tbuckley/cabot-search huggingface dataset:
MNGO-13INCREASED RISK OF PERMANENT NEUROLOGIC DEFICITS FOLLOWING MENINGIOMA RESECTION IN THE ELDERLY
Authors: Arash Nayeri, Philip Brinson, Marc Prablek, Lola Chambless
Journal: Neuro-Oncology (2015)

INTRODUCTION: Recent studies have inconsistently identified increased age as a predictor of higher perioperative morbidity and mortality in patients surgically treated for a meningioma. We sought to quantify the occurrence of permanent neurologic deficits after operative treatment of meningiomas and to analyze the association of such deficits with patient age. METHODS: We conducted a retrospective cohort study on 223 patients who underwent primary meningioma resection at our institution between 2001-2013. All postoperative entries in the medical record were reviewed for each patient and all new neurological deficits were recorded. Postoperative deficits were defined as permanent if clinically evident at one-year postoperatively. Temporary neurological deficits, non-neurological complications, and pre-existing neurological deficits were not included in our analysis. Patients were stratified into two groups, young and elderly, based on age at time of operation of less than 60 years and 60 years and above respectively. Pearson's correlation and Fisher's exact test were utilized to examine the association of age with the rate of postoperative neurologic deficits. RESULTS: Average age at time of operation was 55.0 ± 14.5 years. 137 and 86 patients were included in the young and elderly subgroups respectively. Overall, 27 (12%) patients suffered from permanent neurological deficits postoperatively. There was a significant positive correlation between increased patient age and risk of permanent neurologic deficits (r = 0.17, p = 0.012). The risk of a new neurologic deficit was 7.3% in the young subgroup of patients versus 20.0% in the elderly subgroup. The increased risk of permanent neurologic deficits postoperatively was significantly higher in the elderly group (relative risk = 2.7, p = 0.010). CONCLUSIONS: Increased age is associated with a higher risk of permanent postoperative neurologic deficits after meningioma resection. Elderly patients are at increased risk of postoperative deterioration and this should be carefully considered before proposing resection of a meningioma in this patient subgroup.
Quality of life measures in a phase I trial of noni
Authors: B. F. Issell, C. Gotay, I. Pagano, A. Franke
Journal: Journal of Clinical Oncology (2005)

8217 Background: Noni fruit extract, a popular dietary supplement used by cancer patients (pts) is derived from the traditional healing practices of Pacific Islanders and Asians. Its use is supported by preclinical evidence of anti-cancer activity and anecdotal evidence of helping patients feel and function better Methods: We conducted a phase I dose finding study with capsules containing 500mg ripe noni fruit extract in pts with advanced cancer. First dose level was 4 capsules (2 grams) daily, the highest recommended dosing of the commercial product. Subsequent dose levels were increased by 2 grams daily up to a maximum dose level of 10 grams (20 capsules) daily. A minimum of 5 pts at each dose level were observed for 28 days before new pts were entered at the next higher dose level. In addition to conventional toxicity and response measures, we measured quality of life and symptom status with QLQ C-30, Brief Fatigue Inventory (BFI), and CES-D, depression scale at baseline and every 4 weeks. Results: Pt. Characteristics: 29 pts were assessed for toxicity, quality of life/symptom status and pharmacokinetics. The distribution of performance status, extent of disease and prior treatment did not show any significant variation across the 5 dose levels. Toxicity: There were no adverse events (CTCAE criteria) attributable to noni. Quality of Life: Using a multilevel regression analysis of noni dose (2, 4, 6, 8, 10 grams) and week of study, there was a statistically significant [t(35)=-2.84, p=.006] decrease in pain interference with activities as measured by question 19 on the EORTC QLQ-C30 scale. Also, although not reaching statistical significance, consistent dose response effects were found for global health status (questions 29 & 30), physical functioning (questions 1–5) and fatigue (questions 10, 12, 18). There was no dose response relationship found for the BFI and CES-D measures. Tumor Response: No measured tumor regressions using RESIST criteria were noted. Conclusions: Quality of life measures may be useful for selecting dosing (maximum quality of life sustaining dose) for phase II efficacy trials of non toxic dietary supplements. No significant financial relationships to disclose.
Cellular Composition of Allogeneic and Autologous PBPC Grafts and Patient Engraftment.
Authors: Isabel L. Barbosa, Patricia A. Benevides, Claudia C. Sousa, Sergio B. Machado Lopes, Ana R. Tavares, Fernando Campilho, Antonio Campos, Carlos P. Vaz, Susana R. Sousa, Pedro Pimentel, Alzira Carvalhais
Journal: Blood (2005)
506. In Vivo Transduction of T Cells: The Future of Immunotherapy?
Authors: Inan Edes, Irene Schneider, Qi Zhou, Veit R. Buchholz, Christoph Kemna, Dirk H. Busch, Christian J. Buchholz, Wolfgang Uckert
Journal: Molecular Therapy (2016)

Genetically engineered T cells carrying antigen-specific chimeric antigen receptor (CAR) or T cell receptor (TCR) genes are highly effective in immunotherapy of leukemia and other solid cancers. At present, the modification of T cells requires an ex vivo gene transfer using viral or non-viral vector systems and the subsequent expansion of the engineered T cells to yield therapeutic numbers. However, extended periods of cell culture can lead to an alteration of the T cell phenotype due to antibody and cytokine-driven activation and may negatively influence T cell functionality. To counteract these drawbacks, efforts were undertaken to engineer naive or memory T cells in vitro. However, these T cell subsets are already naturally available in vivo and could be used as a target for genetic engineering if it would be feasible to establish protocols that allow in vivo transduction of a sufficient number of these T cells to achieve tumor rejection or to control infectious diseases. We developed targetable, injectable gamma-retrovirus vectors capable of transducing specifically CD8+ and CD4+ T cells in vivo. We employed the measles virus (MV) envelope glycoproteins hemagglutinin (H) and fusion to generate retroviral vectors (RV), specific for either murine CD8α or murine CD4. To do so, we added single-chain antibody fragment (scFv) coding sequences derived from CD8α or CD4 hybridomas to the carboxy-terminus of the H-protein encoding sequence. We generated CD8α (MVm8) and CD4 (MVm4) targeted RV carrying fluorescence marker or TCR genes. When applying both targeted RV simultaneously in in vitro transduction experiments MVm8 and MVm4 exclusively transduced CD8+ or CD4+, respectively, both in T cell lines and primary mouse T cells. By intravenous injection of MVm8 RV, encoding an ovalbumin- (OVA) reactive TCR (OT-I TCR) linked to luciferase, into Rag2−/− mice previously repopulated with CD8 T cells, we demonstrate that MVm8 RV mediates selective in vivo transduction of CD8+ T cells. The in vivo TCR engineered T cells showed antigen-specific functionality by homing towards sites of antigenic stimulation and persisted long-term, suggesting the formation of memory T cells. Upon in vivo T cell engineering, mice were challenged by OVA-expressing Listeria monocytogenes in an infection model. Notably, protective immunity could be demonstrated and was dependent on the number of in vivo OT-I TCR engineered T cells. In sum, we show that: (i) gamma-retroviruses in combination with a modified MV envelope can be employed as platform for the development of targeting vectors, (ii) these vectors are able to transduce subsets of T cells in vivo as shown for murine CD8+ and CD4+ T cells, and (iii) in vivo engineered T cells are functional and able to provide protective immunity. Currently, we are investigating the potential of in vivo engineered T cells to reject experimentally induced cancer in a mouse model.
Abstract 2241: MDM2 silencing promotes tumor-initiating cells in osteosarcoma and breast cancer
Authors: David J. Olivos, Lindsey D. Mayo
Journal: Cancer Research (2015)

Abstract Chemotherapy has made remarkable strides in the past century to alleviate tumor burden across most cancer types, yet it remains ineffective at achieving complete tumor remission. To improve chemotherapy efficacy and patient survival, novel drugs will require a greater mechanistic understanding of tumor initiating cell (TIC) regulatory pathways. Intratumoral heterogeneity is a major obstacle for conventional targeted treatment modalities, which select for aggressive phenotypes with acquired drug resistance and TIC enrichment. Here we focus on elucidating the role of Mdm2 in mediating TIC levels in osteosarcoma (MG-63, Saos2) and breast cancer (MDA 231, MDA 468, and BT474) cell lines. We demonstrate Mdm2 silencing by ShRNA results in increased levels of Nanog, Oct4a, and Sox2, and diminished expression of ERα and ERβ by western blot. We observed an increase in the immunophenotypic expression of CD133 in ShMdm2 osteosarcoma and breast cancer cell lines by flow cytometry. Our data provides the first evidence that loss of Mdm2 results in increased TIC population. Further analysis will examine the affects of TIC using small molecular inhibitors to Mdm2. This insight will contribute to the molecular foundations defining the role of Mdm2 in TIC and will determine if targeting Mdm2 therapeutically is a prognostic indicator for recurrence. Citation Format: David J. Olivos, Lindsey D. Mayo. MDM2 silencing promotes tumor-initiating cells in osteosarcoma and 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 2241. doi:10.1158/1538-7445.AM2015-2241
190. Adaptive CAR T Cell Design
Authors: Norihiro Watanabe, Sujita Sukumaran, Pradip Bajgain, Salma Ansari, Helen E. Heslop, Cliona M. Rooney, Malcolm K. Brenner, Ann M. Leen, Juan F. Vera
Journal: Molecular Therapy (2016)

Chimeric antigen receptor (CAR) T cell therapy has recently emerged as an attractive approach for the treatment of CD19-expressing hematological malignancies. However extending the success of this strategy to other targets has proven to be more complicated that simply replacing the scFv. To address this issue we have implemented a form of adaptive CAR design whereby a series of sequential modifications are made to a single domain and subsequently tested in vitro and in vivo to assess activity. We illustrate the utility of such a strategy using our published CAR-PSCA (Anurathapan U. et al, Mol Ther. 2014) as a template (CAR-PSCA v1.0) with subsequent iterations coded as versions 2.0, 3.0, 4.0 and 5.0. We now demonstrate how modifications made to a single CAR structural domain can result in enhanced (i) T cell migration, (ii) antigen recognition, and (iii) cell phenotype, ultimately producing superior anti-tumor effects. First, with CAR v2.0 and v3.0 we were able to improve T cell migration, which was evident in NSG mice engrafted s.c. with Capan-1 and treated i.v. with FFluc+ T cells. Ten days post CAR administration we saw a 2 log increase in the T cell signal at the tumor site (4.5±2.3×105 p/s vs 4.8±0.5×107 p/s vs 4.0±1.1×107 p/s, CAR v1.0, v2.0 and v3.0 respectively). Subsequently to enhance in vivo T cell persistence, we next generated CAR v4.0, which resulted in a less differentiated T cell phenotype (Tnaive: 1.8±0.6% to 19.2±4.0%, TCM: 10.4±1.4% to 14.1±3.0%, TEM: 83.5±1.2% to 53.7±6.9% and TEMRA: 4.3±0.9% to 12.9±1.7% - CAR v3.0 and CAR v4.0, respectively). When administered to Capan-1-engrafted NSG mice CAR v4.0 T cells exhibited enhanced in vivo longevity as measured using bioluminescence imaging (7.3±4.6×107 p/s CAR v3.0 vs 2.8±1.7×108 p/s CAR v4.0 T cells - day 35 post-administration). Finally, antigen recognition of CAR-PSCA was further improved in v5.0 where a final modification to the same domain produced superior anti-tumor effects against a PSCA-dim target tumor cell line (DU145) in a 6hr 51Cr-release assay (20.7±5.8% vs 48.4±5.2%, CAR v4.0 vs CAR v5.0, 40:1 E:T). Overall, therefore, implementation of this adaptive design produced a CART cell product with enhanced in vivo anti-tumor activity. This was clearly illustrated when we compared the tumor volume of NSG mice treated with CAR v1.0 or CAR v5.0 T cells (1309±143 mm3 vs 510±53 mm3 on Day 66). Specific details of the modifications conducted in this adaptive CAR design will be presented.
Human Skin 3D Bioprinting Using Scaffold‐Free Approach
Authors: Léa J. Pourchet, Amélie Thepot, Marion Albouy, Edwin J. Courtial, Aurélie Boher, Loïc J. Blum, Christophe A. Marquette
Journal: Advanced Healthcare Materials (2016)

Organ in vitro synthesis is one of the last bottlenecks between tissue engineering and transplantation of synthetic organs. Bioprinting has proven its capacity to produce 3D objects composed of living cells but highly organized tissues such as full thickness skin (dermis + epidermis) are rarely attained. The focus of the present study is to demonstrate the capability of a newly developed ink formulation and the use of an open source printer, for the production of a really complete skin model. Proofs are given through immunostaining and electronic microscopy that the bioprinted skin presents all characteristics of human skin, both at the molecular and macromolecular level. Finally, the printability of large skin objects is demonstrated with the printing of an adult-size ear.
526. Innovative Dual CAR-T Cells to Target B-Cell Leukemia and Opportunistic Fungal Agents
Authors: Pappanaicken Kumaresan, Albert Nathaniel, Harjeet Singh, Janani Krishnamoorthi, Simon Olivares, Sourindra M. Maiti, M. Helen Huls, Tiejuan Mi, Richard E. Champlin, Dimitrios P. Kontoyiannis, Laurence J.N. Cooper
Journal: Molecular Therapy (2015)

Clinical-grade T cells genetically modified to express chimeric antigen receptors (CARs) are used to redirect their specificity to target tumor-associated antigens in vivo. CD19-specific CAR+ T cells have shown promising results in clinical settings against B-cell leukemias and lymphomas. These data provide the foundation for implementing adoptive immunotherapy for other disease states. Opportunistic invasive fungal infections (IFI) cause significant morbidity and mortality in immuno-compromised patients, including those being treated for CD19+ malignancies. Aspergillus and Candida species are the major pathogens account for causing mycosis in high risk patients. In patients with hematologic cancer, the efficacy of current antifungal therapy is limited due to fungal resistance, toxicity and importantly poor immunity of the host against fungi. Adoptive T cell therapy is a viable option to control fungal diseases. We have developed novel gene therapy approach to render genetically modified T cells able to target both fungal infections such as Aspergillus and Candida and B-cell malignancies. To target these fungal pathogens, we adapted the pattern-recognition receptor Dectin-1 to activate T cells via intracellular chimeric CD28 and CD3-ζ (designated D-CAR) upon binding to carbohydrate present in the cell wall of Aspergillus germlings. D-CAR+ T cells exhibited the specificity for β-1,3-glucan and damaged hyphae by secreting perforin and thus inhibited hyphal growth of Aspergillus. To target B-cell malignancies, we co-expressed D-CAR with a CD19-specific CAR, which is currently in use (http://www.nature.com/nrclinonc/journal/v10/n5/fig_tab/nrclinonc.2013.46_T3.html). This was achieved by synchronous electro-transfer of DNA plasmids from the Sleeping Beauty system coding for D-CAR and CD 19-specific CAR. The resultant genetically modified T cells can kill both Candida and Aspergillus as well as CD19+ malignant B cells. Thus, we report a clinically-appealing strategy to develop dual specific CAR+ T cells to control both B-cell malignancies and two of the most medically important fungi affecting in this patient population.
Pralatrexate Is Effective In Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL) with Prior Ifosfamide, Carboplatin, and Etoposide (ICE)-Based Regimens
Authors: Andre Goy, Barbara Pro, Kerry Joanne Savage, Nancy L. Bartlett, Mary Jo Lechowicz, Eric D Jacobsen, Faith Young, Michael Crump, Hossein Borghaei, Brian Link, Steven M. Fruchtman, Owen A. O'Connor
Journal: Blood (2010)
633. A Reproducible and Reliable Non-Invasive Approach to Assess the Efficacy of Gene Therapy in mdx Mice with Relevance to Clinical Trials
Authors: Yafeng Song, Mihail Petrov, Shira Rosenblum, Leon Morales, Hansell H. Stedman
Journal: Molecular Therapy (2016)

The mdx mouse carries a naturally occurring nonsense mutation in the dystrophin gene and has become a critical animal model for research on Duchenne Muscular Dystrophy (DMD). Despite the extensive published studies on muscle structure and function in this model, we still lack appropriate protocols for evaluation of functional rescue in mdx mice using non-invasive tests relevant to the clinically relevant symptoms of DMD. Here we present for the first time results of a complex approach for the evaluation of locomotor and behavioral patterns of mdx mice during running wheel performance in a modified open field monitoring system. These results are examined in the same mice with force grip measurements and serum enzyme biomarker creatine kinase (CK) measurement. The comparison between juvenile congenic wild type (C57Bl10) and mdx mice indicates similarity in parameters such as rest time and the number of times entering and initiating use of the running wheel per day, but highly significant differences with regard to running wheel-associated locomotor activity characteristics including velocity, time, distance per run, and total distance per day. This suggests that exploratory behavior at low work rate is unaffected by dystrophin deficiency, but that the animals respond to as yet uncharacterized sensory inputs that limit their running speed and duration without preventing the desire to re-initiate after rest. This may be viewed as analogous to the early loss of function and metabolic reserve in the juvenile period of DMD disease progression, where boys are described by parents as frustrated at first being unable to keep pace with their friends. As presented in another poster by our group, blinded studies of the response to gene therapy indicates that it is unlikely that this phenotypic difference reflects the mislocalization of neuronal nitric oxide synthase (nNOS) in dystrophin deficiency. In further blinded studies, the open field data correlate with the differences in testing results between the two mouse strains observed in the force grip evaluation and serum levels of CK, offering possible leads for a further mechanistic dissection. These results demonstrate strong evidence in support of the running wheel open field system as a reliable and reproducible approach to assess the therapeutic efficacy in the mouse model of DMD. This approach also provides a platform for dissecting the physiological roles of dystrophin in supporting precisely measurable volitional activities in unrestricted animals, thereby offering potential improvements in the predictive power of preclinical studies of therapeutic efficacy to inform clinical trials.
595. miR-199 Inhibits Tumor Growth and Enhance Chemosensitivity in Osteosarcoma
Authors: song luo, Hua Jin, Meng Xu, Cheng-Xiong Xu
Journal: Molecular Therapy (2015)

Dysregulation of miRNAs is involved in osteosarcoma (OS). Here, we demonstrate that miR-199 is decreased in specimens of OS patients with a poor chemoresponse compared to those with a good chemoresponse. In addition, our clinical data show that decreased miR-199 was associated with poor survival in OS patients. Overexpression of miR-199 inhibited cell growth and chemoresistance. In contrast, inhibition ofmiR-199 or overexpression of target genes stimulated OS cell growth and chemoresistance both in vitro and in vivo. Taken together, these findings suggest that miR-199 is a tumor suppressor miRNA and induction of miR-199 is a potential strategy to inhibit OS progression.
Clinical and Endoscopic Presentation of Primary Gastric Lymphoma: An Italian Multicenter Study.
Authors: Caterina Patti, A. Zullo, L. Tedeschi, F. Di Raimondo, C. Hassan, U. Recine, M. Bibas, A. Miedico, A. Romanelli, M. Vinci, A. Costa, G. Restivo, A. Mistretta, L. Montalbano, C. Linea, C. Marrone, L. Caruso, A. Chiarenza, G. Bonanno, G. Lizzani, F. Stella, S. Mirto, S. Morini, M. Cottone, Alessandro Andriani
Journal: Blood (2005)
Abstract 3103: Cyclin E amplification predicts sensitivity of primary Uterine Serous Carcinoma (USC) cell lines to the cdk2 inhibitor CYC065
Authors: Emiliano Cocco, Stefania Bellone, Salvatore Lopez, Elena Bonazzoli, Federica Predolini, Jonathan D. Black, Alessandro D. Santin
Journal: Cancer Research (2015)

Abstract We evaluated the in vitro effectiveness of the cdk2 inhibitor CYC065 on multiple primary chemotherapy-resistant USC cell lines with or without CCNE1 amplification. CCNE1-amplified primary cell lines were significantly more sensitive than wild type USC cell lines to CYC065 in vitro (i.e., IC50: mean±STDV = 61.75±13.22 nM and 103.16± 21.9 nM for CCNE1-amplified USC-ARK-2 and USC-ARK-7 cell lines, respectively and 539.2±182.1 nM for the wild type USC-ARK-4 cell line, p = 0.0048). Consistently, low concentrations of CYC065 (i.e., 100 - 300 nM) caused a dose dependent arrest in the G1 phase of the cell cycle specifically in CCNE1-amplified primary USC cell lines. Importantly, CCNE1 knockdown in the USC-ARK-2 cell line resulted in a 9.29-fold increase in the CYC065 IC50 when compared to the MOCK-transfected USC-ARK-2 cell line (p = 0.021). Finally, when primary CCNE1-amplified USC cell lines also harboring ERBB2 amplification (50% of CCNE1-amplified USC cell lines) were incubated in vitro with the combination of CYC065 and Herceptin (a monoclonal antibody targeting the product of the ERBB2 gene, HER2/neu), an increased inhibitory effect was reported in the combination treatment when compared to Herceptin or CYC065 used as single agent (i.e.,% viable cells: mean±STDV = 71.4±0.85, 65.4±14.2, 42.2±2.1 for the Herceptin, the CYC065 and the combination treatment on USC-ARK-2, respectively; p = 0.014). Together these findings identify CYC065 as a promising drug to be considered alone or in combination in the treatment of patients harboring CCNE1-amplified USC. Citation Format: Emiliano Cocco, Stefania Bellone, Salvatore Lopez, Elena Bonazzoli, Federica Predolini, Jonathan D. Black, Alessandro D. Santin. Cyclin E amplification predicts sensitivity of primary Uterine Serous Carcinoma (USC) cell lines to the cdk2 inhibitor CYC065. [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 3103. doi:10.1158/1538-7445.AM2015-3103
Preliminary Report of Risk-Based Approach in Korean Patients with Newly Diagnosed Multiple Myeloma.
Authors: Soo-Mee Bang, Jae Hoon Lee, Sung-Soo Yoon, Seonyang Park, Je-Jung Lee, Hyeoung Joon Kim, Doeg Yeon Jo, Yeon Hee Park, Hwi-Joong Yoon, Young-Jin Yuh, Myung-Ju Ahn, Seock Ah Im, Moon Hee Lee, Dong Soon Lee
Journal: Blood (2004)