tbuckley/cabot-search huggingface dataset:
707. Attenuated HIV Does Not Amplify in Primary Human T-Lymphocytes During a Model Ex Vivo Gene Therapy Procedure
Authors: Pratima Cherukuri, Scott Witting, Lilith Reeves
Journal: Molecular Therapy (2016)

Current regulatory guidelines require RCL testing of lentiviral vector preparations used in human clinical trials. Cells transduced ex vivo and cultured four days or more must also be tested before administering to the patient. Attenuated HIV (R8.71) can be considered as a theoretical RCL that could develop from a recombination event with wild-type HIV. Importantly, R8.71 lacks accessory proteins (vip, vif, vpr and nef) that are known to be essential for viral replication in T-lymphocytes. Based on this fact, the risk of a recombinant RCL being amplified in T-lymphocytes during an ex vivo transduction and expansion protocol is questionable. To test this possibility, we transduced human T-lymphocytes with one of two RCL-negative lentiviral vector preparations (eGFP or a chimeric antigen receptor (CAR)) that were spiked or not with R8.71 or wild-type HIV. C8166 cells served as a positive control for cells permissive to R8.71. The transduction and subsequent expansion lasted 10 days total and the experiment was performed on two independent occasions. Using day 10 supernatants from all groups, a full RCL assay (with amplification and indicator phases) was performed. Product enhanced reverse transcriptase (PERT) and P24 ELISA assays served as readouts for the RCL assay. Transduction rates were determined by flow cytometry and found to be 57-60% and 10-37% for the eGFP and CAR vector, respectively. The RCL assay results showed that all T-lymphocyte groups exposed to R8.71 were negative but those exposed to wild-type HIV were positive. C8166 cells exposed to R8.71 or wild-type HIV were positive in the RCL assay. These results suggest that a recombinant RCL that possess the wild-type HIV envelope would NOT amplify in human T-lymphocytes during a model ex vivo transduction procedure. The amplification of an arguably more dangerous VSVG-enveloped recombinant RCL is still possible; however, it could be reliably detected by quicker and less expensive assays such as qPCR to VSVG sequences.
Multiple Myeloma and Microenvironment Formation: The Role of CXCR4/CXCL12 Chemokine Pathway
Authors: Katia Beider, Avichai Shimoni, Odit Gutwein, Merav Leiba, Elena Ribakovsky, Nira Bloom, Amnon Peled, Arnon Nagler
Journal: Blood (2010)
Abstract 819: Fatty acid synthase, cycloxygenase-2 (COX-2) and osteoprotegerin (OPG) expression in invasive breast cancer: Implications in carcinogenesis
Authors: Sudeshna Goswami, Neelam Sharma-Walia
Journal: Cancer Research (2015)

Abstract Breast cancer, the leading cause of death among women with an onset frequency of one in eight, is the most common type of cancer among women. However, despite the advancement in therapy, the mortality rate in breast cancer patients still remains high. The role of various different genes, directly or indirectly, regulating these processes have tremendously added to our knowledge of the complex process of proliferation, which has remained the most important prognostic factor so far. In our previous study, we established Osteoprotegerin (OPG)'s role in aneuploidy, cell proliferation and angiogenesis in breast cancer. We demonstrated that OPG is expressed and secreted at very high levels from the highly invasive breast cancer cell lines SUM149PT and SUM1315MO2 as compared to human normal mammary epithelial cells (HMEC). Here, we demonstrated by mass spectrometry that OPG pulls down fatty acid synthase (FASN), a key enzyme of the fatty acid biosynthetic pathway in breast cancer cells. We observed large number of lipid droplets in SUM149PT and SUM1315MO2 cells in comparison to HMEC by electron microscopy. Human breast cancer tissue samples showed high expression of FASN. Treatment with FASN inhibitor C75 decreased the number of lipid droplets/cell, altered expression of genes involved in cell proliferation, cell signaling (Akt/PI3K, ERK, GSK3β) apoptosis (caspase-3 and caspapse-9) and cell cycle. Treatment with C75 lowered the inflammatory pathway enzyme cyclooxygenase-2 (COX-2) expression and reduced secretion of its inflammatory metabolite prosataglandin E2 (PGE2). We reasoned that there might be crosstalk between OPG, FASN, and COX-2, that sustains the inflammatory pathways, and drives the progression of breast cancer. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 by recombinant human OPG. Collectively, our study indicates the crosstalk between FASN, COX-2 and OPG. Combinatorial drug treatment of these main players of carcinogenesis can be used as a potential therapeutic target to treat highly invasive breast cancer. Citation Format: Sudeshna Goswami, Neelam Sharma-Walia. Fatty acid synthase, cycloxygenase-2 (COX-2) and osteoprotegerin (OPG) expression in invasive breast cancer: Implications in carcinogenesis. [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 819. doi:10.1158/1538-7445.AM2015-819
Abstract 4798: Genomic alterations in ERBB2 define a subset of pleomorphic invasive lobular breast cancer
Authors: Kim M. Hirshfield, Renee Sanders, Heather K. Feld, Nicola Barnard, Li Liang, Hua Zhong, Gyan Bhanot, Amrik S. Sahota, Andrew Brooks, Lorna Rodriguez-Rodriguez, Shridar Ganesan
Journal: Cancer Research (2015)

Abstract Background. Pleomorphic invasive lobular carcinoma represents a unique histologic subset of breast cancer with poorer outcomes as compared with classic invasive lobular carcinoma of the breast. With the recent finding of ERBB2 alterations in recurrent invasive lobular carcinoma, the goal of this study is to define the relationship of ERBB2 alterations in the distinct subset of pleomorphic invasive lobular carcinomas. Methods. Using the provisional invasive breast cancer data set of 962 cases in The Cancer Genome Atlas (TCGA), all breast cancers with CDH1 alterations were identified and pathologic review was performed. Independent identification of ERBB2 genomic alterations was done. The frequency and nature of genomic alterations in ERBB2, PTEN, PIK3CA, and TP53 were determined. FFPE specimens from an additional 18 cases from our own institution have been evaluated using the combination of the RainDance ThunderBolts™ Cancer Panel for validation. Results. Of 116 TCGA breast cancers with CDH1 alterations, 86 were invasive lobular breast cancer. Within this subset, 21 pleomorphic lobular breast cancers were identified based on morphologic review. Nine ERBB2 mutations (42.9%) and three amplifications (14.3%) were found in pleomorphic invasive lobular carcinoma, but none in classic invasive lobular carcinoma (p value 1.92e-9). There were no significance differences in the frequency of TP53, PTEN or PIK3CA alterations in pleomorphic invasive lobular carcinoma as compared to classic invasive lobular carcinoma. Data from the additional 18 validation cases will be presented. Conclusions. Genomic alterations in ERBB2 strongly associate with the finding of pleomorphic invasive lobular but not classic invasive lobular histology. The presence of ERBB2 alterations has therapeutic implications specific to this rare breast cancer subset that could impact outcomes. Comprehensive genomic profiling identifies ERBB2 mutations that are not detected with standard clinical immunohistochemistry or FISH. Citation Format: Kim M. Hirshfield, Renee Sanders, Heather K. Feld, Nicola Barnard, Li Liang, Hua Zhong, Gyan Bhanot, Amrik S. Sahota, Andrew Brooks, Lorna Rodriguez-Rodriguez, Shridar Ganesan. Genomic alterations in ERBB2 define a subset of pleomorphic invasive lobular breast 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 4798. doi:10.1158/1538-7445.AM2015-4798
Treatment with Pegylated Interferon-Alfa-2A (PEG-IFN-α-2A; PEGASYS™) for Patients with Essential Thrombocythemia (ET) and Polycythemia Vera (PV).
Authors: Alfonso Quintas-Cardama, Hagop Kantarjian, Francis Giles, Jorge Cortes, Mary Ann Richie, Gautam Borthakur, Srdan Verstovsek
Journal: Blood (2006)
Abstract 5334: Oncolytic Newcastle disease virus: armed but not dangerous
Authors: Danielle K. Carroll, James Harper, Shannon Burke, Jon Travers, Ruth Franks, Christel Navarro, Xing Cheng, Robert W. Wilkinson, Hong Jin
Journal: Cancer Research (2015)

Abstract Oncolytic viruses are live, replication-competent viruses that infect and/or replicate selectively in tumour cells leading to the destruction of the infected cell. Cell lysis occurs as a natural consequence of the viral life cycle and released virions can infect and kill neighbouring tumour cells leading to an amplified therapeutic effect. Oncolysis has the added benefit of releasing multiple tumour antigens that may further induce an immune-mediated therapeutic response. Newcastle Disease Virus (NDV) is an avian paramyxovirus, which has proven safety and demonstrated efficacy against a variety of preclinical cancer models and in PhI clinical studies as an oncolytic agent, oncolysate or whole cell vaccine. Using reverse genetics, we have generated a recombinant strain of NDV that overcomes environmental and regulatory concerns uncoupling oncolytic potency and avian pathogenicity. Furthermore we have enhanced the immune modulatory properties of NDV by engineering the virus to express granulocyte/macrophage colony-stimulating factor (GM-CSF). We have evaluated the biological characteristics of recNDVGM-CSF in vivo and in vitro. RecNDVGM-CSF selectively replicates in and kills a wide variety of human and mouse tumour cell lines. Additionally NDV infection of cancer cells results in the increased production and secretion of pro-inflammatory cytokines and chemokines which are able to recruit mediators of both the innate and adaptive immune responses. NDV is a potent activator of the type I interferon response and is also able to directly activate many immune cell types. In vivo, using a range of syngeneic and xenograft models we have demonstrated that NDV treatment has profound anti-tumour activity. In a HT1080 fibrosarcoma xenograft model a single administration (intra-tumoural or systemic) was able to cure 80% of tumour bearing mice. In syngeneic mouse tumour models, NDV treatment causes profound changes in the immune suppressive microenvironment and can result in long-lasting anti-tumour immune responses. The inherent properties of NDV (self-propagation, tumour-selective replication, and immunostimulatory properties) coupled with the ability to genetically engineer NDV to express therapeutic transgenes may provide a multi-modal attack on the tumour, delivering greater benefit to patients. Citation Format: Danielle K. Carroll, James Harper, Shannon Burke, Jon Travers, Ruth Franks, Christel Navarro, Xing Cheng, Robert W. Wilkinson, Hong Jin. Oncolytic Newcastle disease virus: armed but not dangerous. [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 5334. doi:10.1158/1538-7445.AM2015-5334
“Zombie” Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York
Authors: Axel J. Adams, Samuel D. Banister, Lisandro Irizarry, Jordan Trecki, Michael Schwartz, Roy Gerona
Journal: New England Journal of Medicine (2016)

New psychoactive substances constitute a growing and dynamic class of abused drugs in the United States. On July 12, 2016, a synthetic cannabinoid caused mass intoxication of 33 persons in one New York City neighborhood, in an event described in the popular press as a "zombie" outbreak because of the appearance of the intoxicated persons.We obtained and tested serum, whole blood, and urine samples from 8 patients among the 18 who were transported to local hospitals; we also tested a sample of the herbal "incense" product "AK-47 24 Karat Gold," which was implicated in the outbreak. Samples were analyzed by means of liquid chromatography-quadrupole time-of-flight mass spectrometry.The synthetic cannabinoid methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate (AMB-FUBINACA, also known as MMB-FUBINACA or FUB-AMB) was identified in AK-47 24 Karat Gold at a mean (±SD) concentration of 16.0±3.9 mg per gram. The de-esterified acid metabolite was found in the serum or whole blood of all eight patients, with concentrations ranging from 77 to 636 ng per milliliter.The potency of the synthetic cannabinoid identified in these analyses is consistent with strong depressant effects that account for the "zombielike" behavior reported in this mass intoxication. AMB-FUBINACA is an example of the emerging class of "ultrapotent" synthetic cannabinoids and poses a public health concern. Collaboration among clinical laboratory staff, health professionals, and law enforcement agencies facilitated the timely identification of the compound and allowed health authorities to take appropriate action.
αvβ3 Integrin-targeted reduction-sensitive micellar mertansine prodrug: Superb drug loading, enhanced stability, and effective inhibition of melanoma growth in vivo
Authors: Ping Zhong, Hao Meng, Jie Qiu, Jian Zhang, Huanli Sun, Ru Cheng, Zhiyuan Zhong
Journal: Journal of Controlled Release (2016)
Randomized phase III study on the effect of early intensification of rituximab in combination with 2-weekly CHOP chemotherapy followed by rituximab or no maintenance in patients with diffuse large B-cell lymphoma: Results from a HOVON-Nordic Lymphoma Group study.
Authors: Pieternella J. Lugtenburg, Peter de Nully Brown, Bronno van der Holt, Francesco D'Amore, Harry R Koene, Henriette W Berenschot, Rob Fijnheer, Olaf Loosveld, Lara H Bohmer, Hans Pruijt, Gregor Verhoef, Mels Hoogendoorn, Romko de Kan, Gustaaf Willem Van Imhoff, Christel van Hooije, King H Lam, Bart de Keizer, Daphne de Jong, Otto S. Hoekstra, Josee M Zijlstra
Journal: Journal of Clinical Oncology (2016)

7504 Background: Rituximab (R)-CHOP is standard treatment for patients with diffuse large B-cell lymphoma (DLBCL). The optimal R dose and schedule is not known. We compared R-CHOP-14 with the same regimen combined with 4 extra R administrations during the first 4 cycles. Patients in complete remission after induction treatment were randomized between observation and R maintenance. Here we report the efficacy results of the first randomization. Methods: Patients with DLBCL, stage II-IV, were randomized between R-CHOP-14 and an experimental arm with R-CHOP-14 combined with extra R 375 mg/m2 IV on day 8 of the first 4 cycles. Response was evaluated using PET-CT scans (Lugano criteria 2014). A Deauville score of ≤ 3 was considered as a complete response. The primary endpoint was metabolic complete remission rate after induction treatment. (www.trialregister.nlNTR1014). Results: 575 patients were randomized (standard arm 286 patients, experimental arm 289 patients). Median age was 65 years (range, 18-80), 50% of patients were 66 years or older and 52% were male. The majority of patients (57%) had a high-intermediate or high aa-IPI score. Baseline patient and disease characteristics were well balanced between treatment arms. No significant difference in CR rate was observed between the two treatment arms, standard arm 84% CR and experimental arm 82% CR (odds ratio = 0.83, 95% CI 0.54-1.28, p=0.40). The observed CR rates in patients ≤ or > 65 years were identical. With a median follow-up of 49 months (maximum 90 months), 3- and 5- year progression free survival (PFS) were 74% and 68% in the standard arm and 71% and 61% in the experimental arm (hazard ratio = 1.23, 95% CI 0.92-1.63, p=0.16). No significant improvement in PFS was noted in subgroups by age (≤ or > 65 years) or gender. Toxicity data will be available at ASCO. Conclusions: In patients with DLBCL treated with R-CHOP-14 rituximab intensification early during treatment did not improve the CR rate or the 3-year PFS. No clinical subgroup benefited from rituximab intensification. Clinical trial information: NTR1014.
Abstract 4552: Apatorsen enhances 5-FU sensitivity in colon cancer cell SW480
Authors: Takehiro Shimada, Masashi Tsuruta, Shingo Akimoto, Kaoru Koishikawa, Koji Okabayashi, Hirotoshi Hasegawa, Yuko Kitagawa
Journal: Cancer Research (2015)

Abstract [Background] Heat Shock Protein (HSP) 27 is a chaperone protein of small molecular weight, which protects cells in response to various stresses. Previously we elucidated that HSP27 was a key molecule in determining 5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC). Thus, apatorsen, an antisense oligonucleotide that suppresses HSP27 levels intracellularly, might overcome 5-FU resistance in CRC. In this basic research, we evaluated the feasibility of adding apatorsen with 5-FU against CRC. [Methods] Human CRC cell line SW480 was treated with apatorsen (1nM, 10nM, 100nM) for 48 hours continuously. HSP27 protein level was determined by immunoblot and densitometry analysis. Next, the cells were exposed by various concentrations of 5-FU for 48 hours following treatment with apatorsen. The in vitro growth inhibition rates (IR) were assessed by MTT assay and we evaluated the change of 5-FU resistance, which was estimated as the drug concentration inducing 50% IR (IC50). [Results] Apatorsen (0, 1, 10, 100nM) successfully suppressed HSP27 protein levels (100, 86.6, 61.0, 50.5%) in a dose-dependent manner. In cell viability assays, apatorsen changed the IC50 of 26.65μg/ml in control into 15.55 (58.3%), 11.28 (42.3%), and 9.18 (34.4%) respectively. [Summaries] Apatorsen significantly enhanced 5-FU sensitivity in the CRC cell line SW480 by suppressing HSP27 levels. HSP27 may serve as a reliable target in enhancing 5-FU chemotherapy for CRC. Therefore, apatorsen is a promising treatment requiring further investigation. Citation Format: Takehiro Shimada, Masashi Tsuruta, Shingo Akimoto, Kaoru Koishikawa, Koji Okabayashi, Hirotoshi Hasegawa, Yuko Kitagawa. Apatorsen enhances 5-FU sensitivity in colon cancer cell SW480. [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 4552. doi:10.1158/1538-7445.AM2015-4552
Abstract 1069: DNA methylation in circulating free DNA as a new biomarker for pancreatic cancer
Authors: Keiko Shinjo, Fumiharu Ohka, Keisuke Katsushima, Akira Hatanaka, Norihisa Ichimura, Zhao Juan, Kenji Yamao, Yutaka Kondo
Journal: Cancer Research (2015)

Abstract Despite the clinical advancement, pancreatic cancer remains one of the most deadly cancers. Pancreatic cancers are often difficult to diagnose and there is no reliable screening biomarker for early detection of this cancer. Epigenetic alterations have emerged as a common hallmark of many types of human cancers as well as pancreatic cancers. Studies have shown that epigenetic dysregulation is associated with multiple steps during carcinogenesis. Therefore, detection of aberrant DNA methylation from blood samples may be a promising diagnostic tool for pancreatic cancers. First, we analyzed KRAS mutation status of 100 samples obtained by Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), which is a safe and accurate technique to perform the pancreatic tissue biopsy, and found that more than 80% of the cells in the samples harbors KRAS mutation indicating high amount of cancer cells in the specimens. Next, we performed genome-wide DNA methylation analysis of 38 EUS-FNA specimens using Illumina Infinium HumanMethylation450 BeadChip. We further analyzed the deposited DNA methylation profiles of other tumor types in the public databases, such as TCGA, and identified 8 marker genes with high frequency and specificity of DNA methylation in pancreatic cancers. We validated the DNA methylation status of these genes by bisulfite pyrosequencing and quantitative methylation specific PCR. These markers were frequently methylated in EUS-FNA samples (95% of samples are methylation positive in at least one marker gene). Now we are analyzing the DNA methylation status in pancreatic cancers and corresponding blood samples in order to identify the most effective set of markers for diagnose pancreatic cancers. Our results suggest that analysis of DNA methylation in the circulating free DNA might be a safe and potent tool for evaluating and staging pancreatic cancers. Citation Format: Keiko Shinjo, Fumiharu Ohka, Keisuke Katsushima, Akira Hatanaka, Norihisa Ichimura, Zhao Juan, Kenji Yamao, Yutaka Kondo. DNA methylation in circulating free DNA as a new biomarker for pancreatic 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 1069. doi:10.1158/1538-7445.AM2015-1069
The “Elderly Project” by the Fondazione Italiana Linfomi (FIL): a prospective multidimensional assessment of elderly patients with diffuse large B-cell lymphoma
Authors: F. Merli, A. Tucci, F. Angrilli, F. Cavallo, G. Cabras, A. Fabbri, C. Mammi, A. Chiappella, D. Gussetti, V. Zilioli, A. Arcari, M. Tani, M. Balzarotti, A. Fedina, L. Marcheselli, M. Spina
Journal: Annals of Oncology (2015)
Abstract 5221: Mammary tumor aggressiveness is exacerbated by endothelial HoxA5 expression
Authors: Josette Northcott, Hans Layman, Nancy Boudreau
Journal: Cancer Research (2015)

Abstract Despite evidence showing a positive correlation between angiogenesis and solid tumor progression, anti-angiogenic therapies have yielded limited, and often, tissue-specific responses. Whereas colorectal and renal cancers show improved responses, anti-angiogenic therapy has not proven effective at clinically managing breast tumor progression or prolonging patient survival. Moreover, anti-angiogenic treatment may promote the emergence of tumors with increased aggression and resistance to standard chemotherapies. Our laboratory has shown that sustained endothelial expression of the anti-angiogenic HoxA5 homeodomain transcription factor reduces angiogenesis and delays progression of squamous cell carcinoma in the KRT14-HPV16 mouse model of skin cancer. We subsequently investigated, whether constitutive endothelial expression of HoxA5 could also impede mammary tumor growth and metastasis. Surprisingly, we observed that endothelial HoxA5 expression increased both primary tumor growth and lung metastasis in the MMTV-PyMT mouse model of breast cancer. Primary tumors from PyMT/HoxA5+ mice exhibited an increased number of large vessels but were significantly more hypoxic, as compared to tumors from control mice. Orthotopic injection of isolated mammary tumor cells from PyMT/HoxA5+ mice into wild-type animals also resulted in larger tumors, as compared to tumor cells isolated from PyMT mice of the same age. Interestingly, although metastasis was increased in the PyMT/HoxA5+ transgenic mice, we did not detect differences in circulating tumor cells, suggesting that tumor cells from PyMT/HoxA5+ mice have increased tumor initiating potential. Thus, while anti-angiogenic HoxA5 expression in the endothelium delays skin tumor progression, more aggressive tumors arise in the mammary gland. We are currently evaluating the response of breast tumors in PyMT/HoxA5+ mice to standard cancer chemotherapeutics, as well as evaluating novel approaches to potentially target more aggressive tumors emerging from chronic hypoxic conditions. Citation Format: Josette Northcott, Hans Layman, Nancy Boudreau. Mammary tumor aggressiveness is exacerbated by endothelial HoxA5 expression. [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 5221. doi:10.1158/1538-7445.AM2015-5221