tbuckley/cabot-search huggingface dataset:
Venous thromboembolic events (VTE) in patients treated with cisplatin as compared to carboplatin-containing regimens.
Authors: N. Dixit, A. Ijaz, L. A. Martin, M. H. Lee
Journal: Journal of Clinical Oncology (2011)

e19679 Background: Data regarding the prevalence of venous thromboembolic events (VTE) with cisplatin-containing regimens has recently gained prominence. Cisplatin is an important chemotherapy agent used in treatment of many cancers. Carboplatin is used in many settings where cisplatin is contraindicated or where toxicity profile may be prohibitive. This study was done to determine incidence of venous thromoboembolism in patients treated with cisplatin as compared to carboplatin containing regimens. Methods: This was a retrospective analysis of patient who received cisplatin-based regimens or carboplatin-based treatment from 2005-2010 at our institution. The study included patients more than 18 years of age who received at least one or more cycles of treatment with either cisplatin or carboplatin. Primary objective was to assess venous thromboembolic events in each arm. Any event which occurred during treatment or within 8 weeks of completion of treatment was considered attributable to the treatment. Results: 111 patients in cisplatin arm and 110 patients in carboplatin arm were included in analysis. Median age was 62 years. Patient with lung cancer were the largest group (37/111 in cisplatin arm and 46/110 in carboplatin arm) followed by gynecologic malignancies, other diagnoses included gastric/esophageal, head and neck and urothlial carcinoma. The incidence of VTE was 23/111 (20.7%) in cisplatin group and 17/110 (15%) in the carboplatin group. The incidence of VTE attributable to treatment was 15/110 (13%) in cisplatin arm and 6/111 (5.5%) in carboplatin arm. Conclusions: This analysis suggests higher incidence of VTE in patients receiving cisplatin containing regimens as compared to carboplatin-containing regimens. Although our sample size is small and it is retrospective data, there is a trend toward increased incidence of VTE with cisplatin. This may be considered in risk/benefit assessment of treatment particularly in patients considered high risk for VTE. Cisplatin N=111 Carboplatin N=110 Male/female 67/44 65/45 Lung cancer 39/111 (35%) 46/110 (42%) No. of events 23/111 (20.7%) 17/110 (15%) Attributable to treatment 15/111 (13%) 6/110 (5.5%)
171. Quantification of Human FVIII and Estimation of Its Molecular Weight: Potential Applications in Gene Therapy for Hemophilia A
Authors: Rajeev Mahimkar, Barrie Carter, Gordon Vehar
Journal: Molecular Therapy (2016)

Current protocols for measurement of FVIII rely on chromogenic or coagulation assays, and are not designed for quantification of FVIII antigen. Development of assays for measuring FVIII antigen may be necessary and beneficial for determining the efficiency of newer therapeutic approaches for Hemophilia A such as gene therapy. Herein, we describe the development of proprietary assays for quantification of human FVIII in plasma matrices from heterologous species, and estimation of the human FVIII molecular weight. A variety of monoclonal antibodies against the FVIII heavy and light chain were screened for their ability to recognize human FVIII from normal human plasma pool, or CHO cell derived recombinant human FVIII-B domain deleted (FVIII-BDD) spiked in mouse and non-human primate (NHP) plasma. Based on the initial screen, a monoclonal each against the human FVIII heavy or the light chain was selected for enrichment, followed by detection using a sheep anti-FVIII polyclonal antibody. Using this sandwich ELISA procedure, a standard curve was generated for human FVIII-BDD antigen in the range of 100 ng/ml - 0.1 ng/ml, and minimal cross reactivity was observed when tested with mouse and NHP plasma pools containing endogenous FVIII antigen. Furthermore, individual mouse strain plasma pools, and individual NHP samples representing different genetic origins were also screened for cross-reactivity to endogenous FVIII antigen and found to be negative. The sandwich ELISA was used to quantify FVIII antigen in defined plasma samples from normal or Hemophilia A human subjects, and antigen levels correlated with the reported FVIII activity. The ELISA procedure was modified and adapted for estimation of the human FVIII antigen molecular weight. FVIII heavy and light chains, from normal human plasma pool or recombinant human FVIII-B domain deleted (FVIII-BDD), were enriched followed by resolution using a denaturing reducing PAGE and western blotting. The apparent migration of heavy and light chain was at the appropriate molecular weights; 90-185 kDa for heavy chain and 70 kDa for light chain. In case of heavy chain from normal human plasma pool, a ladder of differing molecular weights was seen and may be indicative of the differential furin and thrombin dependent processing of the B-domain. Thus, these newly developed assays for quantification of human FVIII and estimation of its molecular weights will be useful for further characterization of gene therapy for Hemophilia A.
化学的最適化を介した新規デュオカルマイシン腫瘍活性プロドラッグ抱合体CRX‐103の発見:in vitro特性化および原理の証明
Authors: NG Hp, Wu G, Saunders O, Martichonok, Roscoe W, Cardarelli P, Astafieva I, King D, Murakata C, Lobl T, Pickford L, Bebbington C, Yarranton G
Journal: Clinical Cancer Research (2001)
TP53 Gene Expression, Correlated with 17p13 Deletion, Is a Significant and Independent Adverse Prognostic Factor in Multiple Myeloma Treated with High-Dose Therapy and Auto-Transplants.
Authors: Wei Xiong, Fenghuang Zhan, Yongsheng Huang, Bart Barlogie, John D. Shaughnessy
Journal: Blood (2006)
64. Broad-Spectrum Anti-HIV RT RNA Aptamers
Authors: Margaret J. Lange, Phuong D.M. Nguyen, Mackenzie K. Callaway, Donald H. Burke
Journal: Molecular Therapy (2015)

Despite recent therapeutic progress, HIV remains a significant problem, due in part to the propensity of the virus to develop resistance. New, broad-spectrum therapeutics targeting diverse HIV strains and drug-resistant mutants could curtail the emergence of viral escape mutants by increasing the genetic barrier to resistance. RNA aptamers that target HIV reverse transcriptase (RT) and inhibit RT activity through competition with primer/template for access to the RT active site. Some aptamer structural families inhibited RT from only certain subtypes of HIV in biochemical assays. For example, family 1 pseudoknots (F1pk) inhibited RT only from HIV-1 subtype B. More recently, we identified several classes of broad spectrum aptamers that biochemically inhibit diverse RT subtypes. However, neither aptamer class has been evaluated in cell culture for the ability to inhibit diverse HIV strains. To evaluate potentially broad-spectrum aptamers in cell culture, we engineered recombinant reporter virus plasmids encoding RT from phylogenetically diverse viruses (HIV-1 subtypes A and B, Group O, and HIV-2) in the HIV-1NL4-3 background, keeping all other viral components constant. Viability of the recombinant viruses was determined using single-cycle infectivity assays to compare each recombinant construct to the parent (HIV-1NL4-3 RT). The new constructs were then tested against aptamers known to inhibit the parent construct. Importantly, aptamer-mediated inhibition correlated with our previous biochemical results when these reporter viruses were produced in cells that expressed aptamers. Broad-spectrum inhibition was observed for one new class of aptamers using representative aptamer 88.1 (6/5 asymmetric loop motif). Notably, aptamer 70.05 (F1pk) inhibited RT from viral strain HXB2 (Group M, subtype B), but not RT from strain MVP5180 (Group O) in infectivity assays. This observation correlates with biochemical results and represents the first demonstration of aptamer-specific resistance in cell culture. In addition, a single point mutation (R277K) demonstrated to confer biochemical resistance also completely abolished inhibition of the provirus expressing HXB2 RT for aptamer 70.05. Thus, viruses expressing RTs from diverse HIV strains in a constant backbone served three functions: (1) to identify RT as the genetic locus responsible for aptamer-mediated inhibition, (2) to demonstrate aptamer-specific resistance for the first time in cell culture, and (3) to assay broad-spectrum activity of our new class of aptamers. Our current work is focused on further exploring aptamer-RT interactions to determine mechanisms governing antiviral specificity and viral encapsidation of anti-HIV RT aptamers.
501. Radioiodinated Adeno-Associated Virus: A Promising New Approach for Monitoring Gene Therapy
Authors: Paresh J. Kothari, Bishnu P. De, Bin He, Conor Foley, Alvin Chen, Maria J. Chiuchiolo, Dolan Sondhi, Stephen Kaminsky, John Babich, Shankar Vallabajosula, Ronald G. Crystal, Douglas Ballon
Journal: Molecular Therapy (2015)

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a form of Batten disease that is caused by mutations in the CLN2 gene. These defects cause widespread neurodegeneration resulting in death by the age of 10-12 years. One treatment for LINCL that has shown promise in animal and clinical studies is gene therapy using adeno-associated virus (AAV) as a vehicle to deliver the CLN2 gene throughout the brain. This is currently accomplished by direct infusion, but there is no way to measure the spatial distribution of administered vector. Iodine-124 labeling of the viral capsid may offer a means for non-invasive determination of spatial distribution using MicroPET imaging. The production of AAVrh.10CLN2 under GMP conditions met endotoxin, mycoplasma, sterility and transgene expression release criteria. Purified AAVrh.10CLN2 was concentrated to 1013 gene copies/ml. Labeling with Na124I was carried out at 2-5 0C under mild oxidizing conditions in pH 7.5 buffer. Following radiolabeling, the product mixture was purified using an anion exchange cartridge and centrifugal filtration. Purified I124-AAVrh.10CLN2 was formulated in a pH 7.4 PBS buffer. The sterile formulation was injected (2 ml at 2.5 μCi/ml) intraparenchymally to the striatum in the murine brain and imaged on a Siemens Inveon MicroPET scanner. Thirty minute PET scans were acquired for each mouse (n=3). For the control group, we performed the same procedure using free Na 124I alone (n=3). The radiolabeling efficiency of AAV was in the range of 12-14%. PET/CT imaging clearly demonstrated the spatial distribution of vector over a ten day period, with minimal 124I uptake in the unblocked thyroid. In contrast, free iodide was rapidly cleared from the brain within 2 days (Figure 1). In conclusion, adeno-associated virus was successfully labeled with 124I and its distribution in the mouse brain was observed. This radiolabeling approach has the potential for wide application in gene therapy trials.
Towards An Improvement of the Coagulation Imbalance in Sickle Cell Disease After Hematopoietic Stem Cell Transplantation: A Preliminary Study
Authors: Denis F Noubouossie, Jan Emmerechts, France Debaugnies, Phu-Quoc Le, Laurence Rozen, Marc F. Hoylaerts, Anne Demulder, Alina Ferster
Journal: Blood (2011)
Abstract 1931: Mathematical modeling predicts exponential growth kinetics for metastases in the lymphatic vessels in the absence of vascularization
Authors: Ruth E. Griswold, Simona Podgrabinska, Suvendu Das, Boyce Griffith, Charles S. Peskin, Mihaela Skobe
Journal: Cancer Research (2015)

Abstract The objective of this study was to examine how the biophysical characteristics of different metastatic niches influence survival and growth of metastatic cells using mathematical modeling. In the lung, metastases can form in the lung parenchyma or in the lymphatic vessels. The presence of cancer metastases in the lung lymphatics is associated with rapid disease progression and extremely poor prognosis for patients. Remarkably, metastases in pulmonary lymphatics are avascular, yet grow larger than metastases in the lung parenchyma. To explain rapid growth of metastases in the lymphatics in the absence of angiogenesis, we have developed a 3D mathematical model of intralymphatic tumor growth. This is a deterministic continuum model based on partial differential equations used to describe avascular tumor growth and adapted to reflect the unique architecture of the lymphatic vasculature. Our model predicts that the cylindrical shape of the lymphatic vessel, which constrains growth of the tumor in two dimensions yet allows indefinite growth along the vessel, enables oxygen levels to remain high throughout the tumor. The greater diffusion coefficient of oxygen in lymph further improves oxygenation of intralymphatic metastases, which rarely become hypoxic. Improved tumor oxygenation leads to decreased tumor cell death and a rapid increase of metastatic burden in the lymphatics. Importantly, our model predicts that the kinetics of growth of intralymphatic metastases is exponential. This contrasts the established view that all tumors follow Gompertzian growth kinetics, i.e., that tumor growth rate decreases as tumor size increases. Furthermore, these findings indicate that the lymphatic niche is a favorable environment for metastatic growth, and that angiogenesis is not always required for the progressive growth of metastases. Finally, our predictions of different growth kinetics of primary tumors and their metastases suggest that the treatment schedules for metastatic disease could be further optimized to achieve better efficacy. Citation Format: Ruth E. Griswold, Simona Podgrabinska, Suvendu Das, Boyce Griffith, Charles S. Peskin, Mihaela Skobe. Mathematical modeling predicts exponential growth kinetics for metastases in the lymphatic vessels in the absence of vascularization. [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 1931. doi:10.1158/1538-7445.AM2015-1931
SURG-14. OPERATIVE MORTALITY RATES OF ACOUSTIC NEUROMA SURGERY: A NATIONWIDE CANCER DATABASE ANALYSIS
Authors: Shearwood McClelland, James D Murphy, Charles R Thomas
Journal: Neuro-Oncology (2016)

Optimal management of acoustic neuroma (AN) involves choosing between three treatment modalities: microsurgical excision, radiation (fractionated stereotactic radiotherapy or stereotactic radiosurgery), or observation with serial imaging. The in-hospital mortality rate of surgery for AN in the United States is 0.5% (McClelland et al., 2011). However, there has yet to be a nationwide examination of the AN surgery mortality rate encompassing the period beyond initial hospital discharge. The National Cancer Data Base (NCDB) from 2004-2013 identified AN patients receiving surgery. Multivariate logistic regression assessed the mortality of surgery at 30 days postoperatively, adjusting for several variables including patient age, race, sex, income, geographic region, primary payer for care, tumor size, and medical comorbidities. A total of 10,136 patients received surgery as solitary treatment for AN. Mortality at 30 days postoperatively occurred in 49 patients (0.5%). Mortality at 60 and 90 days postoperatively occurred in 67 (0.7%) and 81 (0.8%) patients, respectively. At 30 days postoperatively, only a Charlson/Deyo score of 2 (OR=6.6;95%CI=2.6-16.6;p=0.002) was predictive of increased mortality. No other patient demographic, including African-American race (OR=1.9;95%CI=0.7-5.1;p=0.23), minimum age of 65 (OR=2.2;95%CI=0.8-5.6;p=0.11) or government insurance (OR=6.2;95%CI=2.0-18.9;p=0.06) was predictive of 30-day operative mortality. The 30-day mortality rate following surgery for AN is 1/200 (0.5%), which is equivalent to the established in-hospital operative mortality rate, and is 2.5 times higher than the cumulative assessment from single-center studies (Sughrue et al., 2011). No patient demographic other than increasing medical comorbidities reached significance in predicting 30-day operative mortality. The nearly identical rates of 30-day and in-hospital mortality from separate nationwide analyses indicate that nearly all of the operative mortality occurs prior to initial postoperative discharge from the hospital. This mortality rate provides a framework for comparing the true risks and benefits of surgery versus radiation or observation for AN.
Abstract 430: MCP-1/CCL2 and IL-8 regulate proteolytic activity of triple negative inflammatory breast cancer via cathepsin B, ERK1/2, JAK1 and Src signaling pathways
Authors: Sherif A. Ibrahim, Eslam A. Elghonaimy, Mohamed El-Shinawi, Medhat El-Halawany, Mohamed A. Nouh, Tahani El-Mamlouk, Bonnie F. Sloane, Mona Mostafa Mohamed
Journal: Cancer Research (2015)

Abstract Background Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Recently, we have shown that macrophages isolated from the tumor microenvironment of IBC patients secrete monocyte chemoattractant protein-1/CC-chemokine ligand 2 (MCP-1/CCL2) and IL-8 that augment dissemination and metastasis of IB carcinoma cells. However, the precise molecular mechanism by which these cytokines exert their effect is still unclear. Methods In the present study, the triple negative breast cancer (TNBC) cell lines Sum149 (IBC) and HCC70 (non-IBC) cells were employed to analyze the effect of IL-8 and MCP-1/CCL2 on the proteolytic activity using live cell imaging assay, expression of cathepsin B and the activation status of STAT3, AKT, JAK1 and Src. In addition, we enrolled TNBC patients sub-grouped into IBC (n = 15), non-IBC (n = 19) patients. Results Our results revealed that upon stimulation with MCP-1/CCL2 and IL-8, Sum149 cells and HCC70 exhibited an increase in DQ-collagen degradation-mediated proteolytic activity. Mechanistically, MCP-1/CCL2 and IL-8 increase collagen degradation via enhanced expression of cathepsin B single chain mature enzyme (31 kDa) and the heavy chain of double chain mature enzyme (25/26 kDa). Moreover, MCP-1/CCL2 and IL-8 enhance activation of STAT3, ERK1/2 and AKT in both Sum149 and HCC70 cells. Interestingly, we detected over-expression of cathepsin B in the carcinoma tissues of TNBC-IBC patients compared to non-IBC patients. Over expression of cathepsin B found to be associated with activation of Src and ERK1/2, in IBC as compared to non-IBC tissues. Conclusions Our data indicate that MCP-1/CCL2 and IL-8 stimulate proteolytic activity, cathepsin B expression and Src-ERK1/2 pathway in IBC tissues versus non-IBC. Targeting MCP-1/CCL2 and IL-8 in triple negative IBC patients represents a promising therapeutic strategy. Citation Format: Sherif A. Ibrahim, Eslam A. Elghonaimy, Mohamed El-Shinawi, Medhat El-Halawany, Mohamed A. Nouh, Tahani El-Mamlouk, Bonnie F. Sloane, Mona Mostafa Mohamed. MCP-1/CCL2 and IL-8 regulate proteolytic activity of triple negative inflammatory breast cancer via cathepsin B, ERK1/2, JAK1 and Src signaling pathways. [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 430. doi:10.1158/1538-7445.AM2015-430
Molecular Response &lt;1% BCR-ABL IS at 12 Months Is Associated with Improved Overall and Progression-Free Survival. the Randomized German CML-Study IV
Authors: Martin C. Müller, Andreas Hochhaus, Michael Lauseker, Susanne Jung-Munkwitz, Markus Pfirrmann, Armin Leitner, Stefan W. Krause, Nadine Pletsch, Benjamin Hanfstein, Susanne Schnittger, Alois Gratwohl, Jörg Hasford, Susanne Saussele, Rüdiger Hehlmann
Journal: Blood (2010)
The Heatshockprotein-90 Inhibitor IPI-504 Potently Overcomes Tyrosinekinase Inhibitor-Induced Activation of Cell Protection Mechanisms and Degrades HSP-Client Proteins KIT and FLT3 In Acute Leukemia Models
Authors: Marcus Schittenhelm, Tanja Grandl, Emmanuel Normant, Helmut R. Salih, Kerstin M Kampa-Schittenhelm
Journal: Blood (2010)
261. Directed Evolution of an Antibody-Evading Cardiac Tropic AAV Vector
Authors: Melissa A. Kotterman, Bum-Yeol Hwang, David V. Schaffer
Journal: Molecular Therapy (2015)

Gene delivery vectors based on natural serotypes of adeno-associated viruses (AAV) have demonstrated promise in both preclinical models and human clinical trials for several disease targets, including advanced heart failure. However, delivery challenges, including low to no transduction with natural AAV serotypes in the presence of neutralizing antibodies and lack of specific and/or efficient distribution to many potential target tissues, remain obstacles to AAV gene therapy reaching its full potential. Directed evolution has proven to be a powerful approach to generate AAV vectors with novel capabilities, and previous work has shown that AAV can evolve to significantly overcome neutralization by anti-AAV antibodies, both in vitro and in vivo. AAV vectors with enhanced evasion in the presence of anti-AAV antibodies were evaluated for specificity to various tissues. A shuffled AAV variant (Sh100-7) composed of AAV1, 6, and 8 with additional point mutations was found to efficiently and preferentially transduce cardiac tissue. Variant Sh100-7 is capable of enhanced transduction of and specificity for the murine heart in both naïve and human IVIG (intravenous immunoglobulin) passively immunized mice following intravenous administration. In naïve mice, administration of variant Sh100-7 leads to significantly higher gene expression in the heart (over 7-fold higher compared to AAV2). Sh100-7 preferentially transduces the heart compared to all other tissues (including skeletal muscle), and the heart:liver gene expression ratio for Sh100-7 of 60:1 is over 33-fold higher than AAV2 and 6-fold higher than a previously published myocardium-tropic vector. In a human IVIG-passively immunized mouse model, Sh100-7-mediated gene expression in the heart is only decreased 4-fold, while AAV2-mediated gene expression in the heart is decreased 123-fold. In the presence of antibodies, the heart:liver gene expression ratio for Sh100-7 (14:1) remains over 23-fold higher than AAV2. In vivo tropism of Sh100-7 in a large animal model is currently under evaluation. The ability to specifically transduce cardiac cells through intravenous delivery could enable simpler administration of gene therapy products for heart disease and the use of lower doses (which could reduce vector immune responses). Furthermore, the increased resistance to circulating anti-AAV antibodies may enable the use of Sh100-7 in the future treatment of patients with high antibody titers that are currently ineligible for AAV gene therapy.