing in human liver cells, we compared the cellular behaviors of DGAT1-deficient Huh-7.5 cell lines with those of control Huh-7.5 cells. DGAT1-deficient cells acquired dedifferentiated and stem cell-like characteristics, such as formation of aggregates in the presence of high levels of growth factors, high proliferation rates, and loss of albumin secretion. In relation to aggregate formation, the expression level of various adhesion molecules was significantly altered in DGAT1-deficient cells. Microarray data analysis and immunostaining of patient tissue samples clearly showed decreased expression levels of DGAT1 and integrin β1 in patients who have nodular cirrhosis without fatty degeneration. Note: This abstract was not presented at the meeting. Citation Format: Soyoung Chang, Pil Soo Sung, Jungsul Lee, Junseong Park, Eui-Cheol Shin, Chulhee Choi. Prolonged silencing of diacylglycerol acyltransferase-1 induces a dedifferentiated phenotype in human liver 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 4070. doi:10.1158/1538-7445.AM2015-4070
The study of the immature vessel percentage (IVP) as a potential predictive factor for chemotherapy response in breast cancer: A multicenter study.
Authors: A. M. Safar, A. Yacoub, L. Hennings, J. T. Beck, H. J. Spencer, L. F. Hutchins, A. A. Eid
Journal: Journal of Clinical Oncology (2011)

e21038 Background: The abundance of immature blood vessels (endothelial channels devoid of pericyte encasement) is a hallmark of tumor vasculature (TV). This is thought to increase interstitial pressure in the tumor, reduce perfusion, and accordingly compromise response to chemotherapy. We hypothesized that tumors with most immature TV would exhibit the least response to chemotherapy. Immature Vessel Percentage (IVP) assay was proposed as a surrogate of TV immaturity. We investigated whether IVP could serve as a predictive marker for responsiveness to chemotherapy. Moreover, since CT may have an antiangiogenic activity, decline in IVP scores is postulated after neoadjuvant chemotherapy. Methods: Pre-and post-treatment biopsies from breast cancer patients (pts) treated neoadjuvantly with non-bevacizumab-containing chemotherapy in 2 USA institutions were studied. TV was evaluated using double-label immunohistochemistry against von Willebrand Factor (vWF) and smooth muscle actin (aSMA) to colocalize endothelial cells and pericytes, respectively. IVP was calculated as the ratio of immature to mature vessels counted in 5, randomly selected 200X magnification fields. Each sample was evaluated twice. Radiologic and clinical objective response rates (ORR) were estimated clinically and radiologically. Results: Over 400 pts were screened, but only 26 pts samples were evaluable. There is a considerable IVP heterogeneity among the group (mean= 0.734, SD=1.024, range: 0.046 to 4.567). There was no correlation between pre-treatment IVP and the ORR in this cohort (Spearman’s rho= 0.2, p-value= 0.411). We were unable to detect a statistically significant decline in IVP post treatment (p-value=0.883). Conclusions: The degree of TV immaturity, as estimated by IVP, was not predictive of responsiveness to neoadjuvant chemotherapy in this small cohort. The putative chemotherapy effect on TV was not appreciable using IVP. Despite the wide practice of neoadjuvant therapy in breast cancer, there were only few patients with sufficient banked tissue samples available for research endeavors. This constitutes an obstacle to conducting molecular studies like ours.
Azacitidine (AZA) Combined with Idarubicin in Untreated Patients with High Risk MDS – Results of a Phase I/II Study of the Groupe Francophone Des Myelodysplasies
Authors: Lionel Ades, Benoit de Renzis, Ramzi Jeddi, Jacques Delaunay, Thorsten Braun, Mathilde Hunault Berger, Aspasia Stamatoullas, Laurence Sanhes, Benedicte Samey, Fatiha Chermat, Baklis Meddeb, Pierre Fenaux
Journal: Blood (2012)
Abstract 356: Mutaome-based magnolin sensitivity in ovarian cancer cells
Authors: Ji-Hong Song, Woo-Young Kim, Yong-Yeon Cho
Journal: Cancer Research (2015)

Abstract Signaling pathways mediated through Ras/Raf/MEK/ERK and/or PI3K/AKT/mTOR signaling pathways play a key role in cell transformation and cancer development. During carcinogenesis, genomic alterations, accumulation of mutations and amplification of growth signaling, induce cellular phenotype changes including escaping aging, metabolic change of energy source and resistance against therapeutic agents. Recently, our research group has identified a natural compound, magnolin, that inhibits ERK1 and ERK2 kinase activities with about 87 uM and 16.5 uM of IC50, respectively. However, the effect of magnolin in cancer cells has been poorly understood. To explore the effect of magnolin in cancer cells, we examined anti-proliferation effect of magnolin in pancreatic, colon and ovarian cancer cells. We found that striking differences of cancer cell proliferation was observed in ovarian cancer cells, TOV112D and SKOV3, by magnolin treatment. In TCGA mutaome data-base analysis, we found that TOV112D and SKOV3 harbor the different mutations in different genes which are known to involve in chemo-resistance. In cell cycle analysis, we found that TOV112D reduced S-phase of cell cycle and increased G1/G0-phase of cell cycle. Importantly, activation protein profiles in TOV112D and SKOV3 cells by Western blotting showed that phosphorylation of p90RSK including RSK2 was higher in SKOV3 cells compared with TOV112D cells. These results strongly suggested that alteration of p90RSK signaling may play an important role in expression of chemo-resistance in ovarian cancer cells. Citation Format: Ji-Hong Song, Woo-Young Kim, Yong-Yeon Cho. Mutaome-based magnolin sensitivity in ovarian cancer 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 356. doi:10.1158/1538-7445.AM2015-356
Outcome and Prognostic Factors in Patients with Mantle Cell Lymphoma Relapsing After Autologous Stem Cell Transplantation: A Retrospective Study of the EBMT
Authors: Sascha Dietrich, Herve Finel, Ariane Boumendil, Irit Avivi, Liisa Volin, Jan Cornelissen, Jan Walewski, Christoph Schmid, Theo M. de Witte, Harry C. Schouten, Martin Kaufmann, Catherine Sebban, Marek Trneny, Guido Kobbe, Philippe Guardiola, Johannes Schetelig, Michael Pfreundschuh, Jose L. Diez-Martin, Dominique Bordessoule, Stephen Robinson, Peter Dreger
Journal: Blood (2012)