tbuckley/cabot-search huggingface dataset:
Palonosetron in the prevention of chemotherapy-induced nausea and vomiting in children with acute lymphoblastic leukemia treated with high-dose methotrexate.
Authors: H. Schroeder, S. Nadaraja, S. Rosthoej, P. S. Wehner, H. Thomassen
Journal: Journal of Clinical Oncology (2011)

9535 Background: High-dose methotrexate is moderately emetogenic and requires preventive antiemetic therapy. The purpose of this study was to evaluate the antiemetic effect of palonosetron (5 µg/kg) given once 0.5 h before start of 24-hour infusion with high dose methotrexate (HD-MTX) (5g/m2) in children with acute lymphoblastic leukemia (ALL). Methods: From January 2010 until December 2010, 53 children were included in a prospective clinical observational study from all four Danish Childhood Cancer Centers. Information regarding emetic episodes, rescue treatments (any extra antiemetic medication) and nausea were recorded by patients/parents and nurses on questionnaires for a total of 138 HD-MTX courses. Results: The primary end point was complete response (no emetic episodes and no rescue treatments). This was achieved in 86.8% of patients in the acute phase (0-24 hours post-chemotherapy) and 60.4% of patients in the delayed phase (24-66 hours post-chemotherapy). 94.3% of the patients were completely free of emetic episodes in the acute phase, while the same is true for 88.7% in the delayed phase. 90.6% of the patients were completely free of rescue treatments in the acute phase, while the same is true for 66.0% in the delayed phase. When all 138 courses were analyzed independently there were >2 emetic episodes in 2.2% during the acute phase, and in 8% during the delayed phase. More than 2 antiemetic rescue treatments were applied in 0.7% of the courses during the acute phase and in 6.5% during the delayed phase. More than mild nausea was only seen during one course. Conclusions: This study indicates that a single dose of palonosetron is effective in preventing chemotherapy-induced nausea and vomiting in children with ALL treated with HD-MTX. Introduction of palonosetron as standard antiemetic treatment in these children would mean less use of antiemetic medication, fewer intravenous administrations and fewer disturbances for children and parents and finally a reduced workload for the health care worker.
Abstract 5226: Glioma stem cells internalize perivascular bevacizumab via a non-canonical pathway and target it for recycling or degradation
Authors: Gaelle Muller-Greven, Cathleen Carlin, Justin Lathia, Richard Prayson, Manmeet Ahluwalia, Steven Toms, Markus Bredel, Jeremy Rich, Petra Hamerlik, Candece L. Gladson
Journal: Cancer Research (2015)

Abstract Antiangiogenic therapy shows great promise for treatment of cancer. Bevacizumab is a humanized mAb that blocks VEGF-A, thereby inhibiting angiogenesis. It has received FDA approval for patients with recurrent glioblastoma (GBM); however, approximately 30% of patients are non-responsive and the underlying mechanism for the lack of response is not known. It has been assumed that Bevacizumab solely targets circulating VEGF-A; however, VEGF-A found in the perivascular space of GBM tumors could also be an important target. We hypothesized that Bevacizumab is transcytosed across brain endothelial cells (ECs), gains access to the perivascular niche containing glioma stem cells (GSCs), and that differences in GSC endocytosis and trafficking of Bevacizumab to either a recycling or degradation compartment determines a patients’ response. We found that Bevacizumab is internalized by normal and tumor-isolated brain ECs in a time-dependent manner. ECs transcytose 20% of Bevacizumab after 30 minutes, and 40% after 120 minutes. Importantly, we found that 95% of GSCs internalize Bevacizumab within 30 minutes. Internalized Bevacizumab in GSCs can be recycled to the extracellular space via a Rab4+ fast recycling compartment, or degraded via trafficking to the LAMP1+ compartment (late endosome/lysosome). Furthermore, Bevacizumab internalization in GSCs was partially inhibited by a macropinocytosis inhibitor (EIPA) suggesting macropinocytosis is one mechanism of internalization. GSCs do not internalize Bevacizumab via the canonical IgG internalization pathway since they do not express the neonatal Fc Receptor (FcRn). Supporting our in vitro data, we found a gradient of Bevacizumab extending from the vessel into the tumor in an orthotopic xenograft mouse model of GBM administered Bevacizumab, and Bevacizumab was readily detected within perivascular tumor cells. Our data suggest that the transcytosis of Bevacizumab by brain and tumor-associated ECs, and the endocytosis and trafficking of Bevacizumab by perivascular GSCs influences Bevacizumab effectiveness in patients with GBM. Citation Format: Gaelle Muller-Greven, Cathleen Carlin, Justin Lathia, Richard Prayson, Manmeet Ahluwalia, Steven Toms, Markus Bredel, Jeremy Rich, Petra Hamerlik, Candece L. Gladson. Glioma stem cells internalize perivascular bevacizumab via a non-canonical pathway and target it for recycling or degradation. [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 5226. doi:10.1158/1538-7445.AM2015-5226
664. Improving AAV Gene Therapy Safety Analysis: Multiplex LAM-PCR Provide New Insights Into AAV Vector Integration
Authors: Irene Gil-Farina, Christine Käppel, Stefan Wilkening, Esperanza Lopez-Franco, Maria Astrid Paneda, Jesús Prieto, Lisa Spronck, Christof von Kalle, Harald Petry, Gloria Gonzalez-Aseguinolaza, Manfred Schmidt
Journal: Molecular Therapy (2015)

Nowadays, recombinant adeno-associated viruses (rAAV) constitute one of the most successful vectors for human gene therapy. These viral vectors allow a long-term transgene expression mainly due to their ability to form stable concatemeric DNA structures. Interestingly, although it is a rare event, rAAV have been shown to randomly integrate into the host genome. The inverted terminal repeats (ITR) have been shown to be preferred breakage points within the rAAV vectors. Current analysis of AAV integration are based on the linear amplification mediated (LAM)-PCR technology, here the genomic regions adjacent to the ITRs are amplified and sequenced for the determination of the integration sites (IS). However, recent studies have shown that vector breakage may also occur along the whole vector sequence, thus requiring the development of new methods able to identify the integration of internal vector regions. We present a novel method for the detection of rAAV integration based on the LAM-PCR technology by employing simultaneously five primer sets covering the whole AAV vector sequence. This multiplex LAM-PCR was used, in parallel with the standard 5' LAM-PCR, in liver, spleen and adrenal gland biopsies from monkeys injected with 1×1013 viral genomes (vg)/kg or 5×1013 vg/kg of the AAV2/5-AAT-coPBGD vector (this vector has been used in a phase I clinical trial for acute intermittent porphyria). Subsequent 454 sequencing and data analysis of ≈1 million raw sequences for each tissue allowed the identification of near 800 integration sites (IS). As it has been previously reported, vector integration occurs within different regions of the ITR, although preferentially in the C-region. In addition, multiplex LAM-PCR showed breakage at different positions of the AAV vector genome in all the organs analyzed. Our data show the increased sensitivity of this method and its suitability for the analysis of viral integration occurring at inner regions of the rAAV vector. Thus, this new method will provide a deeper insight into the interaction of AAV vectors with the host genome and will contribute to increase the thoroughness of the safety studies for the increasing number of gene therapy clinical trials using rAAV vectors.
522. Murine iPSC-Derived Macrophages Improve the In Vivo Disease Phenotype of Pulmonary Alveolar Proteinosis Due to Csf2rb Deficiency
Authors: Adele Mucci, Jessica Kunkiel, Mania Ackermann, Takuji Suzuki, Christine Happle, Sebastian Brennig, Elena Lopez-Rodriguez, Jens P. Bankstahl, Mark P. Kühnel, Miriam Hetzel, Axel Schambach, Gesine Hansen, Bruce Trapnell, Nico Lachmann, Thomas Moritz
Journal: Molecular Therapy (2016)

Induced pluripotent stem cells (iPSCs) have proven applicability to various areas including disease modeling and cell therapy. Hereditary pulmonary alveolar proteinosis (herPAP) is a rare lung disease caused by mutations within the α- (CSF2RA) or β-chain (CSF2RB) of the GM-CSF receptor gene (CSF2R), resulting in the inability of alveolar macrophages (MΦ) to clear the alveolar spaces from surfactant material. Given the limited treatment options in herPAP, we evaluated the suitability of murine iPSC-derived MΦ (iPSC-MΦ) for disease modelling and as a source for an innovative cell replacement therapy. To this point we first established an efficient and robust protocol to obtain mature and functional MΦ from healthy murine iPSCs. These MΦ closely resemble their counterparts generated in vitro from bone marrow cells with regard to morphology, surface phenotype and function. Furthermore, murine Csf2rb-deficient iPSCs (miPAP) were generated and submitted to our differentiation protocol. miPAP-derived MΦ faithfully recapitulated the defects in GM-CSF signaling and MΦ function present in herPAP patients. Of note, we also evaluated the feasibility, safety and clinical benefit of the intratracheal application of healthy iPSC-MΦ using a clinically relevant in vivo mouse model of herPAP. Following single pulmonary MΦ transplantation (PMT) of 4×106 iPSC-MΦ, specific engraftment was observed in the alveolar spaces for up to 8 weeks as shown by tissue sections and PCR. Moreover, cells displayed donor-specific CD45.1 expression and typical MΦ morphology in vivo and upon re-isolation. No teratoma formation or tissue toxicity was detected in the organs of transplanted mice. Most importantly, following PMT a significant improvement of disease parameters such as reduced protein, M-CSF, GM-CSF and surfactant protein-D (SP-D) concentration was shown in the bronchoalveolar lavage fluid. We also observed a decrease in PAS-positive material in lung sections and a reduction in lung opacity in computer tomography scans. Thus, we here present an efficient differentiation protocol to obtain MΦ from iPSCs for disease modeling and introduce PMT of iPSC-MΦ as an innovative cell therapy for herPAP.
264. In Vivo DNA-Monoclonal Antibody (DMAb) Gene Delivery Protects Against Lethal Bacterial and Viral Challenges in Mice
Authors: Ami Patel, Seleeke Flingai, Sarah T.C. Elliott, Trevor Smith, Megan C. Wise, Stephanie Ramos, Jian Yan, Katherine Schultheis, Amelia A. Keaton, Daniel H. Park, Kate E. Broderick, Niranjan Sardesai, Muthumani Karuppiah, David B. Weiner
Journal: Molecular Therapy (2016)

Therapeutic monoclonal antibodies (mAb) are approved for treatment of several diseases including primary immunodeficiencies, cancer, asthma, and graft transplantation. Yet, only 2 mAbs are approved for administration against infectious diseases: palivizumab (respiratory syncytial virus) and raxibacumab (inhalational anthrax). Numerous protective mAbs targeting recurring and emerging bacterial and viral pathogens have been isolated, however, the high dosage (mg/kg) and associated cost of mAb manufacturing are significant hurdles for routine therapeutic delivery. Recently we have described the development of DNA vector-encoded monoclonal antibodies (DMAbs), as a possible alternative technology. This delivery targets skeletal muscle for invivo transfection to transiently produce and secrete mAb. By optimizing gene design protective levels of antibody are produced in vivo by this technology. We show that expression can last a period of weeks. These designed DMAb formulations encoding the mAb heavy and light chain genes are delivered in vivo by intramuscular injection followed by electroporation (IM-EP). Several DMAbs were developed targeting antimicrobial resistant bacteria, a serious global health concern. Additionally, we also designed DMAbs against a range of viral infections including frequent, emerging, and neglected tropical diseases. Through a series of sequence and formulation optimizations, we are able to achieve serum levels >5ug/mL and as high as 100ug/mL, depending on the DMAb. DMAb serum levels match the protective trough level range of their purified mAb counterparts and perform on par in functional assays (e.g. killing assays, neutralization). DMAb candidates are protective against bacterial and viral challenges in mice, illustrating functionality in vivo. Data from the challenge studies will be presented. Ongoing studies are investigating DMAb gene delivery in larger animal models including rabbits, guinea pigs, and non-human primates. DNA-delivered mAbs is a flexible platform that transforms mAb delivery, allowing for repeat administration, significantly lower production costs, and expands the utility of DNA vector technology for therapeutic gene therapy. This approach may have benefit for routine DMAb gene delivery to prevent nosocomial and community-acquired infections and can be rapidly deployed during an infectious disease outbreak.
17. Gene Therapy Strategies to Treat Fragile X Syndrome
Authors: Jason Arsenault, Shervin Gholizadeh, Enea Koxhioni, Sebok K. Halder, David R. Hampson
Journal: Molecular Therapy (2015)

Fragile X syndrome (FXS) is a severe debilitating neurodevelopmental disorder of the autism spectrum that results from an aberrant trinucleotide repeat extension in the 5' region of the FMR1 gene. This extension pathologically reduces or eliminates the expression of the fragile X mental retardation protein (FMRP). FMRP is known to be a scrupulous translational modulator at the synapse and is also known to stabilize and traffic mRNAs important for proper neurological functions. We utilized C57/BL6 mice with a knock-out of the Fmr1 gene (FMRP-KO) in this study because this mouse model reproduces many of the behavioral phenotypes seen in human Fragile X patients. We used adeno-associated viral vectors (AAV) serotype 2/9, which contains the inverted terminal repeats of serotype 2, the human neuron specific synapsin promoter and the largest isoform of FMRP (isoform 1), as well as downstream woodchuck hepatitis virus post-transcriptional regulatory element and a poly A site to elevate mRNA stability, in order to re-introduce FMRP in the brain of neonatal FMRP KO mice. This vector, as well as a cognate null vector containing no transgene used as a control, were administered via bilateral intra-cerebroventricular injections at different early postnatal time points in wild type (WT) and FMRP-KO mice. AAVs were produced and purified by the University of Pennsylvania Vector Core facility. We also investigated whether FMRP overexpression in WT mice could induce behavioral changes. We tested the treated mice in an array of behavioral tests to monitor changes in autism-associated behaviors such as repetitive stereotypical motions, hyperactivity, deficits in social interaction, and general anxiety. Long term FMRP transgene expression was confirmed by immunocytochemistry and quantitative western immunoblotting where strong forebrain and neuron-specific expression was observed. Overall, we observed partial to full amelioration of certain fragile X phenotypes such as motor activity, sensorimotor gating and open field latency in FMRP-KO mice injected with the AAV-FMRP vectors. Also other observations points towards possible pathological effects due to FMRP overexpression in the forebrain of WT mice; an important consideration for future gene therapy of human FXS. These results show that the time of neonatal injection and the total number of AAV particles administered during intra-cerebroventricular injections can affect the efficacy, distribution of transgene expression, and ultimately, the successful reversal of abnormal behaviors.
Abstract 2530: Bcl-2 and Bcl-xL dual inhibitor, ABT-737, circumvents JNK mediated upregulation of anti-apoptotic molecules in cisplatin treated non-small cell lung cancer models
Authors: Eun Young KIM, Arum Kim, Yoon Soo Chang
Journal: Cancer Research (2015)

Abstract Introduction; Non-small cell lung cancer (NSCLC), which does not have druggable driver oncogene, is treated with cytotoxic chemotherapy, but clinical outcome is suboptimal. Cisplatin is still one of the most commonly used drugs for the treatment of NSCLC, and, however, there are limitations of the therapeutic effect because of the multiple resistance mechanisms. In particular, elevated level of anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-1) triggered by cisplatin-induced DNA damage response correlate with the drug resistance. In this study, we investigated synergic effects of combined treatment with cisplatin and dual inhibitor of Bcl-2/Bcl-xL, ABT-737, in NSCLC models. Materials and Methods; H460 and A549 NSCLC cells, and LSL K-Ras G12D mouse model were used. Protein expression was evaluated by immunoblotting and cytotoxicity was measured by FACS followed by annexin-V and PI staining. LSL Kras G12D mouse were inhaled 5 × 107 PFU AdCre virus at 8 weeks after birth and, in 24 weeks after inhalation, were taken microCT, randomized into 4 groups, and then treated with ABT-737 (50mg/kg, i.p., daily) and/or cisplatin (5 mg/kg, i.p., weekly) for two weeks. Results; There was a dose dependent phosphorylation of JNK, which is most prominent between 6 to 24hr after cisplatin treatment. Expression of anti-apoptotic molecules, Bcl-2, Bcl-w, Bcl-xL, and Mcl-1 were increased by cisplatin treatment in a dose and time dependent manner. JNK specific activator, anisomycin, increased mRNA level of anti-apoptotic molecules. ABT-737 displaced BCL-xL to the cytoplasm and aggregated Bak. Furthermore, ABT-737 released cytochrome C from mitochondria to the cytoplasm. ABT-737 itself showed cytotoxic effects and combination of ABT-737 potentiates cytotoxic effects of cisplatin with strong synergism. Combination of ABT-737 with cisplatin treatment induced significant tumor regression in 2 weeks in LSL K-ras G12D mouse model when compared those treated with single agents or vehicle. Conclusion; Combination of ABT-737 with cisplatin showed synergistic cytotoxic effects and anti-tumor activities in NSCLC preclinical models. These findings suggest that clinical trials using combination with ABT-737 and cisplatin may be beneficial in advanced NSCLC patients. Citation Format: Eun Young KIM, Arum Kim, Yoon Soo Chang. Bcl-2 and Bcl-xL dual inhibitor, ABT-737, circumvents JNK mediated upregulation of anti-apoptotic molecules in cisplatin treated non-small cell lung cancer models. [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 2530. doi:10.1158/1538-7445.AM2015-2530
Abstract POSTER-BIOL-1332: Molecular, cellular and clinical interaction between MDSC and ovarian cancer stemness
Authors: Ilona Kryczek, Tracy X. Cui, Lili Zhao, Linda Vatan, Wojciech Szeliga, Rebecca Liu, Weiping Zou
Journal: Clinical Cancer Research (2015)

Abstract Myeloid derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are important cellular components in the cancer microenvironment, and may affect cancer phenotype and patient outcome. The nature of MDSCs and their interaction with CSCs in ovarian carcinoma are unclear. We examined the interaction between MDSCs and CSCs in patients with ovarian carcinoma. We demonstrate that MDSCs inhibit T cell activation, enhance CSC gene expression, sphere formation and cancer metastasis. MDSCs trigger microRNA101 expression in cancer cells; microRNA101 subsequently represses the co-repressor gene C-terminal binding protein-2 (CtBP2), and CtBP2 directly targets stem cell core genes resulting in increased cancer cell stemness, and increasing metastatic and tumorigenic potential. Increased MDSC density and tumor microRNA101 levels, and decreased tumor CtBP2 expression independently predict poor survival. Collectively, the work identifies a novel immune associated cellular, molecular and clinical network involving MDSCs/microRNA101/CtBP2/stem cell core genes, which extrinsically controls cancer stemness and impacts patient outcome. Citation Format: Ilona Kryczek, Tracy X. Cui, Lili Zhao, Linda Vatan, Wojciech Szeliga, Rebecca Liu, Weiping Zou. Molecular, cellular and clinical interaction between MDSC and ovarian cancer stemness [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1332.
The Oncoprotein LMO2 Is Expressed in a Germinal Center B-Cell-Associated Pattern and Predicts Survival in Patients with Diffuse Large B-Cell Lymphoma.
Authors: Yasodha Natkunam, Eric D. Hsi, Christine Hans, Shuchun Zhao, Behnaz Taidi, Jun Chen, David Y. Mason, Teresa Marafioti, Margaret Jones, Brad Pohlman, Anne S. Hammer, Stephen Hamilton-Dutoit, Abraham Avigdor, Ginette Schiby, Arnon Nagler, Gerald E. Byrne, Ronald Levy, Izidor S. Lossos
Journal: Blood (2006)
Abstract 8197: Serum Dickkopf-1 Level Predicts Cardiac Events in Chronic Heart Failure Patients
Authors: Takeshi Niizeki, Kazuyoshi Kaneko, Toshiki Sasaki, Shigeo Sugawara, Isao Kubota
Journal: Circulation (2011)

Background: The Wnt signaling pathway is an important regulator of adult tissue maintenance and homeostasis. Disorder in Wnt signaling pathway causes cancer, human degenerative disease, and aging-associated heart disorders such as diastolic dysfunction. Dickkopf-1 (DKK-1) is negative regulator protein of the Wnt signaling pathway and is associated with a variety of organic diseases. Chronic heart failure (CHF) is characterized by systemic abnormalities and the myocardium is continually exposed to various stressors such as anoxia, ischemia, inflammation, and free radicals. Increasing age had been reported to increase mortality of CHF patients. Under the hypothesis that DKK-1 as a regulator protein is involved in ventricular remodeling, ongoing myocardial damage, and aging-associated disorders, we aimed to examine the prognostic value of serum DKK-1 in patient with CHF. Methods and Results: Serum DKK-1 level was measured in 210 CHF patients and 62 control subjects by the competitive enzyme-linked immunosorbent assay. Patients were prospectively followed with endpoints of cardiac death or re-hospitalization for worsening CHF during a median follow-up period of 720 days. Serum DKK-1 level was higher in CHF patients than in control subjects and increased with advancing NYHA functional class (P &lt; 0.0001). Furthermore, serum DKK-1 level was significantly increased with aging. There were 88 cardiac events during follow-up period (42%). Serum DKK-1 level was significantly higher in patients with cardiac events than those in event free patients. Kaplan-Meier analysis clearly demonstrated that the high DKK-1 group had a significantly higher incidence of cardiac events than the low DKK-1 group (P &lt; 0.0001). Patients were divided into 3 groups based upon DKK-1 level, and the highest 3 rd tertile was associated with the highest risk of cardiac events (8.68-fold compared to the 1 st tertile). In the multivariate Cox analysis, DKK-1 level was an independent risk factor for cardiac events (hazard ratio 3.66, 95% confidence interval 1.49-4.76, P = 0.0015). Conclusion: Elevated serum DKK-1 level, a major antagonist of the Wnt signaling pathway, is associated to increased cardiac events and provides prognostic information in CHF patients.