tbuckley/cabot-search huggingface dataset:
Abstract LB-242: PTEN regulates the CD20 antigen expression and affects rituximab-based therapy of lymphoma malignancies
Authors: Beata Pyrzynska, Kamil Bojarczuk, Marta Siernicka, Michal Dwojak, Malgorzata Bobrowicz, Nina Miazek, Piotr Zapala, Agnieszka Zagozdzon, Jakub Golab, Magdalena Winiarska
Journal: Cancer Research (2015)

Abstract The therapeutic strategies currently used in B cell malignancies include the treatment with monoclonal antibodies (rituximab and ofatumumab) directed against CD20 antigen. These antibodies specifically eliminate B cells by triggering indirect effector mechanisms of the immune system, like complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), or immunophagocytosis. In many patients, the reduced level of CD20 antigen on the surface of tumor B cells leads to the resistance to anti-CD20 therapy. The aim of this study was to explore the molecular mechanisms governing the regulation of CD20 expression in lymphoma cells as a potential explanation of the resistance to rituximab/ofatumumab therapy. We previously observed that CD20 mRNA expression is significantly affected by the SRC family inhibitors. Here, we report that also PTEN tumor suppressor is a negative regulator of CD20 expression. To uncover the transcriptional mechanisms governing the CD20 expression we employed the construct encoding the promoter region of CD20 cloned upstream of the firefly luciferase gene. Overexpression of wild-type PTEN (but not the phosphatase-deficient mutant) strongly affected the promoter activity and the expression of CD20, leading to decreased binding of rituximab and ofatumumab and increased resistance of tumor cells to complement-dependent cytotoxicity. Using the truncated versions of the CD20 promoter we identified a particular region (-313/-198) as the major region sensitive to PTEN overexpression. We found that the negative regulation of CD20 promoter activity by PTEN was mediated by inhibition of AKT signaling. We observed that the overexpression of constitutively active AKT1 (CA-AKT1) overcame the negative effect of PTEN and sensitized cells to rituximab/ofatumumab treatment. The results of our studies indicate that PTEN status in tumor cells should therefore be considered when analyzing the mechanisms of resistance of B cell malignancies to anti-CD20 therapies. Citation Format: Beata Pyrzynska, Kamil Bojarczuk, Marta Siernicka, Michal Dwojak, Malgorzata Bobrowicz, Nina Miazek, Piotr Zapala, Agnieszka Zagozdzon, Jakub Golab, Magdalena Winiarska. PTEN regulates the CD20 antigen expression and affects rituximab-based therapy of lymphoma malignancies. [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 LB-242. doi:10.1158/1538-7445.AM2015-LB-242
A Phase I Study of TG101348, An Orally Bioavailable JAK2-Selective Inhibitor, in Patients with Myelofibrosis
Authors: Animesh D. Pardanani, Jason Gotlib, Catriona Jamieson, Jorge Cortes, Moshe Talpaz, Richard M. Stone, Michael H Silverman, Jolene Shorr, D. Gary Gilliland, Ayalew Tefferi
Journal: Blood (2008)
Abstract B03: Pancreatic cancer stem cells: can it be restrained?
Authors: Neha Chopra, Sangeeta Choudhury, Saima Wajid, Kriti Jain, Rizwana Mirza
Journal: Cancer Research (2016)

Abstract Over the past decades world-wide, research towards not only understanding the biology, but also attempting to decrease the mortality rate in pancreatic carcinoma has become the forefront in cancers of solid tumor. Recent evidences suggest that pancreatic carcinomas harbour a distinct subpopulation of putative cancer stem cells defined by their self-renewal capacity, differentiation ability, tumorigenicity and ability to drive towards metastasis. Therefore, there is not only a need to identify this population, and also design newer approaches to target these chemo-resistant cell populations, especially in pancreatic cancer which till date shows 5-year survival rate to be below 5%. Our study identified the potential of CD44hiCD24lo MiaPaCa2/PanC1 cells to possess lower capability to generate spheroids whereas CD44hiCD24hi MiaPaCa2/PanC1 showed higher spheroid forming capacity. Spheroids obtained from both cell-lines showed similar metastatic cancer gene expression pattern. However, a distinctive CXCR4 expression levels were observed between CD44hiCD24lo PanC1-spheroids and CD44hiCD24hi PanC1-spheroids. It was also observed that EMT, CXCR4 and Muc1 were highly expressed in MiaPaCa2-spheroids. Hence, suggesting only a sub-population of tumor cells behave as “cancer initiating cells/stem-like cells” which are associated with cell-cell adhesion and cell matrix interaction. In order to determine the role of cancer stem-like cells (spheroids/CSCs) to migrate and invade to metastasize particularly in pancreatic carcinoma, experiments were designed to evaluate their self-renewal capability and epithelial to mesenchymal transition (EMT) and their association with developmental genes. An exponential spheroid formation was observed along with stem cell transcriptional genes (Oct4 and Nanog). Interestingly, MiaPaCa2-spheroids exhibited higher expression levels of Sox-2, MMP-9 and Vimentin in comparison to PanC1-spheroids suggesting that MiaPaCa2-spheroids may be more aggressive or has higher invasive potential. It appears that pancreatic CSCs undergoing EMT probably express higher levels of Sox-9, Ngn-3, Pdx-1 and c-Myc genes which attributes to its embryonic stemness. The results from the study clearly project the role of CSCs in pancreatic carcinoma and thus further studies to delineate the mechanism which might lead to suppression of pancreatic CSCs is crucial. In this direction, a pilot study has been initiated to explore the potential of Mesenchymal Stem Cells to target the pancreatic CSCs. Citation Format: Neha Chopra, Sangeeta Choudhury, Saima Wajid, Kriti Jain, Rizwana Mirza.{Authors}. Pancreatic cancer stem cells: can it be restrained? [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B03.
Risk Factors Associated with VOD with RIC and MAC Hematopoietic Stem Cell Transplant and the Early Estimation of VOD
Authors: Shoichi Nagakura, Tetsuyuki Kiyokawa, Michihiro Hidaka, Takahiro Yano, Kazutaka Sunami, Seiichi Okamura, Naokuni Uike, Motohiro Hamaguchi, Takahiro Matsui, Keizo Horibe, Kensaku Sato, Toshiro Kawakita, Fumio Kawano
Journal: Blood (2008)
115. Tumor Microenvironment-Targeting Hybrid Vector System Utilizing Oncolytic Adenovirus Complexed with pH-Sensitive and Bioreducible Polymer
Authors: Jung-Woo Choi, Dayananda Kasala, Chang Yoon Moon, Soo-Jung Jung, Sung Wan Kim, Chae-Ok Yun
Journal: Molecular Therapy (2016)

Oncolytic adenoviruses (Ads) have shown great promise in cancer gene therapy but their efficacy has been compromised by potent immunological, biochemical, and specific tumor-targeting limitations. To take full advantage of the innate cancer-specific killing potency of oncolytic Ads but also exploit the subtleties of the tumor microenvironment, we have generated a pH-sensitive and bio-reducible polymer (PPCBA)-coated oncolytic Ad. Ad-PPCBA complexes showed higher cellular uptake at pH 6.0 than pH 7.4 in both high and low coxsackie and adenovirus receptor-(CAR)-expressing cells, thereby demonstrating Ad-PPCBA's ability to target the low pH hypoxic tumor microenvironment and overcome CAR dependence for target cell uptake. Endocytic mechanism studies indicated that Ad-PPCBA internalization is mediated by macropinocytosis instead of the CAR-dependent endocytic pathway that internalizes naked Ad. VEGF-specific shRNA-expressing oncolytic Ad complexed with PPCBA (RdB/shVEGF-PPCBA) elicited much more potent suppression of U87 human brain cancer cell VEGF gene expression in vitro, and human breast cancer MCF7 cell/Matrigel plug vascularization in a mouse model, when cancer cells had been previously infected at pH 6.0 versus pH 7.4. Moreover, intratumorally and intravenously injected RdB/shVEGF-PPCBA nanocomplexes elicited significantly higher therapeutic efficacy than naked virus in U87-tumor mouse xenograft models, reducing IL-6, ALT, and AST serum levels. These data demonstrated PPCBA's biocompatibility and capability to shield the Ad surface to prevent innate immune response against Ad after both intratumoral and systemic administration. Taken together, these results demonstrate that smart, tumor-specific, oncolytic Ad-PPCBA complexes can be exploited to treat both primary and metastatic tumors.
Radiofrequency Catheter Ablation for Atrioventricular Node Reentry Tachycardia with Multiple Slow Atrioventricular Node Pathways.
Authors: Muneshige Kaibara, Atsushi Konoe, Shojiro Isomoto, Osmar A. Centurion, Tetsuya Hirata, Osamu Hano, Ryoji Sakamoto, Keiji Iwamoto, Zhigang Liu, Motonobu Hayano, Katsusuke Yano
Journal: Circulation (1995)

Catheter ablation was attempted in 2 patients with atrioventricular node reentry tachycardia which showed fast, intermediate and slow anterograde atrioventricular node pathways. Radiofrequency currents were applied within a restricted area of the tricuspid annulus between the His bundle and the ostium of the coronary sinus where presumed slow pathway potentials were identified. Eliminaition of both the intermediate and the slow pathways, with preservation of anterograde and retrograde fast pathway conduction, was achieved in both patients.
OC-001 Pancreatic stellate cells secrete IGF-1 and express IGF-1 receptors: defining a potential autocrine role in pancreatic fibrosis: Abstract OC-001
Authors: M Patel, J E Collins, R C Benyon, D R Fine
Journal: Gut (2010)

<h3>Introduction</h3> Pancreatic stellate cells (PSC) are exposed to supranormal concentrations of insulin via the islet–acinar portal system. We initially hypothesised that this might influence PSC numbers by effects on proliferation or apoptosis. This effect could be mediated via insulin receptors or via receptors for insulin-like growth factor (IGF-1). In this context, we examined the role of IGF-1 and insulin in the prevention of pancreatic stellate cell apoptosis. Following initial experiments, it became apparent that PSC can synthesise IGF-1, we therefore examined whether IGF-1 might be an autocrine growth factor in cultured stellate cells. The aims were to determine (1) the expression of IGF-1 and insulin receptor by PSC; (2) the secretion of IGF-1 by pancreatic stellate cells; (3) the effects of IGF-1 on PSC proliferation and apoptosis. <h3>Methods</h3> Culture-activated rat PSCs were used between passages 1 and 4 and serum deprived prior to all experiments. PSC proliferation was determined by [<sup>3</sup>H]-thymidine incorporation. Apoptosis was determined with acridine orange counting of apoptotic bodies and caspase 3 activity assays. Western blotting and immunocytochemistry were used to demonstrate the presence of IGF-1 and insulin receptors. Real-time quantitative PCR was used to detect receptor mRNA. A sandwich ELISA was used to determine the secretion of IGF-1, and real-time quantitative PCR use to confirm mRNA expression. <h3>Results</h3> Activated PSC express protein and mRNA for IGF-1 and insulin receptors. IGF-1 secretion is upregulated 2.40-fold following serum withdrawal compared with 16% FCS (see Abstract 001). This upregulation is also seen at the level of mRNA in response to serum withdrawal. Exogenous IGF-1 (100 ng/ml) and insulin (10 000 ng/ml) prevented cycloheximide-induced PSC apoptosis in a concentration-dependent manner, 63% at 24 h, and 71% at 24 h, respectively. There was moderate effect on PSC proliferation following exposure to IGF-1 but not with insulin. <h3>Conclusion</h3> These data suggest that IGF-1 has an autocrine role in reducing PSC apoptosis on serum withdrawal. Inhibiting IGF-1 expression or blocking the IGF-1 receptor may increase susceptibility to apoptosis. This represents a potential therapeutic target for prevention or treatment of pancreatic fibrosis.
Abstract 2647: Anti-tumor activity of sHA8k, a HYAL1 hyaluronidase inhibitor, in bladder cancer cells
Authors: Andre R. Jordan, Juan Chipollini, Luis Lopez, Travis Yates, Vinata Lokeshwar
Journal: Cancer Research (2015)

Abstract INTRODUCTION AND OBJECTIVE: Tumor cell-derived hyaluronidase HYAL1, which degrades hyaluronic acid (HA) into angiogenic fragments, promotes tumor growth and metastasis. HYAL-1 is an independent prognostic marker for predicting metastasis. Small molecular mass sulfated hyaluronic acid (sHA) derivatives (sHA8k) inhibit HYAL1 activity through a mixed inhibition mechanism. Antitumor activity of sHA8k and mechanism of action was evaluated in BCa models.. METHODS: Effect of sHA8k (0-40 ug/ml) on cell proliferation and apoptosis was examined in BCa cells (253J-Lung, HT1376, UMUC-3, T24, RT4) by cell counting and Cell Death ELISA kit. Matrigel invasion and Boyden chamber assays were used to test the effect of sHA8k on invasive activity. Effect of sHA on signaling, apoptosis cascade, HA receptor (CD44, RHAMM), EMT markers (β-catenin, E-cadherin, Snail, Twist) levels, was evaluated by Q-pCR and immunoblotting assays. Angiogenic fragment addition and mAkt transfection were performed to elucidate mechanism of action. Athymic mice bearing 253J-Lung xenografts were treated with sHA (25 and 50 mg/kg) by i.p. injection. RESULTS: sHA8k inhibited proliferation, motility and invasion in BCa cells that expressed HYAL-1. At IC50 for HAase activity inhibition (∼ 20-μg/ml), sHA induced &amp;gt; 3-fold apoptosis and inhibited invasive activity of BCa cells. sHA8k induced caspase-3, -8, -9 activation, up-regulation of Fas, Fas-L, FADD, DR4, DR5 and E-cadherin. sHA8k downregulated CD44, RHAMM, bcl-2, phospho(p)-Akt, pGSK3β, pβcatenin(ser552), snail and Twist expression. Effect of sHA8k were attenuated by angiogenic HA fragments or overexpression of m-Akt and downregulation of CD44 and RHAMM mimicked sHA8k effects. sHA significantly inhibited 253J-Lung xenograft growth. The majority of the animals did not form palpable tumors at 50-mg/kg dose. No weight loss or serum and organ toxicity was observed in sHA treated animals. Biochemical analysis of tumors also showed the same alterations in Akt and EMT pathways as observed cell culture. CONCLUSION: This is the first study that shows sHA8k, a small molecular mass HYAL-1 inhibitor has potent antitumor activity. Support: R01 CA 72821-14 (VBL) Citation Format: Andre R. Jordan, Juan Chipollini, Luis Lopez, Travis Yates, Vinata Lokeshwar. Anti-tumor activity of sHA8k, a HYAL1 hyaluronidase inhibitor, in bladder 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 2647. doi:10.1158/1538-7445.AM2015-2647
Haploidentical Peripheral Blood Stem Cell Transplantation for Relapsing/Refractory Neuroblastoma.
Authors: Jacek Toporski, Helga Björgvinsdóttir, Anders Castor, Josefina Dykes-Horwath, Mikael Garkavij, Solveig Hafsteinsdóttir, Jesper Heldrup, Lars Hjorth, Gunnar Juliusson, Helena Mörse, Charlotta Schaedel, Stefan Scheding, Jan Tenvall, Thomas Wiebe, Albert N. Bekassy
Journal: Blood (2006)
Rapid 5-fluorouracil plasma quantification by immunoassay: Validation with FOLFOX6 clinical samples.
Authors: S. J. Salamone, C. N. Benfield, J. B. Courtney, R. L. Harney, D. R. Kozo, Y. Li, G. D. Lundell
Journal: Journal of Clinical Oncology (2011)

563 Background: 5-fluorouracil (5-FU) is one of the most widely used chemotherapy agents in the treatment of colorectal cancer. Studies over the last 30 years have demonstrated wide pharmacokinetic variability of 5-FU which can lead to undue toxicity and suboptimal treatment. Recent clinical studies have demonstrated that managing plasma 5-FU levels and adjusting doses to target steady state concentrations effectively minimizes toxicity and improves outcome. Methods: An existing immunoassay using a novel antibody to 5-FU was modified to directly quantify 5-FU in patient plasma samples without any sample pretreatment. The assay was adapted to Beckman Coulter AU analyzers and to Roche COBAS c 111 analyzer. Method comparison to LC-MS/MS, limit of detection (LoD), lower limit of quantitation (LLoQ), precision, and linearity of the assay were evaluated. The assay was also validated by testing samples of patients being treated by modified FOLFOX6 from an on-going clinical trial ( NCT00943137 ). Results: The modified immunoassay was confirmed to have a linear reportable range from 85 to 18,000ng/mL and a LoD of 52ng/mL. The immunoassay was established to have good precision (CV&lt;6%) around the medical decision points for FOLFOX and FOLFIRI regimens. Method comparison of the immunoassay obtained by testing 58 clinical samples from patients under 5-FU treatment provides excellent correlation to LC- MS/MS: Deming slope 1 ± 0.05, R &gt; 0.98. Another 82 samples of patients on modified FOLFOX6 regimen from clinical trial (( NCT00943137 ) were tested using the immunoassay and range of these sample were reported to be from 95 to 2,970 ng/mL. Conclusions: The assay provided the performance required to rapidly quantify 5-FU plasma concentrations. It was fast (time to 1st result &lt; 10 minutes), precise, correlated well to a physical method, required only 100uL sample on the analyzer and 7ul for actual testing per assay, and was easily adapted to a variety of clinical analyzers. Clinical and pharmacokinetic laboratories could use this assay to introduce an evidence-based approach to optimize 5-FU dosing that would have higher throughput, simpler methodology, and require less labor, space or expense than the physical methods. [Table: see text]
Guideline-Based Prescribing in Frail Elderly Patients
Authors: Jennifer Tjia, Kate Lapane
Journal: JAMA Internal Medicine (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
464. Clinical Development of Gene Therapy for Neurotransmitter Deficiency Disorder
Authors: Waldy San Sebastian, John Forsayeth, Lluis Samaranch, Krystof S. Bankiewicz
Journal: Molecular Therapy (2015)

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder in which recessive inactivating mutations in the gene encoding the AADC enzyme lead to deficient synthesis of dopamine, norepinephrine, epinephrine and serotonin. This disease causes prominent motor symptoms, including hypokinesia, hypotonia, oculogyric crises, and dystonia. Additional symptoms include emotional lability, sleep disturbance and cognitive impairment. Because of the specific step at which AADC functions in the monoamine neurotransmitter biosynthetic pathway, patients do not respond to therapy with levodopa. There is no cure for AADC deficiency and most patients derive little symptomatic benefit from currently available medical therapies. In children with AADC deficiency, midbrain neurons that normally express AADC are intact. Gene replacement therapy, targeted to substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), should result in significant clinical benefit in pediatric patients. We expect that delivery of a small quantity of AAV2-hAADC to these discrete midbrain regions will result in AADC production that can directly activate the full biosynthetic pathway. The therapeutic intervention we have devised involves highly precise, MRI-guided infusion of vector into SNc and VTA and this presented significant technical challenges. In addition, the severely impaired patient population required intensive logistical and ethical considerations in the development of the clinical protocol. We recently obtained Investigational New Drug (IND) approval (#16127) for a Phase I/II study to treat AADC pediatric deficiency with AAV2-hAADC. In this presentation, we will discuss the technical, medical and regulatory challenges that were resolved as we assembled this gene transfer protocol.
512. Tumor-Associated Macrophages Via Up-Regulation of PD1 Ligands Protect Neuroblastoma from Immunotherapy With NKT Cells Expressing GD2-Specific Chimeric Antigen Receptor
Authors: Daofeng Liu, Amy N. Courtney, Andras Heczey, Ekaterina Marinova, Gengwen Tian, Linjie Guo, Xiuhua Gao, Gianpietro Dotti, Leonid S. Metelitsa
Journal: Molecular Therapy (2015)

Immunotherapy with Natural Killer T cells engineered to express a GD2-specific chimeric antigen receptor (CAR.GD2 NKTs) demonstrated potent anti-tumor activity in a metastatic model of neuroblastoma in humanized (hu)NSG mice. However, tumors eventually progressed without the loss of GD2 expression suggesting that tumor escape is due to inhibition of effector function of CAR. GD2 NKTs. Since NKTs co-localize and specifically interact with M2-like tumor-associated macrophages (TAMs), we examined whether TAMs inhibit effector functions of NKT and CAR.GD2 NKT cells. In vitro experiments revealed a reciprocal inhibition of NKTs and M2-polarized macrophages. We found that NKTs selectively kill M2-polarized macrophages or induce their differentiation toward M1-like cells. However, both M2- and M1-macrophages suppressed NKT-cell proliferation and IFNγ production in response to TCR or CAR stimulation. This was associated with rapid up-regulation of PD-L1 and PD-L2 on both M2 and M1 macrophages upon addition of supernatant from activated NKT cells. Moreover, M1 macrophages constitutively expressed PD-L1 and were resistant to NKT-cell cytotoxicity. The analysis of tumor tissues in hu-NSG mice revealed strong up-regulation of PD-L1 expression exclusively on TAMs and not on neuroblastoma cells after treatment with CAR. GD2 NKTs. Neither neuroblastoma cells nor TAMs expressed PD1 ligands in untreated mice or in primary NB tissues from patients with stage 4 disease. Importantly, a combination of CAR.GD2 NKT cell immunotherapy with anti-PD1 blocking mAb produced durable tumor regression. The results provide a rationale for a combined use of CAR-redirected NKT cells with PD1-blocking therapeutics for immunotherapy of neuroblastoma and possibly other solid tumors.