tbuckley/cabot-search huggingface dataset:
669. rAAV-Based and Intraprostatically Delivered miR-34a Therapeutics for Efficient Inhibition of Prostate Cancer Progression
Authors: Jianzhong Ai, Yi Lu, Jia Li, Qin Su, Qiang Wei, Hong Li, Guangping Gao
Journal: Molecular Therapy (2016)

Prostate cancer (PCa) is the second most common diagnosed cancer and the fifth cause of cancer-related mortality for males worldwide. At present, there is no effective treatment for PCa. Towards further understanding molecular mechanism and developing therapeutics for PCa, we investigated the role of miR34a in PCa progression. Previous studies have reported that miR-34a was significantly downregulated in PCa cells; therefore, modulation of miR34a expression might be a promising therapeutic approach for PCa treatment. To this end, we first verified the downregulation of miR34a in prostate tumor from transgenic adenocarcinoma mouse prostate (TRAMP) model. We found that overexpression of miR-34a could significantly inhibit the cell cycle of PC3 cells (a human PCa cell line) by prolonging G1 and shortening S phases through targeting cyclin D1 (CCND1). To investigate if in vivo gene delivery of pri-miR34a to the prostates of TRAMP mice can inhibit PCa progression, we opted to screen 12 serotypes of rAAVs, an efficient and safe in vivo gene delivery platform with serotype dependent tissue tropisms for efficient prostate in vivo and PCa cell in vitro transduction. Among several leading candidate vectors (i.e. AAV6.2, AAV7 and AAV9) identified, we first tested the concept of intraprostatic injection of rAAV9 pri -miR34a (4×1011 GCs/prostate) to 8-week old TRAMP mice for inhibition of PCa progression. We observed that the treatment lowered body weights significantly (p < 0.05) as compared to the control group starting from 24 weeks after injection, likely resulted from the higher tumor burden in the control group. rAAV9.pri -miR34a treatment also significantly extended the lifespan of TRAMP mice (p < 0.05). Moreover, we confirmed that the proliferation and neoplasia in the treated prostates were significantly diminished when compared to those in the control group. Currently, the experiments are under the way to elucidate the molecular mechanism of overexpressed miR34a to slow down PCa progression. Taken together, our results demonstrated, for the first time, the potentials of rAAV-mediated efficient modulation of miRNA expression in the prostate for inhibiting PCa progression and studying molecular mechanisms in PCa development.
Comparison between NAC-S and CRT in overall survival for patients with esophageal squamous cell carcinoma (JCOG1406-A)
Authors: Motoo Nomura, Ken Kato, Junki Mizusawa, Kozo Kataoka, Nobutoshi Ando, Kei Muro, Atsushi Ohtsu, Hiroyasu Igaki, Hiroyuki Daiko, Yuko Kitagawa
Journal: Annals of Oncology (2015)
Chemoresistance Can Be Reliably Overcome with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT/ASCT) for Relapsed and Refractory Hodgkin's Lymphoma
Authors: Alina S. Gerrie, Maryse M. Power, Kerry J. Savage, John D. Shepherd, Joseph M. Connors
Journal: Blood (2011)
Rituximab Plus Dose Enhancement and Biweekly Administration of CHOP for Newly-Diagnosed Patients with Diffuse Large-B-Cell Lymphoma.
Authors: Francisco Javier, E. Ríos, M. Almagro, J.M. Durán-Cabral, J.N. Rodríguez, S. Durán-Nieto, J. Bergua, L. Martino, A. Romero, M.V. Martín-Reina, J.L. Gil
Journal: Blood (2005)
710. Surface Adsorptive Loss of rAAV on Materials Used in cGMP Manufacturing
Authors: Monica Jiang, Colleen M. Dupuis, Amy A. Medeiros, Samuel C. Wadsworth, K. Reed Clark, Christopher J. Morrison
Journal: Molecular Therapy (2016)

Continued interest in using rAAV vectors as therapies for a range of indications with varying prevalence often translates to increased manufacturing scales. A significant challenge that is encountered is the use of different manufacturing materials during the transition between early research and development and the clinical manufacturing scale. For example, manufacturing components, ranging from bioprocessing bags and hard plastics to bioprocess tubing and filters can be constructed of different materials and are not often engineered for use with rAAV. In this work we investigate the loss of rAAV to non-specific surface adsorption on various materials of construction. In addition, the effect of different background matrices was also investigated. These data demonstrate that surface adsorptive loss of rAAV can be significant, and that losses can vary significantly even for materials of similar construction. To mitigate adsorptive loss, several surfactants and other components were examined for their ability to reduce surface adsorption of rAAV. A number of these agents were identified as viable options for cGMP manufacturing. These results provide insight for the development of scaleable, more robust and higher yielding manufacturing processes to meet the continued demand for rAAV therapeutics.
Distinct Clinical and Cytogenetic Characteristics and Poor Prognosis in Children with Acute Erythroid Leukemia: A Report from the JPLSG AML-05 Study
Authors: Daisuke Tomizawa, Akio Tawa, Nobutaka Kiyokawa, Akitoshi Kinoshita, Hayato Miyachi, Yuka Yamashita, Keizo Horibe, Shotaro Iwamoto, Takao Deguchi, Norio Shiba, Hiroshi Moritake, Akira Shimada, Daisuke Hasegawa, Takashi Taga, Eiichi Ishii, Souichi Adachi
Journal: Blood (2015)
394. Baseline Data for Patients Participating in the Phase 2a rAAV.sFlt-1 Gene Therapy Trial for Exudative Age-Related Macular Degeneration
Authors: Elizabeth P. Rakoczy, Chooi-May Lai, Aaron L. Magno, Martyn A. French, Thomas W. Chalberg, Steven D. Schwartz, Mark S. Blumenkranz, Ian J. Constable
Journal: Molecular Therapy (2015)

rAAV.sFlt-1 has the potential to provide long-term treatment of retinal neovascular diseases following a single injection by driving expression of sFlt-1, a potent (Kd 10 pM), naturally-occurring VEGF inhibitor. Here we present the baseline data for subjects with exudative age-related macular degeneration (AMD) enrolled in an investigator-sponsored, single center, Phase 2a safety study of rAAV.sFlt-1 gene therapy. Of the 32 randomized subjects, 21 were randomized to the rAAV.sFlt-1 group and 11 to the ranibizumab control group. All subjects were treated with two initial intravitreal injections of ranibizumab and then followed monthly for the need for rescue ranibizumab injections based on pre-specified criteria for evidence of active exudative AMD. Subjects underwent a thorough ophthalmic examination at baseline, and clinical laboratory assessments included blood biochemistry, complete blood count, and T-cell response. Anti-AAV antibodies (both total and neutralizing), AAV capsid protein, and sFlt-1 protein levels were also measured. Baseline demographics were 100% Caucasian, 59% female, and average age 79+7 years. All subjects had active subfoveal choroidal neovascularization secondary to exudative AMD, and the average visual acuity was 59+15 EDTRS letters (Snellen equivalent 20/63). Subjects had received an average of 10 anti-VEGF injections prior to enrolment. Anti-AAV antibody results indicated that 25% of subjects serum contained neutralizing antibody titres 1/100-1/500 while 19% had titres 1/20-1/100. All subjects tested negative for presence of AAV capsid in fluids at baseline. sFlt-1 protein averaged 13.9+5.4 pg/ml in urine, 116+5.9 pg/ml in serum, and 229+12.7 pg/ml in saliva. One patient had IgM deficiency and 6/32 patients had lymphopenia or T cell deficiency and/or CD8 lymphopenia. No other immune defects that might pose a hazard to the use of the rAAV vector were identified. In conclusion, the study subjects had characteristics representative of a population with exudative AMD and are appropriate for enrollment in a safety study for rAAV.sFlt-1.
Crispr/Cas9- Mediated Genome Editing of Human CD34+ Cells Upregulate Fetal Hemoglobin to Clinically Relevant Levels in Single Cell-Derived Erythroid Colonies
Authors: Bibhu Mishra, Song Chou, Michelle I Lin, Elizabeth J Paik, Ying Zhang, Ruibin Liang, Kaleigh Tomkinson, Michael Pettiglio, Andrew Sanginario, Melanie Allen, Thomas Cradick, Matthias John, Tirtha Chakraborty, Chad A Cowan, Rodger Novak, Ante S Lundberg
Journal: Blood (2016)
Abstract 2231: Type II transglutaminase is an epidermal squamous cell carcinoma stem cell survival protein
Authors: Matt Fisher, Wen Xu, Gautam Adhikary, Candace Kerr, Richard Eckert
Journal: Cancer Research (2015)

Abstract Cancer stem cells are thought to be responsible for rapid tumor growth, metastasis and enhanced tumor survival following drug treatment. For this reason, there is a major emphasis on identifying proteins that can be targeted to kill cancer stem cells or control their growth. Our studies suggest that transglutaminase type II (TG2) is such a target in epidermal squamous cell carcinoma. TG2 was originally described as a transamidase that catalyzes formation of ϵ-(γ-glutamyl)lysine bonds. However, subsequent studies reveal that TG2 is a GTP binding protein that plays an important role in cell signaling and survival. In the present study we show that TG2 is a target for anti-stem cell therapy in human squamous cell carcinoma. We identify TG2 as highly elevated in epidermal cancer stem cells (ECS cells) and show that TG2 knockdown or suppression of TG2 function with inhibitors reduces ECS cell survival, spheroid formation, matrigel invasion and migration. The reduction in survival is associated with activation of apoptosis. Mechanistic studies, using TG2 mutants suggest that the GTP-binding activity is required for maintenance of ECS cell growth and survival. These studies suggest that TG2 has an important role in maintaining cancer stem cell survival, invasive and metastatic behavior, and is an important therapeutic target to reduce survival of cancer stem cells in epidermal squamous cell carcinoma. Citation Format: Matt Fisher, Wen Xu, Gautam Adhikary, Candace Kerr, Richard Eckert. Type II transglutaminase is an epidermal squamous cell carcinoma stem cell survival protein. [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 2231. doi:10.1158/1538-7445.AM2015-2231
Abstract 4952: WWOX and LOT1 genes are down-regulated in non-small cell lung cancer (NSCLC)
Authors: Onur Baykara, Seda Ekizoglu Eratak, Kamil Kaynak, Hikmet Koseoglu, Nur Buyru
Journal: Cancer Research (2015)

Abstract Lung cancer is a result of uncontrolled cell growth in lung tissue and is the most common type of cancer leading to death in men and second after breast cancer in women. Even though smoking is the main reason of lung cancer, genetic and environmental factors play an important role in the onset and prognosis of the disease. The WW domain-containing oxidoreductase (WWOX) gene is a putative tumor suppressor gene located on chromosome 16q23.3-24.1 and is composed of 9 exons. Several studies have reported the role of WWOX gene in different types of carcinomas including lung, breast, ovarian, stomach and nasopharyngeal cancer. The 46kDa WWOX protein has two WW (tryptophan) domains which can recognize and bind the proline-rich region (PPXY) of other proteins. Its main function is to inhibit tumor cell growth. WWOX also plays an important role in wnt/beta-catenin signaling pathway. The lost-on-transformation 1 (LOT1/ZAC1/PLAGL1) gene is another putative tumor suppressor gene located on chromosome 6q24-25, a common site known for loss of heterozygosity in many tumors. Deletions of the 6q region are observed in different types of cancers including breast, prostate, small cell lung cancer and mesotheliomas. The LOT1 gene codes for a 55 kDa protein with seven C2H2 type zinc finger motifs located in amino terminal half of the protein. This zinc-finger nuclear transcription factor interacts with other proteins and transcription factors exerting antiproliferative effects in cancer cells. The aim of this study was to investigate the expression levels of the WWOX and LOT1 genes by RT-PCR in tumor tissue samples from 39 patients with non small cell lung cancer (NSCLC). We observed down-regulation of WWOX and LOT1 expression in 82.1% and 48.7% of the patients, respectively. Expression levels of both genes were down-regulated simultaneously in 18 (46.1%) of the patients. When we analyzed the association between gene expression and age, sex, smoking, histology and stage, we found that WWOX expression was decreased in 28 of 31 (90.3%) patients older than 50 years (p = 0.02). Lower expression levels of both genes supports the hypothesis that WWOX and LOT1 act as tumor suppressors in NSCLC and that both genes may have a common effect on tumor progression which warrants further studies to analyze a possible cooperation between the two proteins. Citation Format: Onur Baykara, Seda Ekizoglu Eratak, Kamil Kaynak, Hikmet Koseoglu, Nur Buyru. WWOX and LOT1 genes are down-regulated in non-small cell lung cancer (NSCLC). [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 4952. doi:10.1158/1538-7445.AM2015-4952
Outcome of Adult Patients with Philadelphia Negative B Cell Acute Lymphoblastic Leukemia after Frontline Therapy Failure
Authors: Punit L Jain, Koji Sasaki, Hagop Kantarjian, Farhad Ravandi, Jorge E. Cortes, Guillermo Garcia-Manero, Prithviraj Bose, Naval Daver, Tapan Kadia, Srdan Verstovsek, Marina Konopleva, Nitin Jain, Guillermo Bravo Montalban, Sherry Pierce, Elias Jabbour
Journal: Blood (2015)
Tumor Stiffening, a Key Determinant of Tumor Progression, is Reversed by Nanomaterial-Induced Photothermal Therapy
Authors: Iris Marangon, Amanda A. K. Silva, Thomas Guilbert, Jelena Kolosnjaj-Tabi, Carmen Marchiol, Sharuja Natkhunarajah, Foucault Chamming's, Cécilia Ménard-Moyon, Alberto Bianco, Jean-Luc Gennisson, Gilles Renault, Florence Gazeau
Journal: Theranostics (2016)

Tumor stiffening, stemming from aberrant production and organization of extracellular matrix (ECM), has been considered a predictive marker of tumor malignancy, non-invasively assessed by ultrasound shear wave elastography (SWE). Being more than a passive marker, tumor stiffening restricts the delivery of diagnostic and therapeutic agents to the tumor and per se could modulate cellular mechano-signaling, tissue inflammation and tumor progression. Current strategies to modify the tumor extracellular matrix are based on ECM-targeting chemical agents but also showed deleterious systemic effects. On-demand excitable nanomaterials have shown their ability to perturb the tumor microenvironment in a spatiotemporal-controlled manner and synergistically with chemotherapy. Here, we investigated the evolution of tumor stiffness as well as tumor integrity and progression, under the effect of mild hyperthermia and thermal ablation generated by light-exposed multi-walled carbon nanotubes (MWCNTs) in an epidermoid carcinoma mouse xenograft. SWE was used for real-time mapping of the tumor stiffness, both during the two near infrared irradiation sessions and over the days after the treatment. We observed a transient and reversible stiffening of the tumor tissue during laser irradiation, which was lowered at the second session of mild hyperthermia or photoablation. In contrast, over the days following photothermal treatment, the treated tumors exhibited a significant softening together with volume reduction, whereas non-treated growing tumors showed an increase of tumor rigidity. The organization of the collagen matrix and the distribution of CNTs revealed a spatio-temporal correlation between the presence of nanoheaters and the damages on collagen and cells. This study highlights nanohyperthermia as a promising adjuvant strategy to reverse tumor stiffening and normalize the mechanical tumor environment.
Abstract 2332: Converging molecular effectors of airway lineage specification and metastasis in lung cancer
Authors: Don X. Nguyen
Journal: Cancer Research (2015)

Abstract Lung adenocarcinoma (LUAD) is a deadly and heterogeneous subtype of non-small cell lung cancer. During LUAD progression, the emergence of alternate epithelial lineage fates in primary tumors correlates with poor outcome. The underlying mechanisms and biological consequences of these phenomena are poorly understood. Using an integrated approach, we previously examined the molecular relationship between cell differentiation states, lung cancer subtypes, and clinical outcome, to discover a novel role for several lineage-restricted transcription factors in the pathogenesis of LUAD (1). Specifically, we identified the alveolar specification factor, HOPX, as an inhibitor of metastatic progression. Herein we show that down-regulation of its function in a subset of human tumors correlates with DNA hypermethylation, aberrant tumor differentiation, and relapses. HOPX restricts the metastatic potential of LUAD cells, by modulating converging transcriptional programs of airway epithelial differentiation, malignant invasion, and metabolic adaptation in response to the extracellular microenvironment. Mechanistically, HOPX mediates its functions in part through the regulation of previously uncharacterized long-intergenic long non-coding RNAs with potential roles in lung development. Our findings demonstrate that perturbation of intrinsic cell lineage pathways is a determinant of metastasis in specific lung cancers. The implications of these findings for the origin(s) and treatment of LUAD metastasis will be further discussed. (1) Cheung, W.K.C., Zhao, M., Liu, Z., Stevens, L.E., Cao, P.D., Fang, J.E., Westbrook, T.F., and Nguyen, D.X. (2013). Cancer Cell, 23 (6): 725-738. Citation Format: Don X. Nguyen. Converging molecular effectors of airway lineage specification and metastasis 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 2332. doi:10.1158/1538-7445.AM2015-2332
The Epstein-Barr Virus Lytic Protein BZLF1 As a Candidate Target Antigen for Vaccine Development
Authors: Alex S. Hartlage, Tom Liu, John T. Patton, Sabrina L Garman, Xiaoli Zhang, Habibe Kurt, Gerard Lozanski, Mark E Lustberg, Michael A. Caligiuri, Robert A. Baiocchi
Journal: Blood (2014)
Biochemical disease-free survival and toxicity associated with permanent prostate brachytherapy for men &lt; 60 years of age
Authors: R. J. Patel, D. J. Perry, J. Maier, J. A. Fugazzi, C. Zuniga, A. J. Frazier
Journal: Journal of Clinical Oncology (2004)

4718 Background: To evaluate the biochemical disease-free survival (bDFS) and GI/GU toxicity for men 60 years of age or less who underwent transperineal ultrasound-guided I-125 permanent prostate brachytherapy (PPB). Methods: A total of 71 patients, age ≤ 60 underwent transperineal ultrasound guided PPB using I-125 for clinical stage T1c –T2a, Nx, M0 (2002 AJCC), Gleason score 6, adenocarcinoma of the prostate from November 1995 to December 2002. No patients received external beam radiation therapy. 18 patients (25%) received neoadjuvant hormonal manipulation with a median duration of 5 months (range, 2–10). The median patient age was 57 years (range, 42–60). 77% (55/71) reported erectile function sufficient for vaginal penetration prior to therapy. Patients were followed for PSA response/relapse, and GI/GU morbidity. Median follow-up was 34 months (range, 7 –81). Results: The actuarial bDFS rate was 93.0 % at 5 years. The median post-treatment prostate-specific antigen (PSA) nadir was 0.5 ng/mL. A total of 7% (5/71) developed acute urinary retention, and 3% (2/71) reported rectal bleeding in follow-up. One patient required a TURP as a complication for obstruction, and developed chronic incontinence thereafter. Chronic incontinence was not reported by any other patients. Of the patients potent prior to treatment, 65% (36/55) reported potency without the aid of medications, and 20% (11/55) with the assistance of medication, at the date of last follow-up. The remainder 15% (8/55) reported impotence, or no interest regaining erectile function. Conclusions: Early stage, good prognosis, prostate cancer patients ≤ 60 years of age have a high probability of bDFS following I-125 PPB. Risk of incontinence and rectal injury is low. Although potency is affected by therapy, the overall risk of erectile dysfunction is low (15%) when medical therapy is initiated. No significant financial relationships to disclose.
Hsp and MDR gene upregulation during hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinosis.
Authors: M. Gasser, M. Vetterlein, M. Lazariotou, T. Grimmig, C. T. Germer, J. Pelz, A. M. Waaga-Gasser
Journal: Journal of Clinical Oncology (2011)

e21072 Background: Peritoneal carcinosis (PC) is diagnosed in 10-20% of gastric, colorectal and ovarian cancer. Hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly integrated into multimodal treatment strategies. We analyzed relevant HSPs that confer resistance to physical stresses (elevated temperatures) as well as profiles of the specific MDR gene ABCB5 in patients with PC. Methods: Patients with different adenocarcinomas and additional PC that underwent HIPEC therapy between 10/08 and 01/11 in our department (gastric, colorectal and ovarian cancer, n=14) were included in the study. HIPEC therapy was performed under specific conditions (1hr permanent chemotherapeutical flux via external pump into the abdominal cavity after resection of relevant tumor masses with elevated temperature up to 43°C). Tumors were analyzed before and after HIPEC therapy for heat shock proteins (HsP), multi drug resistence (MDR)1, and additionally for stem cell marker ABCB5 and CD133 expression, characteristic for putative tumor initiating cells in PC using immunohistology, Western Blot, and RT-qPCR. Results: Hsp70/72 gene and protein expression was upregulated in all investigated tumors both before and after HIPEC therapy. Upregulated protein and gene expression was also shown for ABCB5, MDR1 and CD133 pre- and post-HIPEC therapy. Immunohistological protein expression and Western blot results strongly correlated with each other in individualized studied patient tumors. In vitro hyperthermia assays (37-43°C) were additionally performed with the human colon tumor cell line HT-29 confirming the influence of hyperthermia. Conclusions: HIPEC based therapeutic approaches to achieve antiproliferative and apoptosis inducing effects in patients with isolated PC of different adenocarcinomas are influenced by highly conserved HSP mechanisms and multidrug resistance genes. Studying HSP and MDR profiles in the tumors seem to be a valuable tool for prognostic evaluation of individual patients with PC before HIPEC therapy and guiding therapy to specific chemotherapeutic agents.
Understanding County-Level, Cause-Specific Mortality
Authors: Cheryl R. Clark, David R. Williams
Journal: JAMA (2016)

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