tbuckley/cabot-search huggingface dataset:
60. Engineering AAV Vector for the Delivery of Human BuChE to Protect Against Exposure to Organophosphates
Authors: Angelica Medina-Jaszek, Omua Ahokhai, Maryam Taheri, Muhammad Arif, Anna Tretiakova, James M. Wilson
Journal: Molecular Therapy (2016)

Human butyrylcholinesterase (hBuChE) is a widely-distributed enzyme that may play a role in nerve conduction, can hydrolyze various toxic esters (e.g., cocaine), and acts as a potent scavenger of organophosphates (OP) including pesticides and chemical warfare agents. Major limitations prohibiting the development of purified hBuChE as a mainstream biologic drug include: limited availability of human plasma, limited scalability of manufacturing, high cost of purified human-derived product, and the need for intravenous administration. In addition, the preventive uses of hBuChE are limited by its relatively short half-life. In an attempt to address some of these limitations, several methods for the production of recombinant hBuChE in vitro (cell lines) and in vivo (transgenic animals, plants) were developed; however, the resulting recombinant proteins presented with unfavorable pharmacokinetic profiles making them unsuitable for preventive uses. Alternatively, adenovirus-mediated delivery of hBuChE is very effective, but is not a candidate for development due to the inherent immunogenicity of the vector. Expression of hBuChE peaks at around 4 days post IV administration of the adenoviral vector, and the peak is followed by a rapid decline, with minimal expression being detectable 10 days post-administration. AAV vectors present a radically different, non-immunogenic hBuChE delivery platform, which is not reliant on protein purification and has the flexibility to deliver the product into both liver and muscle. AAV technology engineers the recipient's own cells to produce sustainable pharmacologic amounts of hBuChE on demand and/or replenish the exhausted scavenger via a single dose of hBuChE-expressing vector under the control of a constitutive promoter. Through the systematic optimization of AAV-hBuChE vectors, we achieved not only rapid onset of hBuChE expression in mice, but also sustainable, long-term expression for at least 2 months with no decline. AAV-hBuChE expressed at 100 units/ml of serum at 24 hours post vector administration into mouse muscle, with steady-state expression levels of up to 30,000 units/ml of serum at 1 month. The optimization parameters included selection of the protein isoform, tetramerization partner, coding sequence, as well as promoters and other regulatory elements. Overall, approximately 40 vectors were evaluated in comparative studies. Based on previous findings, the levels of hBuChE expressed by our platform are predicted to be protective in OP challenges, which we plan to perform in future studies. In the future, the use of our platform can be expanded to include populations that are occupationally exposed to pesticides. This approach may also be applicable for the delivery of other protective human enzymes, such as the use of rhodanese to protect against cyanides or glutathione against 2-chloro-acetophenone.
Targeting Cereblon with the High Affinity Immunomodulatory Compound CC-220: A Novel Therapeutic Agent for B Cell Dyscrasias
Authors: Peter H Schafer, Emily Rychak, Derek Mendy, Anastasia Parton, Lori Capone, Antonia Lopez-Girona, Jilly F Evans, Tom O Daniel, Rajesh Chopra
Journal: Blood (2012)
Advancing the cause of research registration: The first 500 registrations of the ResearchRegistry.com
Authors: R. Agha, A.J. Fowler, C. Limb, Y. Al Omran, H. Sagoo, K. Koshy, D.J. Jafree, M.O. Anwar, Peter McCulloch, D.P. Orgill
Journal: International Journal of Surgery (2016)
Second-line chemotherapy with capecitabine (CAP) and oxaliplatin (OX) in patients with pancreatic or biliary tree adenocarcinoma (ADC).
Authors: J. Mane, E. Iruarrizaga, I. Rubio, E. Fonseca, E. Iza, R. Casas, I. Marrodan, M. Martinez, R. Fernandez, S. Carrera
Journal: Journal of Clinical Oncology (2011)

308 Background: Pancreatic and biliary tree ADC represent poor prognostic tumors. Gemcitabine is usually considered the first- line chemotherapy and after that no standard treatment has been established. CAP and OX have demonstrated some activity in metastatic (M1) and locally advanced (LA) pancreatic cancer, and the combination of these drugs confers additional benefit as well. We conducted this study in order to establish the efficacy of this schedule on pancreatic and biliary tree ADC. Methods: Pts with M1 or LA pancreatic or biliary tree ADC with progression to one previous chemotherapy treatment were included. Performance status≤2, age≥18 years and adequate renal and hepatic function were selected. Schedule of chemotherapy: CAP 1000 mg/m 2 bid on days 2 to 15 and OX 130 mg/m 2 on day 1 of a 3-week cycle. RECIST criteria were used for assessment of response and NCI-CTCAE v 3.0 for toxicity. Results: Between April 2006 and March 2010, 40 pt were included. Male/female: 29/11. Mean age: 60.7 years (37-74). Pancreatic/biliary: 23/17. PS 0/1/2: 3/27/10. LA/ M1: 1/39. Mean number of cycles: 2.50 (1-10). Disease response per pt, partial/ stable disease/progression/not evaluated: 1/9/21/9. Tumor control (partial/stable disease): 10 pt (22%). Hematologic toxicity (grade1/2/3/4) (%) per pt: neutropenia 5/2.5/7.5/0; thrombocytopenia 15/5/2.5/5; anemia 42.5/10/52.5/0. Nonhematologic toxicity (grade 1/2/3) (%) per pt: asthenia 10/45/17.5; emesis 22.5/15/2.5.; anorexia 12.5/35/7.5; diarrhea 7.5/12.5/5; neurotoxicity 42.5/17.5/2.5; hand-foot syndrome 5/2.5/2.5. One toxic death was reported. Median time to progression: 15 weeks (95% CI 6.6-23.3). Median survival time: 19 weeks (95% CI 10.4-27.5). For pts with PS0 or 1 median overall survival was 23 weeks (95% CI 6.3-39.6) and for pts with PS2 was 8 weeks (95% CI 5.3-1.6) (p 0.004). Conclusions: Advanced pancreatic and biliar ADC have unfavorable prognosis. After first-line treatment, CAPOX shows a tolerable toxicity and some activity and it can represent an alternative on selected pretreated pts. No significant financial relationships to disclose.
ACTR-55. ADVANCES IN MANAGEMENT OF LOW-GRADE GLIOMAS
Authors: Sumul Raval, Victoria Momyer, Kelsey Murray, Ruchi Raval
Journal: Neuro-Oncology (2016)

Low-grade gliomas (LGGs) are common brain tumors that arise from various glial cells of the brain. The complex and variable backgrounds of LGGs cause difficulties in assigning therapies. In this report, we compile findings relating to LGG genetics and treatment options in order to create a coherent summary for referential use. We compiled 70 articles from the past ten years that cover a broad range of topics pertaining to LGGs, including molecular, genetic, epigenetic, morphological, and other diagnostic factors, as well as prognosis and treatment options. Molecular basis and histology of the tumor must be addressed for proper treatment. The 1p/19q co-deletion indicator has been considered the gold standard of glioma diagnosis and prognosis, but oft-sighted mutations in the IDH1 and IDH2 genes have given rise to three subgroups of 1p/19q co-deleted tumors, each associated with specific patterns of glial cells. Other molecular markers and microRNA expression patterns have been studied for possible diagnostic/prognostic methods. Microsurgical resection is the singular treatment with highest overall survival (OS) and quality of life (QOL). Total gross resection is optimal, with patients having a 5-year OS of 100% with 90% tumor resection. Low doses of radiation are as effective as high doses and are better tolerated. Additionally, radiation followed by PCV chemotherapy caused major increases in OS. Temozolomide also offers a favorable toxicity profile and QOL; additionally, seizure reduction is an early and consistent prognostic marker for survival after treatment with Temozolomide. The “wait and see” approach for treatment is no longer the standard for LGGs. Immediate treatment after diagnosis is recommended. Gross total resection (if achievable) is the most favorable treatment, with the highest OS and QOL. The use of chemotherapy and radiotherapy is recommended. Histological background and genetic markers are vital for determining a treatment plan.
A Phase 2 Study of Idelalisib Monotherapy in Previously Untreated Patients ≥65 Years with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
Authors: Andrew D. Zelenetz, Nicole Lamanna, Thomas J. Kipps, Steven E. Coutre, Susan O'Brien, Maria Aiello, Yoonjin Cho, Ronald L. Dubowy, Ian W. Flinn
Journal: Blood (2014)
419. Efficacy of Rambo for Sarcoma Therapy
Authors: Maninder Khosla
Journal: Molecular Therapy (2016)

Soft Tissue Sarcoma (STS), a cancer which forms in the connective tissue, requires aggressive treatment. Metastatic soft tissue sarcomas are associated with a median prognosis of about twelve months accompanied frequently with many signs and symptoms leading to a poor quality of life. These tumors frequently have angiogenic properties. Angiogenesis is responsible for the formation of new blood vessels and is associated with local progression and increased metastatic disease. Strategies that work to block angiogenesis are currently being investigated as a treatment for STS. Oncolytic virus therapy is a novel treatment strategy that utilizes modified viruses to specifically replicate and lyse cancer cells. The combination of angiogenesis inhibitors with oncolytic virus treatment has not been tested for STS. Here we tested the effect of combining oncolytic viral therapy with antiangiogenic gene therapy. RAMBO is a HSV-1 derived oncolytic virus that codes for the production of Vstat120, a gene with potent antiangiogenic effects. We have tested a panel of sarcoma cells and shown effective infection and lysis of these cells by RAMBO and HSVQ-1 in vitro. In vivo, we compared the antitumor efficacy of RAMBO and HSVQ-1 against sarcoma tumors grown in mice. Briefly, mice were implanted with 150-300mm3 A673 sarcoma tumors were injected with a PBS, HSVQ-1, or RAMBO (5.5×106 pfu). Mice were followed for tumor size over a period of time. Tumor volumes over time were logarithm (base 2) transformed for variance stabilization. The linear mixed model was used to compare the three groups while accounting for the variance-covariance structure due to repeated measures at different days from the same mouse. Statistically significant improvement in antitumor efficacy was observed in RAMBO treated tumors, compared to HSVQ-1 and control. H&E staining of tumor tissue reveals large areas of necrosis in RAMBO treated tumors. RAMBO and its inherent antiangiogenic gene therapy demonstrated significant efficacy in these sarcoma models and further investigations are underway with combination therapeutic strategies.
Effects of surgery with BCNU wafer placement on neurocognitive function in patients with one to three brain metastases.
Authors: M. G. Ewend, C. A. Meyers, E. Silva, M. Booth-Jones, S. Jain, S. Brem
Journal: Journal of Clinical Oncology (2011)

2015 Background: Neurocognitive function (NCF) protection and tumor control are goals of brain metastasis (BM) therapy. Whole brain radiation therapy (WBRT) reduces recurrence after surgery but has potential effects on NCF. Wafers containing BCNU, implanted into the surgical cavity, deliver high doses of local chemotherapy aimed at preventing local recurrence. We examined NCF and local recurrence rates in pts with BM treated with surgery/BCNU wafers but without WBRT. Methods: This prospective, multicenter, phase II study enrolled patients with 1-3 BM. The single/dominant lesion was resected and BCNU-wafers were placed in the cavity; radiosurgery was permitted for up to 2 other BM. WBRT was deferred. The primary endpoint was NCF, assessed at baseline (presurgical) then every 2-3 months up to 12 months. Specific NCF testing included tests of memory, executive function and fine motor coordination. NCF preservation was defined as improvement or no more than 1 standard deviation decline compared with the pt’s pre-op baseline. Results: Of 59 BCNU wafer pts median age was 63 years, 83% had 1 BM, and 41% had non small-cell lung cancer. Baseline RPA status was 1 (36%) or 2 (64%). Compared with the baseline, all three NCF domains improved at all time points, demonstrating significant improvements in executive function (4, 6, 9, 12 months) and memory (6,12 months) (Table). NCF preservation rates by domain: memory 70% (39/56), executive function 76% (41/54), and fine motor 66% (36/55). Local and distant recurrence rates were 23.5% (12/51) and 45% (23/51). Six pts had 10 drug-related serious adverse events; all resolved by end of study. There were 44 treatment-related adverse events; most common were headache (8.5%), convulsion (6.8%), and nausea (5.1%). Conclusions: BM pts treated with surgery/BCNU wafers showed improvement in memory and executive function after surgery. This treatment strategy also achieved local control rates comparable to historical rates with surgery plus WBRT. NCF change from baseline Z-score (SD) change from baseline 2 mo 4 mo 6 mo 9 mo 12 mo Memory +0.1 +0.5 +0.9* +0.4 +0.9* Executive function +0.2 +0.7* +0.7* +0.5* +0.5* Fine motor +0.2 +0.3 +0.4 +0.4 +0.5 Abbreviation: SD, standard deviation. * p<0.05
Outcome of the Japanese Immune Tolerance Induction (ITI) Registry and Predictors of Successful ITI
Authors: Keiji Nogami, Masashi Taki, Tadashi Matsushita, Shouichi Ohga, Hideji Hanabusa, Toshiaki Oka, Yasuo Horikoshi, Kagehiro Amano, Midori Shima
Journal: Blood (2015)
GM-CSF Secreting Leukemia Cell Vaccinations after Allogeneic Reduced-Intensity Peripheral Blood Stem Cell Transplantation (SCT) for Advanced Myelodysplastic Syndrome (MDS) or Refractory Acute Myeloid Leukemia (AML).
Authors: Vincent Ho, Glenn Dranoff, Haesook Kim, Mildred Pasek, Corey Cutler, Edwin Alyea, John Koreth, Joseph H. Antin, Robert J. Soiffer
Journal: Blood (2006)
Abstract 3927: Structural and mechanistic insights into the roles of RIAM in integrin signaling
Authors: Jinhua Wu
Journal: Cancer Research (2015)

Abstract Changes in integrin signaling promotes tumor cell proliferation, metastasis and survival. The Rap1-interacting adaptor molecule (RIAM) mediates integrin activation by responding to Rap1 activation and recruiting talin, the integrin activator, to the plasma membrane (PM). The structural details of how RIAM is recognized by Rap1 and in turn recruits talin are lacking. We have elucidated the specificities for RIAM interacting with Rap1 and talin via X-ray crystallography and functional analyses. Crystal structure of Rap1 in complex with the central structural module of RIAM reveals essential specificity determinants, especially a Lys31 residue that is oppositely charged in other Ras GTPases. Furthermore, our study on the RIAM:talin interaction suggests that the talin-binding site 1 (TBS1) of RIAM is required for recruiting cytoplasmic talin to the PM, primarily via an interaction with the R8 domain of talin. Interestingly, an unexpected kink in the helical TBS1 fragment is required for inducing integrin activation. These characteristics are not seen in other related molecules including the highly homologous Lpd, providing the molecular basis for the specific signaling function of RIAM that mediates the integrin activation. Citation Format: Jinhua Wu. Structural and mechanistic insights into the roles of RIAM in integrin signaling. [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 3927. doi:10.1158/1538-7445.AM2015-3927
Bortezomib Could Reduce Cell Viability by Activation of Heme Oxygenase 1 in Multiple Myeloma Cells
Authors: Daniele Tibullo, Cesarina Giallongo, Ignazio Barbagallo, Piera La Cava, Nunziatina Parrinello, Giovanni Li Volti, Giuseppe A Palumbo, Concetta Conticello, Francesco Di Raimondo
Journal: Blood (2012)
Implication of <i>p16<sup>INK4a</sup></i> and <i>RASSF1A</i> promoter methylation in patients with resectable non-small cell lung cancer (NSCLC)
Authors: J. Wang, D. Liu, J. Lee, C. Lu, D. Stewart, L. Mao
Journal: Journal of Clinical Oncology (2004)

7150 Background::p16INK4a and RASSF1A are frequently inactivated by de novo PM in NSCLC. The goal of this study was to determine the prognostic roles of p16INK4a and RASSF1A PM in patients with resectable NSCLC Methods: status of p16INK4a and RASSF1A was determined in 119 tumors from patients with NSCLC (70 stage I/II and 49 stage IIIA) using methylation-specific PCR. Survival was estimated with the Kaplan-Meier method. Associations between methylation status and survival were determined by the log-rank test and Cox proportional hazards analysis Results: PM of p16INK4a and RASSF1A was detected in 58 (49%) and 46 (39%) tumors, respectively. Thirty-six (30%) tumors exhibited PM of both genes. In patients with stage I/II tumors, p16INK4a PM was strongly associated with poor overall, disease-free, and disease-specific survival (P = 0.002, P = 0.0006, and P = 0.0005, respectively, log-rank test) while the association between RASSF1A PM and survival was not significant. However, RASSF1A PM was a strong predictor of poor survival in patients with stage IIIA NSCLC (P< 0.0001, P = 0.0006, P< 0.0001, for overall, disease-free, and disease-specific survival, respectively). p16INK4a and RASSF1A PM were the only independent predictors of survival in multivariate analysis, and PM of both genes was associated with strikingly poor clinical outcome. In patients with stage IIIA tumors, all 11 patients in this category died of disease within 3 years after surgery, while 13 of 21 patients whose tumors had PM at only one gene died in 5 years, and 5 of 17 patients whose tumors had no PM died in 6.5 years ( P< 0.0001, log-rank test) Conclusions::p16INK4a and RASSF1A PM may be useful prognostic biomarkers for patients with resectable NSCLC. Stage IIIa patients whose tumors exhibited PM of both genes demonstrated significantly worse survival. Because these patients often receive adjuvant therapies, it would be worthwhile to examine relationships between PM status and response to therapy. No significant financial relationships to disclose.
Switch to tenofovir-based therapy or to continue adefovir-based therapy in CHB patients with suboptimal response to adefovir-based combination?
Authors: Byung-Cheol Song
Journal: Clinical and Molecular Hepatology (2016)

See the Original "Efficacy of switching from adefovir to tenofovir in chronic hepatitis B patients who exhibit suboptimal responses to adefovir-based combination rescue therapy due to resistance to nucleoside analogues (SATIS study)" on page 443.
When Trust in God Means Preemptive Refusal of C-Section
Authors: Birgitta Sujdak Mackiewicz, Stephen Thompson
Journal: The American Journal of Bioethics (2016)

Mrs. Ford, 20 weeks pregnant, preemptively refuses a C-section. Her lack of faith in God, she believes, led to the second-trimester miscarriage of her first child. She has seen Dr. Raymond twice. D...
MPTH-09. ANALYSIS OF SURVIVAL AND PROGNOSTIC FACTORS IN ANAPLASTIC GLIOMAS
Authors: Jong Hee Chang, Je Beom Hong, Eui Hyun Kim, Seok Gu Kang, Se Hoon Kim, Chang Ok Suh
Journal: Neuro-Oncology (2016)

The aim of this study was to evaluate survival rate and the prognostic factors in anaplastic gliomas. We retrospectively analyzed clinical, radiological, pathological, and molecular findings of 118 patients with anaplastic glioma who were newly diagnosed at our institute between 2000 and 2013. We analyzed the overall survival(OS) and progression free survival (PFS) according to specific pathological subtype, the influence of prognostic factors, and cut off points. There were 60 cases (50.9%) of anaplastic astrocytoma (AA), 30 (25.4%) of anaplastic oligodendroglioma (AO), and 28 (23.7%) of anaplastic oligoastrocytoma (AOA). Median follow-up duration was 66.1 months. The median OS was 48.4 months in total anaplastic glioma group. In AA subgroup, the median OS was 22.5 months and in AOA and AO subgroups, median OS could not be reached. Isocitrate dehydrogenase-1(IDH1) mutation was found in 4 cases in AA group (7%), 18 in AOA (64%), and 19 in AO (63%). 1p/19q co-deletion was found in 3 cases in AA group (5%), 10 in AOA (36%), and 23 in AO (77%). O6-methylguanine-DNA methyltransferase (MGMT) methylation was found in 22 cases in AA group (37%), 21 in AOA (75%), and 22 in AO (73%). In univariate analysis, preoperative age, Karnofsky performance score, tumor’s location in eloquent area, IDH1 mutation status, 1p/19q co-deletion status, MGMT methylation status, and extent of resection measured in contrast enhanced T1-weighted and T2-weighted MRI were significantly associated with OS. In multivariate subgroup analysis, extent of resection and IDH 1 mutation status were statistically significant prognostic factors. Cut off points of extent of resection measured in contrast enhanced T1-weighted and T2-weighted MRI were 99.9% and 84.8%, respectively. In anaplastic gliomas, IDH 1 mutation status, complete resection of contrast enhanced portion (99.9%), and more than 85% resection of non-enhanced portion have prognostic impact on the patient survival.
Abstract 180: Expanding the definition of core binding factor leukemia
Authors: John A. Fischer, Stefano Rossetti, Arani Datta, Alessandro Beghini, Nicoletta Sacchi
Journal: Cancer Research (2015)

Abstract The core binding factor (CBF) transcription factor complex regulates coding and non-coding genes that play a critical role in hematopoiesis. Chromosomal rearrangements involving the two CFB subunits, RUNX1 and CFB beta, are common in acute myeloid leukemia (AML). The fusion proteins resulting from these rearrangements deregulate the transcription of RUNX1-target genes, including microRNAs critical for KIT-mediated proliferation (e.g. miR-221) and myeloid differentiation (e.g. miR-223). We found that overexpression of miR-17, which downregulates RUNX1 level by targeting RUNX1-UTR, recapitulates the biological effects of CBF-AML fusion proteins by affecting the transcription of common coding and non-coding RUNX1-targets. Consistently, increased levels of miR-17 can be detected in AML patient samples displaying increased KIT level, but without evidence of CBF mutations. Based on these finding, we propose that the definition of CBF-AML leukemia can be expanded to accommodate leukemia induced not only by genetic factors but also epigenetic factors, such as microRNAs targeting RUNX1. Acknowledgements: Funding for this study was provided by a Roswell Park Alliance Foundation award, the University of Rochester-RPCI pilot grant, and the Mark Diamond Research Fund. Citation Format: John A. Fischer, Stefano Rossetti, Arani Datta, Alessandro Beghini, Nicoletta Sacchi. Expanding the definition of core binding factor leukemia. [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 180. doi:10.1158/1538-7445.AM2015-180
Danusertib Hydrochloride (PHA-739358), a Multi-Kinase Aurora Inhibitor, Elicits Clinical Benefit in Advanced Chronic Myeloid Leukemia and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia .
Authors: Jorge Cortes-Franco, Hervé Dombret, Philippe Schafhausen, Tim H Brummendorf, Nicolas Boissel, Fabio Latini, Laura Capolongo, Bernard Laffranchi, Silvia Comis
Journal: Blood (2009)
Assessment of Clinical Safety and Estimate of Survival in Iraqi Patients with Chronic Myeloid Leukemia Switched From Glivec (β-Crystalline Form of Imatinib Mesylate) to an α-Crystalline Copy of Imatinib Mesylate
Authors: Marc Botteman, Matthew Magestro, Alaa Fadhil Alwan, Paul W Manley, Oleg Zernovak, Richard C. Woodman
Journal: Blood (2012)