1) The study evaluated a boronated monoclonal antibody (BD-L8A4) that targets the EGFRvIII receptor for the treatment of EGFRvIII-positive rat glioma (F98npEGFRvIII) using boron neutron capture therapy (BNCT).
2) Biodistribution studies found higher retention of BD-L8A4 in EGFRvIII-positive tumors compared to negative tumors after 24 hours.
3) BNCT studies then showed that F98npEGFRvIII-bearing rats treated with BD-L8A4 alone or with boronophenylalanine (BPA) had significantly prolonged survival compared to controls, with some rats
Boronated Cetuximab CCR tumor targeting in BNCTkent.riley
This document describes a study evaluating boronated cetuximab (BD-C225) for boron neutron capture therapy (BNCT) of epidermal growth factor receptor (EGFR) positive gliomas. In vitro, BD-C225 showed preferential uptake in EGFR positive glioma cells compared to EGFR negative cells. In vivo, rats with EGFR positive glioma tumors received intracerebral BD-C225, achieving high boron levels in the tumors. BNCT with BD-C225 alone or combined with boronophenylalanine extended survival compared to controls. The results provide support for using molecularly targeted boron delivery agents like BD-C225 for BNCT of brain tumors.
This study evaluated the effectiveness of a 3-carboranyl thymidine analogue (3CTA), designated N5–2OH, as a boron delivery agent for boron neutron capture therapy (BNCT) of brain tumors. Target validation studies using wild-type and mutant thymidine kinase 1 (TK1) L929 cell lines implanted in mice found higher boron levels and tumor cell kill in TK1-expressing tumors after BNCT with N5–2OH. Subsequent studies in rats with intracerebral RG2 gliomas found significantly increased survival times when tumors were treated with either N5–2OH alone or combined with boronophenylalanine compared to boronophenyl
Detection of hepatitis b virus (hbv) dna among blood donors with h bs ag posi...Alexander Decker
1) The study aimed to detect Hepatitis B virus (HBV) DNA through nested polymerase chain reaction (PCR) technique in 13 blood donor samples that tested positive for Hepatitis B surface antigen (HBsAg) in Tuban District, Indonesia.
2) Nested PCR using two different primer pairs found HBV DNA in all 13 samples, while the first PCR with a single primer pair only found HBV DNA in 3 of the 13 samples.
3) Using two different primer pairs in nested PCR can help detect HBV DNA that may be missed by a single primer pair, given that all samples were previously positive for HBsAg.
This document discusses the marriage of translational medicine and big data. It notes that predicting treatment response to known oncogenes like EGFR is complex and requires detailed understanding of genetic backgrounds. Networks can identify genes causal for disease. The approach uses probabilistic causal network models, with over 80 publications validating the scientific approach. Sage Bionetworks is building disease maps and data repositories through collaborations with industry, foundations, government and academia. Fundamentally, biological science hasn't changed due to omics but iterative networked approaches are needed to generate, analyze and support new disease models.
This document summarizes recent advances in the anticancer properties of berberine. Berberine is an alkaloid extracted from plants that has been used in traditional Chinese and Ayurvedic medicines. It has diverse pharmacological activities including antimicrobial, anti-inflammatory, and anticancer effects. Berberine shows anticancer activity against various cancer types in vitro and in vivo. Ongoing clinical trials are investigating berberine's effects on cancer as well as other diseases. Chemical modifications of berberine have produced derivatives with improved binding to DNA and anticancer activity. In particular, NAX035 has shown efficacy against mesothelioma in vitro and in vivo models at well-tolerated doses.
The role of integrase inhibitors in first line and later antiretroviral thera...Hivlife Info
This document discusses integrase inhibitors for the treatment of HIV. It summarizes clinical trials comparing the integrase inhibitors raltegravir, elvitegravir, and dolutegravir to efavirenz and atazanavir/ritonavir in treatment-naive patients. The studies found integrase inhibitors were as effective as or better than comparators in suppressing HIV, with fewer side effects. Raltegravir given once daily was inferior to twice daily dosing. Elvitegravir/cobicistat was found to be noninferior to efavirenz and atazanavir/ritonavir through 144 weeks.
Raltegravir was the first HIV integrase inhibitor discovered. It was developed through extensive medicinal chemistry efforts at IRBM Science Park, optimizing properties like potency, pharmacokinetics, and resistance profile. Key developments included investigating substitutions on pyrimidine-based scaffolds and ultimately identifying the N-methylpyrimidinone series. Raltegravir demonstrated potent antiviral activity against HIV with no observed toxicity in clinical trials. Its approval in 2007 marked a new class of antiretroviral drugs for treating HIV infection.
Src jbbr-20-120 Dr. ihsan edan abdulkareem alsaimary PROFESSOR IN MEDICAL M...dr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
Boronated Cetuximab CCR tumor targeting in BNCTkent.riley
This document describes a study evaluating boronated cetuximab (BD-C225) for boron neutron capture therapy (BNCT) of epidermal growth factor receptor (EGFR) positive gliomas. In vitro, BD-C225 showed preferential uptake in EGFR positive glioma cells compared to EGFR negative cells. In vivo, rats with EGFR positive glioma tumors received intracerebral BD-C225, achieving high boron levels in the tumors. BNCT with BD-C225 alone or combined with boronophenylalanine extended survival compared to controls. The results provide support for using molecularly targeted boron delivery agents like BD-C225 for BNCT of brain tumors.
This study evaluated the effectiveness of a 3-carboranyl thymidine analogue (3CTA), designated N5–2OH, as a boron delivery agent for boron neutron capture therapy (BNCT) of brain tumors. Target validation studies using wild-type and mutant thymidine kinase 1 (TK1) L929 cell lines implanted in mice found higher boron levels and tumor cell kill in TK1-expressing tumors after BNCT with N5–2OH. Subsequent studies in rats with intracerebral RG2 gliomas found significantly increased survival times when tumors were treated with either N5–2OH alone or combined with boronophenylalanine compared to boronophenyl
Detection of hepatitis b virus (hbv) dna among blood donors with h bs ag posi...Alexander Decker
1) The study aimed to detect Hepatitis B virus (HBV) DNA through nested polymerase chain reaction (PCR) technique in 13 blood donor samples that tested positive for Hepatitis B surface antigen (HBsAg) in Tuban District, Indonesia.
2) Nested PCR using two different primer pairs found HBV DNA in all 13 samples, while the first PCR with a single primer pair only found HBV DNA in 3 of the 13 samples.
3) Using two different primer pairs in nested PCR can help detect HBV DNA that may be missed by a single primer pair, given that all samples were previously positive for HBsAg.
This document discusses the marriage of translational medicine and big data. It notes that predicting treatment response to known oncogenes like EGFR is complex and requires detailed understanding of genetic backgrounds. Networks can identify genes causal for disease. The approach uses probabilistic causal network models, with over 80 publications validating the scientific approach. Sage Bionetworks is building disease maps and data repositories through collaborations with industry, foundations, government and academia. Fundamentally, biological science hasn't changed due to omics but iterative networked approaches are needed to generate, analyze and support new disease models.
This document summarizes recent advances in the anticancer properties of berberine. Berberine is an alkaloid extracted from plants that has been used in traditional Chinese and Ayurvedic medicines. It has diverse pharmacological activities including antimicrobial, anti-inflammatory, and anticancer effects. Berberine shows anticancer activity against various cancer types in vitro and in vivo. Ongoing clinical trials are investigating berberine's effects on cancer as well as other diseases. Chemical modifications of berberine have produced derivatives with improved binding to DNA and anticancer activity. In particular, NAX035 has shown efficacy against mesothelioma in vitro and in vivo models at well-tolerated doses.
The role of integrase inhibitors in first line and later antiretroviral thera...Hivlife Info
This document discusses integrase inhibitors for the treatment of HIV. It summarizes clinical trials comparing the integrase inhibitors raltegravir, elvitegravir, and dolutegravir to efavirenz and atazanavir/ritonavir in treatment-naive patients. The studies found integrase inhibitors were as effective as or better than comparators in suppressing HIV, with fewer side effects. Raltegravir given once daily was inferior to twice daily dosing. Elvitegravir/cobicistat was found to be noninferior to efavirenz and atazanavir/ritonavir through 144 weeks.
Raltegravir was the first HIV integrase inhibitor discovered. It was developed through extensive medicinal chemistry efforts at IRBM Science Park, optimizing properties like potency, pharmacokinetics, and resistance profile. Key developments included investigating substitutions on pyrimidine-based scaffolds and ultimately identifying the N-methylpyrimidinone series. Raltegravir demonstrated potent antiviral activity against HIV with no observed toxicity in clinical trials. Its approval in 2007 marked a new class of antiretroviral drugs for treating HIV infection.
Src jbbr-20-120 Dr. ihsan edan abdulkareem alsaimary PROFESSOR IN MEDICAL M...dr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
This document discusses using molecular genotyping methods to investigate the genetic diversity of Mycobacterium tuberculosis strains in Taiwan. It provides background on M. tuberculosis and describes several genotyping methods including restriction fragment length polymorphism (RFLP), spoligotyping, variable number tandem repeats (VNTR), and mycobacterial interspersed repetitive units (MIRU). The study aims to evaluate the genotyping efficiency of these methods, select appropriate genetic markers, and establish high-throughput protocols. Preliminary results on 479 samples from Taiwan show discrimination of strains by region, age, gender and genotype. Locus discrimination power and Hunter-Gaston discrimination index are also reported for different genotyping methods.
This document summarizes a study on the preparation of F(ab')2 trastuzumab fragment for use in synthesizing a 177Lu radioimmunoconjugate. Key points:
1. Trastuzumab was purified from preservatives by dialysis.
2. Pepsin digestion at a ratio of 1:4 (enzyme:antibody) for 18 hours at 37°C was found to completely digest trastuzumab into F(ab')2 fragments.
3. F(ab')2 fragments were purified from other fragments using a Sephadex G-25 column and characterized using SEC-HPLC and SDS-PAGE, showing 98% purity and a molecular weight of
The document discusses new drugs for the treatment of lymphomas. It outlines several monoclonal antibodies that target antigens on B-cells, including CD20, CD19, CD22 and CD37. Ofatumumab and GA-101 are new anti-CD20 monoclonal antibodies that exhibit enhanced binding and cell-killing properties compared to Rituximab. Inotuzumab Ozogamicin is an antibody-drug conjugate targeting CD22 that is internalized and releases a cytotoxic drug, showing promising activity in early clinical trials.
The document discusses using computational methods to help eradicate disease. It outlines the typical long timelines and high costs involved in drug discovery. It then describes using the ChemGenome software to analyze genome sequences and identify potential drug targets, generate lead molecules that bind to targets, and identify 24 hit molecules that could be tested for treating hepatitis B virus. The overall process takes genome sequences as input and outputs potential drug candidates to help streamline the drug discovery process in silico.
Stephen Friend NIH PPP Coordinating Committee Meeting 2012-02-16Sage Base
The document discusses using networked team approaches and integrating omics data to build better disease maps through public-private partnerships like CTCAP and Arch2POCM. It proposes sharing clinical and genomic data from comparator arms of trials to create models and de-risking novel drug targets through developing test compounds in a precompetitive space to accelerate new therapies.
This document summarizes a study investigating the relationship between activation of the alpha7 nicotinic acetylcholine receptor (α7nAChR) and the nuclear factor erythroid 2–related factor 2 (Nrf2) in antagonizing renal ischemia-reperfusion injury. The study examined the effects of a selective α7nAChR agonist on apoptosis and apoptotic signaling in renal epithelial cells subjected to hypoxia-reoxygenation injury. It was found that the agonist attenuated apoptosis and modulated levels of apoptotic proteins like caspase-3 and Bax. Inhibition of Nrf2 partially blocked these effects, indicating Nrf2 mediates the anti-apoptotic effects of α7nAChR activation
This document summarizes research investigating the binding affinity of four fungal peptides (Pneumocandin B0, Aureobasidin G, WF 11899A, and Echinocandin B) to the protein cFLIP using molecular docking software. The key findings were:
1) Pneumocandin B0 showed the highest binding affinity to cFLIP with a binding energy of -455.18.
2) Aureobasidin G had the second highest binding affinity with an energy of -414.96.
3) All four fungal peptides showed potential to inhibit cFLIP and could enhance TRAIL-mediated apoptosis in cancer cells, though further in vitro and in vivo studies
Stephen Friend Food & Drug Administration 2011-07-18Sage Base
The document discusses potential opportunities for participating in clinical trial projects that study network perturbations in clinical specimens to better understand how to select effective drug targets for different diseases and patients. It describes four potential projects: 1) a clinical trial comparator arm project, 2) a project to decode biology using drug compounds, 3) an oncology non-responders project, and 4) a project to free up failed drug compounds. It asks what actions the FDA or other executive/legislative bodies might take regarding these projects.
This document summarizes information presented about Mycobacterium tuberculosis and tuberculosis. It discusses that M. tuberculosis grows slowly, doubling every 24 hours, and takes 3-4 weeks to culture. It also notes that tuberculosis infects around 2 billion people globally and causes 1.6 million deaths per year. The document also mentions that multidrug resistant tuberculosis is emerging worldwide and there are an estimated 50 million people infected with multidrug resistant strains.
Antimicrobial Agents and Chemotherapy 2003 47(8)2674-2681Dinesh Barawkar
This document summarizes research demonstrating that dinucleotide analogs can inhibit the RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV), representing a novel approach for antiviral therapy. Specifically, it shows that dinucleotide analogs can serve as inhibitors of de novo initiation of RNA synthesis by the HCV NS5B RdRp. The presence of a 5'-phosphate group on the dinucleotide compounds was required for efficient inhibition. Optimal inhibitory activity also depended on the potential for base pairing between the 3' ends of the analog and the viral RNA template. These findings suggest dinucleotide analogs may provide a new strategy for targeting the initiation step of HCV RNA replication.
Two new drugs for colorectal cancer may offer new hope for late stage patients, and they might hit the market in 2013.
Dr. Rich Goldberg, physician-in-chief of the Ohio State University Medical Center and a leader in colorectal cancer research is going to give you the straight facts about these drugs:
* What hope might they offer?
* What side effects do they cause?
* Will either be the right drug for you?
About Dr. Goldberg:
Dr. Richard Goldberg is an internationally renowned gastrointestinal oncologist and the physician-in-chief at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Institute (OSUCCC-James). He is a member and former chair of the National Cancer Institute Colorectal Task Force and an international leader in evaluating new agents for the treatment of colorectal cancer and researching inherited colorectal cancer syndromes
The document summarizes research on expressing HIV-1 antigens in plants as a potential vaccine. The researchers found that transient expression in plants is a viable alternative to transgenic plants. They determined that targeting the HIV-1 Gag protein Pr55Gag and its derivative p17/24 to chloroplasts yielded the highest levels of these proteins. Mice vaccinated with p17/24 produced from chloroplasts developed strong CD4+ and CD8+ T cell responses and HIV-specific antibodies, showing it is a promising vaccine candidate.
This document discusses translational models of drug-induced liver injury. It begins by outlining the integrated mechanistic drug safety approach, which investigates chemicals, patients, and the interaction between the two. A key part of this approach is understanding the mechanisms of drug bioactivation and the consequences for cellular toxicity. Paracetamol is used as a case study, as it is a common cause of drug-induced liver injury. The document explores the mechanisms of paracetamol toxicity, including how its reactive metabolite NAPQI causes oxidative stress and depletion of glutathione, leading to liver cell damage through both necrosis and inflammation. It also discusses the role of the Nrf2 transcription factor in regulating the antioxidant response and adapting cells to
This document discusses recent updates in the diagnosis of tuberculosis (TB). Direct diagnostic methods discussed include microscopic examination of samples after staining, various culture methods, and nucleic acid amplification tests. Microscopic examination remains the quickest method but has limited sensitivity. Culture allows for identification of the causative organism and is more sensitive but takes longer. Newer rapid culture methods using broth take less time than traditional solid culture. Molecular tests like PCR and LAMP can directly detect TB from samples and provide results faster than culture, but require more validation and quality control.
This document summarizes a study that evaluated the use of a recombinant Toxoplasma gondii surface antigen 1 (SAG1) for the serodiagnosis of acute and chronic Toxoplasma infections in humans. The researchers cloned the SAG1 gene from T. gondii genomic DNA and expressed the recombinant protein in E. coli. They then used the recombinant SAG1 antigen in ELISA tests to detect IgM and IgG antibodies in human sera, comparing it to a commercial ELISA kit. The recombinant SAG1 ELISA showed 93% sensitivity and 95% specificity for IgG detection, and 87% sensitivity and 95% specificity for IgM detection, demonstrating its potential as a diagnostic tool for toxoplasmosis
This document discusses using data intensive science to build better disease models in a collaborative manner. It notes that current disease models often assume pathways are well understood enough to infer therapies, but reality is more complex with overlapping pathways. The document proposes a "data intensive" approach using large datasets, interoperable IT, open information systems, and hosting evolving computational models. This could help build better disease maps by facilitating identification of causal genes and evolutionary weak spots through probabilistic network models. The document advocates creating an "information commons" to advance such collaborative modeling beyond current incentives.
This document describes a study that used bioinformatics tools to analyze the interaction between a 14-amino acid peptide derived from buffalo prolactin (buPRL) and the bradykinin B1 receptor. Molecular docking was performed between structures of the receptor and the peptide, as well as somatostatin and a scrambled version of the peptide. The docking results indicated that the buPRL peptide binds to the receptor's active site, similarly to somatostatin. The binding energies of the buPRL peptide-receptor complex and somatostatin-receptor complex were comparable, suggesting the buPRL peptide may act as an antagonist of the kallikrein-kinin system by binding to
This document summarizes the current status of boron neutron capture therapy (BNCT) for treating cancer. BNCT uses a two-step process where a boron-containing compound selectively delivers boron-10 to cancer cells, then a neutron beam causes the boron-10 to undergo fission, releasing particles that destroy the cancer cells. The document reviews the most commonly used boron delivery agents, ongoing clinical trials for treating brain tumors and other cancers, and critical issues still needing to be addressed like developing more selective boron agents and demonstrating clear therapeutic efficacy in randomized clinical trials.
The goal of this study was to analyze the effects of Csk knockouts on development of the initial segment of the epididymis. Immunofluorescence staining of control and Csk knockout mice found no differences in expression of proteins related to proliferation and differentiation. However, platelet-derived growth factor beta (PDGF-β), which enhances capillary growth, showed significantly higher expression in knockout mice at 8 weeks, suggesting increased angiogenesis over time without Csk inhibition. Further analysis is needed but this preliminary result indicates Csk knockouts may lead to time-sensitive increased vascularization in the initial epididymis segment.
This document summarizes a study comparing a new bombesin peptide antagonist (JMV4168) to agonists for targeting gastrin releasing peptide receptors (GRPR) overexpressed on prostate and breast cancers. In vitro assays showed JMV4168 bound to GRPR-expressing cells, with most radiation dose from the cell surface, unlike the agonist which was mostly internalized. In vivo studies in mice found JMV4168 had fast clearance from the pancreas and other tissues, suggesting it could be safely used for clinical imaging and treatment of GRPR-overexpressing tumors. The antagonist showed superior profile compared to agonists.
This document discusses using molecular genotyping methods to investigate the genetic diversity of Mycobacterium tuberculosis strains in Taiwan. It provides background on M. tuberculosis and describes several genotyping methods including restriction fragment length polymorphism (RFLP), spoligotyping, variable number tandem repeats (VNTR), and mycobacterial interspersed repetitive units (MIRU). The study aims to evaluate the genotyping efficiency of these methods, select appropriate genetic markers, and establish high-throughput protocols. Preliminary results on 479 samples from Taiwan show discrimination of strains by region, age, gender and genotype. Locus discrimination power and Hunter-Gaston discrimination index are also reported for different genotyping methods.
This document summarizes a study on the preparation of F(ab')2 trastuzumab fragment for use in synthesizing a 177Lu radioimmunoconjugate. Key points:
1. Trastuzumab was purified from preservatives by dialysis.
2. Pepsin digestion at a ratio of 1:4 (enzyme:antibody) for 18 hours at 37°C was found to completely digest trastuzumab into F(ab')2 fragments.
3. F(ab')2 fragments were purified from other fragments using a Sephadex G-25 column and characterized using SEC-HPLC and SDS-PAGE, showing 98% purity and a molecular weight of
The document discusses new drugs for the treatment of lymphomas. It outlines several monoclonal antibodies that target antigens on B-cells, including CD20, CD19, CD22 and CD37. Ofatumumab and GA-101 are new anti-CD20 monoclonal antibodies that exhibit enhanced binding and cell-killing properties compared to Rituximab. Inotuzumab Ozogamicin is an antibody-drug conjugate targeting CD22 that is internalized and releases a cytotoxic drug, showing promising activity in early clinical trials.
The document discusses using computational methods to help eradicate disease. It outlines the typical long timelines and high costs involved in drug discovery. It then describes using the ChemGenome software to analyze genome sequences and identify potential drug targets, generate lead molecules that bind to targets, and identify 24 hit molecules that could be tested for treating hepatitis B virus. The overall process takes genome sequences as input and outputs potential drug candidates to help streamline the drug discovery process in silico.
Stephen Friend NIH PPP Coordinating Committee Meeting 2012-02-16Sage Base
The document discusses using networked team approaches and integrating omics data to build better disease maps through public-private partnerships like CTCAP and Arch2POCM. It proposes sharing clinical and genomic data from comparator arms of trials to create models and de-risking novel drug targets through developing test compounds in a precompetitive space to accelerate new therapies.
This document summarizes a study investigating the relationship between activation of the alpha7 nicotinic acetylcholine receptor (α7nAChR) and the nuclear factor erythroid 2–related factor 2 (Nrf2) in antagonizing renal ischemia-reperfusion injury. The study examined the effects of a selective α7nAChR agonist on apoptosis and apoptotic signaling in renal epithelial cells subjected to hypoxia-reoxygenation injury. It was found that the agonist attenuated apoptosis and modulated levels of apoptotic proteins like caspase-3 and Bax. Inhibition of Nrf2 partially blocked these effects, indicating Nrf2 mediates the anti-apoptotic effects of α7nAChR activation
This document summarizes research investigating the binding affinity of four fungal peptides (Pneumocandin B0, Aureobasidin G, WF 11899A, and Echinocandin B) to the protein cFLIP using molecular docking software. The key findings were:
1) Pneumocandin B0 showed the highest binding affinity to cFLIP with a binding energy of -455.18.
2) Aureobasidin G had the second highest binding affinity with an energy of -414.96.
3) All four fungal peptides showed potential to inhibit cFLIP and could enhance TRAIL-mediated apoptosis in cancer cells, though further in vitro and in vivo studies
Stephen Friend Food & Drug Administration 2011-07-18Sage Base
The document discusses potential opportunities for participating in clinical trial projects that study network perturbations in clinical specimens to better understand how to select effective drug targets for different diseases and patients. It describes four potential projects: 1) a clinical trial comparator arm project, 2) a project to decode biology using drug compounds, 3) an oncology non-responders project, and 4) a project to free up failed drug compounds. It asks what actions the FDA or other executive/legislative bodies might take regarding these projects.
This document summarizes information presented about Mycobacterium tuberculosis and tuberculosis. It discusses that M. tuberculosis grows slowly, doubling every 24 hours, and takes 3-4 weeks to culture. It also notes that tuberculosis infects around 2 billion people globally and causes 1.6 million deaths per year. The document also mentions that multidrug resistant tuberculosis is emerging worldwide and there are an estimated 50 million people infected with multidrug resistant strains.
Antimicrobial Agents and Chemotherapy 2003 47(8)2674-2681Dinesh Barawkar
This document summarizes research demonstrating that dinucleotide analogs can inhibit the RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV), representing a novel approach for antiviral therapy. Specifically, it shows that dinucleotide analogs can serve as inhibitors of de novo initiation of RNA synthesis by the HCV NS5B RdRp. The presence of a 5'-phosphate group on the dinucleotide compounds was required for efficient inhibition. Optimal inhibitory activity also depended on the potential for base pairing between the 3' ends of the analog and the viral RNA template. These findings suggest dinucleotide analogs may provide a new strategy for targeting the initiation step of HCV RNA replication.
Two new drugs for colorectal cancer may offer new hope for late stage patients, and they might hit the market in 2013.
Dr. Rich Goldberg, physician-in-chief of the Ohio State University Medical Center and a leader in colorectal cancer research is going to give you the straight facts about these drugs:
* What hope might they offer?
* What side effects do they cause?
* Will either be the right drug for you?
About Dr. Goldberg:
Dr. Richard Goldberg is an internationally renowned gastrointestinal oncologist and the physician-in-chief at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Institute (OSUCCC-James). He is a member and former chair of the National Cancer Institute Colorectal Task Force and an international leader in evaluating new agents for the treatment of colorectal cancer and researching inherited colorectal cancer syndromes
The document summarizes research on expressing HIV-1 antigens in plants as a potential vaccine. The researchers found that transient expression in plants is a viable alternative to transgenic plants. They determined that targeting the HIV-1 Gag protein Pr55Gag and its derivative p17/24 to chloroplasts yielded the highest levels of these proteins. Mice vaccinated with p17/24 produced from chloroplasts developed strong CD4+ and CD8+ T cell responses and HIV-specific antibodies, showing it is a promising vaccine candidate.
This document discusses translational models of drug-induced liver injury. It begins by outlining the integrated mechanistic drug safety approach, which investigates chemicals, patients, and the interaction between the two. A key part of this approach is understanding the mechanisms of drug bioactivation and the consequences for cellular toxicity. Paracetamol is used as a case study, as it is a common cause of drug-induced liver injury. The document explores the mechanisms of paracetamol toxicity, including how its reactive metabolite NAPQI causes oxidative stress and depletion of glutathione, leading to liver cell damage through both necrosis and inflammation. It also discusses the role of the Nrf2 transcription factor in regulating the antioxidant response and adapting cells to
This document discusses recent updates in the diagnosis of tuberculosis (TB). Direct diagnostic methods discussed include microscopic examination of samples after staining, various culture methods, and nucleic acid amplification tests. Microscopic examination remains the quickest method but has limited sensitivity. Culture allows for identification of the causative organism and is more sensitive but takes longer. Newer rapid culture methods using broth take less time than traditional solid culture. Molecular tests like PCR and LAMP can directly detect TB from samples and provide results faster than culture, but require more validation and quality control.
This document summarizes a study that evaluated the use of a recombinant Toxoplasma gondii surface antigen 1 (SAG1) for the serodiagnosis of acute and chronic Toxoplasma infections in humans. The researchers cloned the SAG1 gene from T. gondii genomic DNA and expressed the recombinant protein in E. coli. They then used the recombinant SAG1 antigen in ELISA tests to detect IgM and IgG antibodies in human sera, comparing it to a commercial ELISA kit. The recombinant SAG1 ELISA showed 93% sensitivity and 95% specificity for IgG detection, and 87% sensitivity and 95% specificity for IgM detection, demonstrating its potential as a diagnostic tool for toxoplasmosis
This document discusses using data intensive science to build better disease models in a collaborative manner. It notes that current disease models often assume pathways are well understood enough to infer therapies, but reality is more complex with overlapping pathways. The document proposes a "data intensive" approach using large datasets, interoperable IT, open information systems, and hosting evolving computational models. This could help build better disease maps by facilitating identification of causal genes and evolutionary weak spots through probabilistic network models. The document advocates creating an "information commons" to advance such collaborative modeling beyond current incentives.
This document describes a study that used bioinformatics tools to analyze the interaction between a 14-amino acid peptide derived from buffalo prolactin (buPRL) and the bradykinin B1 receptor. Molecular docking was performed between structures of the receptor and the peptide, as well as somatostatin and a scrambled version of the peptide. The docking results indicated that the buPRL peptide binds to the receptor's active site, similarly to somatostatin. The binding energies of the buPRL peptide-receptor complex and somatostatin-receptor complex were comparable, suggesting the buPRL peptide may act as an antagonist of the kallikrein-kinin system by binding to
This document summarizes the current status of boron neutron capture therapy (BNCT) for treating cancer. BNCT uses a two-step process where a boron-containing compound selectively delivers boron-10 to cancer cells, then a neutron beam causes the boron-10 to undergo fission, releasing particles that destroy the cancer cells. The document reviews the most commonly used boron delivery agents, ongoing clinical trials for treating brain tumors and other cancers, and critical issues still needing to be addressed like developing more selective boron agents and demonstrating clear therapeutic efficacy in randomized clinical trials.
The goal of this study was to analyze the effects of Csk knockouts on development of the initial segment of the epididymis. Immunofluorescence staining of control and Csk knockout mice found no differences in expression of proteins related to proliferation and differentiation. However, platelet-derived growth factor beta (PDGF-β), which enhances capillary growth, showed significantly higher expression in knockout mice at 8 weeks, suggesting increased angiogenesis over time without Csk inhibition. Further analysis is needed but this preliminary result indicates Csk knockouts may lead to time-sensitive increased vascularization in the initial epididymis segment.
This document summarizes a study comparing a new bombesin peptide antagonist (JMV4168) to agonists for targeting gastrin releasing peptide receptors (GRPR) overexpressed on prostate and breast cancers. In vitro assays showed JMV4168 bound to GRPR-expressing cells, with most radiation dose from the cell surface, unlike the agonist which was mostly internalized. In vivo studies in mice found JMV4168 had fast clearance from the pancreas and other tissues, suggesting it could be safely used for clinical imaging and treatment of GRPR-overexpressing tumors. The antagonist showed superior profile compared to agonists.
Bifidobacterium strain that helps reduce body fatBiopolis_SL
Bifidobacterium animalis subsp. lactis strain CECT 8145 is able to reduce body fat content and improve metabolic syndrome biomarkers. Here, we report the draft genome sequence of this strain, which may provide insights into its safety status and functional role.
The document summarizes the results of a summer scholarship project investigating the interactions between FZR1, an activator of the anaphase promoting complex/cyclosome, and several potential protein targets. Using techniques like immunohistochemistry, western blotting, and immunoprecipitation, the localization and interactions of PP2A-α, CDC14B, and NEDL2 were analyzed in wild type and FZR1 knockout postnatal mouse testis tissue. PP2A-α results were found to be too variable to draw conclusions. CDC14B localization differences were observed between wild type and knockout tissue, but no interaction with FZR1 was detected, though further optimization may be warranted. Improved staining of NED
mRNA rather than DNA may become the nucleotide framework for new classes of drugs and vaccines. Exciting preclinical results in prophylaxis and initial clinical data in oncology suggest that mRNA technology could be translated into improvements in lung cancer and other diseases.
1) The document summarizes a presentation on chemotherapy options and management issues in HER-2 negative metastatic breast cancer.
2) It discusses whether to use single-agent chemotherapy or combinations, and whether combinations should be given simultaneously or sequentially. The data shows combinations yield higher response rates but similar survival and more toxicity compared to sequential single agents.
3) New chemotherapy agents discussed include eribulin, ixabepilone, and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). Biological agents discussed for HER-2 negative disease include PARP inhibitors and bevacizumab.
Jianying Xiao has over 16 years of experience in pharmaceutical research. She has expertise in in vivo and in vitro drug discovery techniques related to drug metabolism, infectious diseases, immunology, and cardio-metabolic disorders. She is proficient in various research techniques including animal handling, molecular biology, cell culture, and data analysis software. Jianying has worked at Merck & Co. for over 18 years, leading numerous projects that resulted in publications, patents, and awards. Her work has advanced drug programs from research through clinical trials.
1) The C-terminal carboxylate group of integrin β1 is necessary for its association with the kindlin-2 adapter protein. Affinity measurements indicate this interaction is coordinated by a putative carboxylate-binding motif in the FERM subdomain F3 of kindlin-2.
2) Injection of mRNA encoding mutant integrin β1 cytoplasmic tails that lack the C-terminal carboxylate group perturbed laterality organ development in zebrafish, indicating the carboxylate group is required for physiological functions.
3) The unusual interaction between integrin β1 and kindlin-2 identified here represents a novel protein-protein interaction mode governed mainly by the integrin
Summary of PROTAC Degraders in Clinical Trials.pdfDoriaFang
A major class of molecules that may enable such proteins to be modulated through TPD are known as proteolysis-targeting chimera (PROTAC) protein degraders. Here we talk about the summary of PROTAC degraders in clinical trials.
Clinical Trials in BNCT at the MIT Research Reactorkent.riley
A phase I clinical trial was conducted to evaluate neutron capture therapy for brain tumors. 24 patients with glioblastoma or melanoma metastases to the brain received boronophenylalanine followed by neutron irradiation. Doses were escalated in cohorts from 8.8 to 14.2 RBE-Gy. The most common side effects were alopecia and temporary increased intracranial pressure. More serious adverse events included respiratory failure in two elderly patients and one treatment-related death. Two patients showed a complete response, and tumor volume decreased in most patients. The trial demonstrated neutron capture therapy can achieve a clinical response with acceptable toxicity.
GU ASCO 2023 Targeted Therapy in mCRPC.pptxDoQuyenPhan1
Rana R. McKay is an associate professor of medicine and genitourinary oncology team lead who presented on emerging investigational targets and combinations for prostate cancer. The presentation discussed CDK4/6 inhibitors like abemaciclib, ribociclib, and palbociclib which drive cell cycle progression by phosphorylating Rb. Ongoing clinical trials were summarized that are exploring CDK4/6 inhibitors combined with standard therapies for metastatic castration-resistant prostate cancer or with novel agents like 177Lu-PSMA-617. Combining a PI3K/AKT/mTOR inhibitor, ipatasertib, with abiraterone was also discussed based on results from
This document summarizes key points about precision medicine in stage IV lung adenocarcinoma as an example:
- Biomarker testing like EGFR, ALK, ROS1 is essential to select appropriate targeted therapies and has become standard practice, with 92% of non-squamous cases tested for EGFR and 79% for ALK.
- Ongoing clinical trials are exploring new targets like RET fusions, NTRK fusions, and KRAS G12C mutations and corresponding therapies.
- Next-generation sequencing allows comprehensive genomic profiling but challenges include methodology, turnaround time, and reporting of clinically relevant alterations.
- Liquid biopsies show promise for resistance mechanisms but have
The document describes the Center of Cancer Nanotechnology Excellence (CCNE) at the University of Maryland. CCNEs link physical scientists and engineers working at the nanoscale with cancer biologists and oncologists to enable multi-disciplinary research on cancer-oriented nanotechnology. The Maryland CCNE will focus on pancreatic and lung cancer, with projects including targeted drug delivery using silicon nanotubes, surfactant nanovesicles, and magnetic particles. The center will have cores for translational research, bioinformatics, and analytical characterization. It will evaluate vitamin-targeted nanoparticles for chemotherapy delivery, having shown riboflavin receptors are upregulated in breast cancer cells and may enable targeted delivery.
The document discusses several topics regarding meningococcal disease and vaccines:
- It summarizes recent advances in meningococcal B vaccines, including two investigational vaccines in development by Pfizer and Novartis.
- It analyzes clinical trial data from both vaccines which demonstrate acceptable safety profiles and immunogenicity against diverse meningococcal strains.
- Using genetic and antigen characterization methods, it estimates that the Novartis 4CMenB vaccine could provide 72.9% coverage against group B strains in England and Wales.
- It also briefly discusses pneumococcal disease epidemiology and the impact of pneumococcal conjugate vaccination programs in the UK.
Human, Eukaryotic And Vitro Associations Of Murine Sec...Rachel Davis
The document describes experiments to study the effects of vitamin D receptor (VDR) binding to vitamin D response elements (VDREs). Reporter plasmids containing wildtype or mutant VDREs upstream of firefly luciferase were constructed. These plasmids were transfected into HEK293T cells to assess VDR binding and activation of luciferase expression in response to vitamin D treatment.
This study aimed to investigate the bactericidal potential of Mycobacterium tuberculosis targets under various in vivo simulated in vitro conditions and in vivo in mice. Using antisense RNA to inhibit five target genes, the study evaluated target cidality under six physiological conditions in vitro and in vivo. It identified aroK, which encodes shikimate kinase, as an in vivo bactericidal target based on correlations between in vitro and in vivo cidality data. The study suggests that the low pH in vitro model best predicts in vivo cidality and identifies targets with potential for anti-tuberculosis drug development.
This document describes the development of a novel fluorescent protein-based sensor for detecting 2-oxoglutarate (2OG) levels in living cells. The sensor, termed mOGsor, was created by inserting the 2OG-binding domain GAF from the NifA protein into yellow fluorescent protein (YFP). mOGsor exhibits increased fluorescence intensity upon binding to 2OG in a concentration-dependent manner. Testing showed mOGsor has high specificity for 2OG and fast kinetics. Using mOGsor, the authors were able to monitor real-time changes in 2OG levels in E. coli cells under different nutrient conditions. mOGsor represents an improvement over previous FRET-based 2OG sensors by providing a
Similar to Boronated Monoclonal Antibody LA84 for BNCT (20)
Performance Characteristics of the MIT Epithermal Neutron Irradiation Facilitykent.riley
This document summarizes the performance characteristics of the first fission converter-based epithermal neutron beam (FCB) designed for boron neutron capture therapy (BNCT) at the Massachusetts Institute of Technology (MIT). Key findings include:
1) The FCB provides an epithermal neutron flux of 4.6 × 109 n cm-2 s-1, making it the most intense BNCT source in the world. It achieves low specific photon and fast neutron absorbed doses.
2) Measurements confirm the beam achieves a therapeutic dose rate of 1.7 RBE Gy min-1 at a depth of 97 mm using boronated phenylalanine, with an average therapeutic ratio of
Selective Irradiation of the Mouse Gut Vasculaturekent.riley
This study investigated whether selective irradiation of vascular endothelial cells contributes to the loss of intestinal crypt stem cells and development of gastrointestinal syndrome. Mice received whole-body neutron irradiation, with or without boron-containing liposomes in the blood to selectively increase radiation dose to endothelial cells. Intestinal crypt regeneration was then assessed. The results showed that increasing the endothelial cell dose up to 3-fold did not further reduce crypt stem cell survival beyond the effects of whole-body irradiation alone. This indicates that endothelial cell damage is not causative for loss of intestinal crypt stem cells or development of gastrointestinal syndrome.
MIT User Center for Neutron Capture Therapy Resarchkent.riley
The MIT User Center for Neutron Capture Therapy Research provides specialized facilities and capabilities to support preclinical and clinical research in neutron capture therapy (NCT). The Center has two neutron beam facilities located at the Massachusetts Institute of Technology Research Reactor - a thermal neutron beam well-suited for small animal and cell culture studies, and an epithermal beam for clinical studies. Researchers can access these beams as well as capabilities like boron analysis, dosimetry, cell and animal research labs. The Center aims to support the widespread international effort to develop NCT as an effective cancer treatment.
RBE of the MIT clinical epithermal neutron beamkent.riley
This document summarizes a study that determined the relative biological effectiveness (RBE) of an epithermal neutron beam at the Massachusetts Institute of Technology (MIT) using intestinal crypt regeneration in mice. Mice were irradiated with the MIT neutron beam at depths of 2.5 cm and 9.7 cm, receiving absorbed doses between 2.6 and 12.3 Gy over 7 to 62 minutes. Control irradiations using 6 MV photons were also performed. Crypt survival curves were generated and fit using linear-quadratic models to estimate RBE values of 1.50 ± 0.04 at 2.5 cm and 1.03 ± 0.03 at 9.7 cm depth for the neutron beam relative to photons.
This document provides a critical review of fission reactor neutron sources for neutron capture therapy (NCT). It summarizes that epithermal neutron beams, favored for treating deep tumors, have been constructed or are being constructed at several reactors worldwide, with some newer beams approaching theoretical optimum purity. At least one such high-quality beam is suitable for routine therapy. Reactor-based epithermal beams with near-optimum characteristics are currently available and more can be constructed. Suitable reactors include low-power reactors using the core directly or a fission converter as the neutron source. Thermal neutron beams have also been available for years with near-optimum properties for small animal studies or shallow tumors.
This document describes a new tissue-equivalent plastic called A-181 that accurately simulates the photon and neutron absorption properties of brain tissue. A-181 was formulated to match the recommended hydrogen and nitrogen content of brain tissue for applications using low-energy neutrons like boron neutron capture therapy (BNCT). Measurements using A-181 and the standard muscle tissue equivalent plastic A-150 in a BNCT beam show good agreement with Monte Carlo calculations and demonstrate A-181's suitability for neutron dosimetry in brain tissue.
1) The study evaluated a boronated monoclonal antibody (BD-L8A4) that targets the EGFRvIII receptor for the treatment of rat glioma tumors expressing EGFRvIII using boron neutron capture therapy (BNCT).
2) Biodistribution studies found that BD-L8A4 accumulated more in EGFRvIII-positive tumors compared to EGFRvIII-negative tumors and boron levels in normal tissues remained low.
3) BNCT studies then found that rats receiving BD-L8A4 alone or with boronophenylalanine (BPA) had significantly longer survival times compared to controls, with some rats experiencing long-term survival or being
Unifying Dose Prescriptions in the Americaskent.riley
1) A dosimetry intercomparison was performed between the boron neutron capture therapy (BNCT) groups at the Massachusetts Institute of Technology (MIT) and Comisión Nacional de Energía Atómica (CNEA) in Argentina to enable combined analysis of patient data between centers.
2) In-air and depth dose measurements were made in a water phantom at the RA-6 reactor hyperthermal neutron beam facility in Bariloche, Argentina.
3) Calculated dose profiles from CNEA's treatment planning system required normalizations of 1.0 for thermal neutrons, 1.13 for photons, and 0.74 for fast neutrons to match dosimetry measurements made by
Radiation Resistance of Teflon as a Filter Moderator Materialkent.riley
This document summarizes the results of irradiating polytetrafluoroethylene (PTFE, also known as Teflon) samples with mixed fields of fast neutrons and gamma rays. Samples were irradiated to doses ranging from 0.3 to 50 million Gy for gamma rays and 0.13 to 80 thousand Gy for fast neutrons. The irradiated samples showed high levels of embrittlement but minimal changes (less than 1.5%) in properties like weight loss, fluorine loss, and swelling even at the highest doses. PTFE appears to have adequate physical and chemical stability for use in neutron filter applications in nuclear reactors.
Lithium Filtration for Improved Dose Penetration in BNCTkent.riley
This document summarizes research into adding an optional 6Li filter to an existing epithermal neutron beam used for boron neutron capture therapy (BNCT) to treat brain tumors. Monte Carlo simulations and measurements were used to design and test a removable 8mm thick 6Li filter. The filter improved penetration of thermal neutrons to depths of 9.9cm while maintaining tumor selectivity. Recalculating past treatment plans showed the filter could increase minimum deliverable tumor doses by up to 9% without increasing normal tissue doses. The filter provides an incremental enhancement to the clinical beam that may help establish a therapeutic window for treating deeper tumors.
Comparison of 7 Epithermal Neutron Beamskent.riley
This document compares the dosimetric characteristics of seven epithermal neutron beams used for boron neutron capture therapy (BNCT) clinical trials in Sweden, Finland, Czech Republic, Netherlands, and United States. Measurements were taken of neutron fluence and absorbed dose in air and in a water phantom using standardized methods. Results showed the fast neutron and photon contamination levels varied between facilities, as did the epithermal neutron flux intensities available. However, penetration depth was sufficient (>8 cm) for treating brain lesions at the midline for all beams. The data provide the first consistent measurement of beam performance across centers and will help normalize calculated patient dosimetry between facilities.
A State of the Art Epithermal Neutron Irradiation Facility for BNCTkent.riley
This document summarizes a state-of-the-art epithermal neutron irradiation facility for neutron capture therapy located at the Massachusetts Institute of Technology (MIT). The facility uses a fission converter-based epithermal neutron beam (FCB) that provides a high intensity beam suitable for clinical trials of boron neutron capture therapy (BNCT). The FCB operates independently of other reactor experiments and can deliver irradiation in under 10 minutes with automated monitoring and safety controls. It is part of a larger BNCT program at MIT that also includes a prompt gamma neutron activation analysis facility to measure boron levels in tissues.
1) A variable collimator was designed, constructed, and tested for use in an epithermal neutron beam for boron neutron capture therapy (BNCT) at MIT.
2) The collimator was optimized using Monte Carlo simulations and constructed from a mixture of lead spheres cast in epoxy resin loaded with boron carbide or lithium fluoride to provide neutron shielding.
3) Beam profiles and collateral dose measurements in a half-body phantom demonstrated the collimator provides sufficient shielding and a well-defined, uniform beam suitable for BNCT clinical studies.
The document discusses measuring prompt gamma emission during proton therapy to provide in situ range verification. Experiments were conducted using a 150 MeV proton beam on a PMMA phantom, measuring gamma rays at 90 degrees to the beam axis at different depths. Measurements showed a steady increase in gamma emission through the entrance region, followed by a sharp decline at the Bragg peak, consistent with other studies. Monte Carlo simulations were also performed and agreed with measurements, showing promise for using prompt gamma detection to characterize proton beam range during treatment.
International Dosimetry Exchange for Boron Neutron Capture Therapykent.riley
The document discusses the potential for a more formal collaboration between BNCT clinical centers to collectively analyze clinical outcomes data. It proposes that a coordinated effort could help advance the field by increasing patient statistics, standardizing practices, and facilitating comparisons to other treatments. Previous informal cooperation between centers has been successful, and a more organized international initiative modeling existing efforts like the International Dosimetry Exchange could provide insights to optimize protocols and assess normal tissue tolerances.
Best 20 SEO Techniques To Improve Website Visibility In SERPPixlogix Infotech
Boost your website's visibility with proven SEO techniques! Our latest blog dives into essential strategies to enhance your online presence, increase traffic, and rank higher on search engines. From keyword optimization to quality content creation, learn how to make your site stand out in the crowded digital landscape. Discover actionable tips and expert insights to elevate your SEO game.
Webinar: Designing a schema for a Data WarehouseFederico Razzoli
Are you new to data warehouses (DWH)? Do you need to check whether your data warehouse follows the best practices for a good design? In both cases, this webinar is for you.
A data warehouse is a central relational database that contains all measurements about a business or an organisation. This data comes from a variety of heterogeneous data sources, which includes databases of any type that back the applications used by the company, data files exported by some applications, or APIs provided by internal or external services.
But designing a data warehouse correctly is a hard task, which requires gathering information about the business processes that need to be analysed in the first place. These processes must be translated into so-called star schemas, which means, denormalised databases where each table represents a dimension or facts.
We will discuss these topics:
- How to gather information about a business;
- Understanding dictionaries and how to identify business entities;
- Dimensions and facts;
- Setting a table granularity;
- Types of facts;
- Types of dimensions;
- Snowflakes and how to avoid them;
- Expanding existing dimensions and facts.
How to Get CNIC Information System with Paksim Ga.pptxdanishmna97
Pakdata Cf is a groundbreaking system designed to streamline and facilitate access to CNIC information. This innovative platform leverages advanced technology to provide users with efficient and secure access to their CNIC details.
Building Production Ready Search Pipelines with Spark and MilvusZilliz
Spark is the widely used ETL tool for processing, indexing and ingesting data to serving stack for search. Milvus is the production-ready open-source vector database. In this talk we will show how to use Spark to process unstructured data to extract vector representations, and push the vectors to Milvus vector database for search serving.
Generating privacy-protected synthetic data using Secludy and MilvusZilliz
During this demo, the founders of Secludy will demonstrate how their system utilizes Milvus to store and manipulate embeddings for generating privacy-protected synthetic data. Their approach not only maintains the confidentiality of the original data but also enhances the utility and scalability of LLMs under privacy constraints. Attendees, including machine learning engineers, data scientists, and data managers, will witness first-hand how Secludy's integration with Milvus empowers organizations to harness the power of LLMs securely and efficiently.
Ivanti’s Patch Tuesday breakdown goes beyond patching your applications and brings you the intelligence and guidance needed to prioritize where to focus your attention first. Catch early analysis on our Ivanti blog, then join industry expert Chris Goettl for the Patch Tuesday Webinar Event. There we’ll do a deep dive into each of the bulletins and give guidance on the risks associated with the newly-identified vulnerabilities.
How to Interpret Trends in the Kalyan Rajdhani Mix Chart.pdfChart Kalyan
A Mix Chart displays historical data of numbers in a graphical or tabular form. The Kalyan Rajdhani Mix Chart specifically shows the results of a sequence of numbers over different periods.
UiPath Test Automation using UiPath Test Suite series, part 6DianaGray10
Welcome to UiPath Test Automation using UiPath Test Suite series part 6. In this session, we will cover Test Automation with generative AI and Open AI.
UiPath Test Automation with generative AI and Open AI webinar offers an in-depth exploration of leveraging cutting-edge technologies for test automation within the UiPath platform. Attendees will delve into the integration of generative AI, a test automation solution, with Open AI advanced natural language processing capabilities.
Throughout the session, participants will discover how this synergy empowers testers to automate repetitive tasks, enhance testing accuracy, and expedite the software testing life cycle. Topics covered include the seamless integration process, practical use cases, and the benefits of harnessing AI-driven automation for UiPath testing initiatives. By attending this webinar, testers, and automation professionals can gain valuable insights into harnessing the power of AI to optimize their test automation workflows within the UiPath ecosystem, ultimately driving efficiency and quality in software development processes.
What will you get from this session?
1. Insights into integrating generative AI.
2. Understanding how this integration enhances test automation within the UiPath platform
3. Practical demonstrations
4. Exploration of real-world use cases illustrating the benefits of AI-driven test automation for UiPath
Topics covered:
What is generative AI
Test Automation with generative AI and Open AI.
UiPath integration with generative AI
Speaker:
Deepak Rai, Automation Practice Lead, Boundaryless Group and UiPath MVP
For the full video of this presentation, please visit: https://www.edge-ai-vision.com/2024/06/building-and-scaling-ai-applications-with-the-nx-ai-manager-a-presentation-from-network-optix/
Robin van Emden, Senior Director of Data Science at Network Optix, presents the “Building and Scaling AI Applications with the Nx AI Manager,” tutorial at the May 2024 Embedded Vision Summit.
In this presentation, van Emden covers the basics of scaling edge AI solutions using the Nx tool kit. He emphasizes the process of developing AI models and deploying them globally. He also showcases the conversion of AI models and the creation of effective edge AI pipelines, with a focus on pre-processing, model conversion, selecting the appropriate inference engine for the target hardware and post-processing.
van Emden shows how Nx can simplify the developer’s life and facilitate a rapid transition from concept to production-ready applications.He provides valuable insights into developing scalable and efficient edge AI solutions, with a strong focus on practical implementation.
AI 101: An Introduction to the Basics and Impact of Artificial IntelligenceIndexBug
Imagine a world where machines not only perform tasks but also learn, adapt, and make decisions. This is the promise of Artificial Intelligence (AI), a technology that's not just enhancing our lives but revolutionizing entire industries.
Driving Business Innovation: Latest Generative AI Advancements & Success StorySafe Software
Are you ready to revolutionize how you handle data? Join us for a webinar where we’ll bring you up to speed with the latest advancements in Generative AI technology and discover how leveraging FME with tools from giants like Google Gemini, Amazon, and Microsoft OpenAI can supercharge your workflow efficiency.
During the hour, we’ll take you through:
Guest Speaker Segment with Hannah Barrington: Dive into the world of dynamic real estate marketing with Hannah, the Marketing Manager at Workspace Group. Hear firsthand how their team generates engaging descriptions for thousands of office units by integrating diverse data sources—from PDF floorplans to web pages—using FME transformers, like OpenAIVisionConnector and AnthropicVisionConnector. This use case will show you how GenAI can streamline content creation for marketing across the board.
Ollama Use Case: Learn how Scenario Specialist Dmitri Bagh has utilized Ollama within FME to input data, create custom models, and enhance security protocols. This segment will include demos to illustrate the full capabilities of FME in AI-driven processes.
Custom AI Models: Discover how to leverage FME to build personalized AI models using your data. Whether it’s populating a model with local data for added security or integrating public AI tools, find out how FME facilitates a versatile and secure approach to AI.
We’ll wrap up with a live Q&A session where you can engage with our experts on your specific use cases, and learn more about optimizing your data workflows with AI.
This webinar is ideal for professionals seeking to harness the power of AI within their data management systems while ensuring high levels of customization and security. Whether you're a novice or an expert, gain actionable insights and strategies to elevate your data processes. Join us to see how FME and AI can revolutionize how you work with data!
HCL Notes und Domino Lizenzkostenreduzierung in der Welt von DLAUpanagenda
Webinar Recording: https://www.panagenda.com/webinars/hcl-notes-und-domino-lizenzkostenreduzierung-in-der-welt-von-dlau/
DLAU und die Lizenzen nach dem CCB- und CCX-Modell sind für viele in der HCL-Community seit letztem Jahr ein heißes Thema. Als Notes- oder Domino-Kunde haben Sie vielleicht mit unerwartet hohen Benutzerzahlen und Lizenzgebühren zu kämpfen. Sie fragen sich vielleicht, wie diese neue Art der Lizenzierung funktioniert und welchen Nutzen sie Ihnen bringt. Vor allem wollen Sie sicherlich Ihr Budget einhalten und Kosten sparen, wo immer möglich. Das verstehen wir und wir möchten Ihnen dabei helfen!
Wir erklären Ihnen, wie Sie häufige Konfigurationsprobleme lösen können, die dazu führen können, dass mehr Benutzer gezählt werden als nötig, und wie Sie überflüssige oder ungenutzte Konten identifizieren und entfernen können, um Geld zu sparen. Es gibt auch einige Ansätze, die zu unnötigen Ausgaben führen können, z. B. wenn ein Personendokument anstelle eines Mail-Ins für geteilte Mailboxen verwendet wird. Wir zeigen Ihnen solche Fälle und deren Lösungen. Und natürlich erklären wir Ihnen das neue Lizenzmodell.
Nehmen Sie an diesem Webinar teil, bei dem HCL-Ambassador Marc Thomas und Gastredner Franz Walder Ihnen diese neue Welt näherbringen. Es vermittelt Ihnen die Tools und das Know-how, um den Überblick zu bewahren. Sie werden in der Lage sein, Ihre Kosten durch eine optimierte Domino-Konfiguration zu reduzieren und auch in Zukunft gering zu halten.
Diese Themen werden behandelt
- Reduzierung der Lizenzkosten durch Auffinden und Beheben von Fehlkonfigurationen und überflüssigen Konten
- Wie funktionieren CCB- und CCX-Lizenzen wirklich?
- Verstehen des DLAU-Tools und wie man es am besten nutzt
- Tipps für häufige Problembereiche, wie z. B. Team-Postfächer, Funktions-/Testbenutzer usw.
- Praxisbeispiele und Best Practices zum sofortigen Umsetzen
Have you ever been confused by the myriad of choices offered by AWS for hosting a website or an API?
Lambda, Elastic Beanstalk, Lightsail, Amplify, S3 (and more!) can each host websites + APIs. But which one should we choose?
Which one is cheapest? Which one is fastest? Which one will scale to meet our needs?
Join me in this session as we dive into each AWS hosting service to determine which one is best for your scenario and explain why!
Salesforce Integration for Bonterra Impact Management (fka Social Solutions A...Jeffrey Haguewood
Sidekick Solutions uses Bonterra Impact Management (fka Social Solutions Apricot) and automation solutions to integrate data for business workflows.
We believe integration and automation are essential to user experience and the promise of efficient work through technology. Automation is the critical ingredient to realizing that full vision. We develop integration products and services for Bonterra Case Management software to support the deployment of automations for a variety of use cases.
This video focuses on integration of Salesforce with Bonterra Impact Management.
Interested in deploying an integration with Salesforce for Bonterra Impact Management? Contact us at sales@sidekicksolutionsllc.com to discuss next steps.
Introduction of Cybersecurity with OSS at Code Europe 2024Hiroshi SHIBATA
I develop the Ruby programming language, RubyGems, and Bundler, which are package managers for Ruby. Today, I will introduce how to enhance the security of your application using open-source software (OSS) examples from Ruby and RubyGems.
The first topic is CVE (Common Vulnerabilities and Exposures). I have published CVEs many times. But what exactly is a CVE? I'll provide a basic understanding of CVEs and explain how to detect and handle vulnerabilities in OSS.
Next, let's discuss package managers. Package managers play a critical role in the OSS ecosystem. I'll explain how to manage library dependencies in your application.
I'll share insights into how the Ruby and RubyGems core team works to keep our ecosystem safe. By the end of this talk, you'll have a better understanding of how to safeguard your code.
Introduction of Cybersecurity with OSS at Code Europe 2024
Boronated Monoclonal Antibody LA84 for BNCT
1. Cancer Therapy: Preclinical
Molecular Targeting and Treatment of EGFRvIII-Positive Gliomas
Using Boronated Monoclonal Antibody L8A4
Weilian Yang,1Rolf F. Barth,1Gong Wu,1Shinji Kawabata,1ThomasJ. Sferra,2 Achintya K. Bandyopadhyaya,3
Werner Tjarks,3 Amy K. Ferketich,4 Melvin L. Moeschberger,4 PeterJ. Binns,5 Kent J. Riley,5
Jeffrey A. Coderre,6 Michael J. Ciesielski,7 Robert A. Fenstermaker,7 and Carol J.Wikstrand8
Abstract Purpose: The purpose of the present study was to evaluate a boronated EGFRvIII-specific
monoclonal antibody, L8A4, for boron neutron capture therapy (BNCT) of the receptor-positive
rat glioma, F98npEGFRvIII.
Experimental Design: A heavily boronated polyamido amine (PAMAM) dendrimer (BD)
was chemically linked to L8A4 by two heterobifunctional reagents, N-succinimidyl 3-
(2-pyridyldithio)propionate and N-(k-maleimidoundecanoic acid)hydrazide. For in vivo studies,
F98 wild-type receptor-negative or EGFRvIII human gene-transfected receptor-positive
F98npEGFRvIII glioma cells were implanted i.c. into the brains of Fischer rats. Biodistribution studies
were initiated 14 days later. Animals received [125I]BD-L8A4 by either convection enhanced
delivery (CED) or direct i.t. injection and were euthanized 6, 12, 24, or 48 hours later.
Results: At 6 hours, equivalent amounts of the bioconjugate were detected in receptor-positive
and receptor-negative tumors, but by 24 hours the amounts retained by receptor-positive gliomas
were 60.1% following CED and 43.7% following i.t. injection compared with 14.6% ID/g by
receptor-negative tumors. Boron concentrations in normal brain, blood, liver, kidneys, and spleen
all were at nondetectable levels (<0.5 Ag/g) at the corresponding times. Based on these favorable
biodistribution data, BNCT studies were initiated at the Massachusetts Institute of Technology
Research Reactor-II. Rats received BD-L8A4 (f40 Ag 10B/f750 Ag protein) by CED either alone
or in combination with i.v. boronophenylalanine (BPA; 500 mg/kg). BNCT was carried out
24 hours after administration of the bioconjugate and 2.5 hours after i.v. injection of BPA for those
animals that received both agents. Rats that received BD-L8A4 by CED in combination with
i.v. BPA had a mean F SE survival time of 85.5 F 15.5 days with 20% long-term survivors
(>6 months) and those that received BD-L8A4 alone had a mean F SE survival time of
70.4 F 11.1 days with 10% long-term survivors compared with 40.1 F 2.2 days for i.v. BPA and
30.3 F 1.6 and 26.3 F 1.1days for irradiated and untreated controls, respectively.
Conclusions: These data convincingly show the therapeutic efficacy of molecular targeting of
EGFRvIII using either boronated monoclonal antibody L8A4 alone or in combination with BPA
and should provide a platform for the future development of combinations of high and low molec-
ular weight delivery agents for BNCTof brain tumors.
Boron neutron capture therapy (BNCT) is based on the
Authors’ Affiliations: Departments of 1Pathology and 2Pediatrics and Children’s
selective delivery of 10B to a tumor followed by neutron
Research Institute, 3College of Pharmacy, and 4School of Public Health,The Ohio
State University, Columbus, Ohio; 5Nuclear Reactor Laboratory and 6Department of irradiation. The resulting nuclear capture and fission reactions
Nuclear Engineering, Massachusetts Institute of Technology, Cambridge, Massa- (10B + n ! [11B] ! 4He + 7Li) yield a-particles (4He) and
chusetts; 7Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New recoiling 7Li nuclei. Administration of the boron delivery
York; and 8Department of Pathology, Duke University, Durham, North Carolina agent(s) and neutron irradiation can be manipulated indepen-
Received 1/23/06; revised 3/31/06; accepted 4/20/06.
Grant support: NIH grants 1R01CA098945 (R.F. Barth) and 1R01NS39071 (T.J.
dently, so that the interval between them can be optimized to
Sferra); Roswell Park Alliance Foundation (R.A. Fenstermaker); and U.S. give the greatest tumor-to-normal tissue boron concentration
Department of Energy through the program of Innovations in Nuclear Infrastructure ratios. For BNCT to be successful, there must be a sufficient
and Education, Office of Nuclear Energy, Science andTechnology Contract nos. DE- amount of 10B in the tumor, low levels in blood and normal
FG07-02ID14420 and DE-FG07-02 (K14420) and Office of Environmental and
tissues in the field of irradiation, and enough low-energy
Biological Research contract no. DE-FG02-02ER63358.
The costs of publication of this article were defrayed in part by the payment of page thermal neutrons must be delivered to the tumor site. The
charges. This article must therefore be hereby marked advertisement in accordance major challenge for effectively treating high-grade gliomas with
with 18 U.S.C. Section 1734 solely to indicate this fact. BNCT is the delivery of sufficient amounts of 10B and neutrons
Requests for reprints: Rolf F. Barth, Department of Pathology, The Ohio State to individual tumor cells to sustain a lethal 10B(n,a)7Li capture
University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210. Phone:
614-292-2177; Fax: 614-292-7072; E-mail: rolf.barth@ osumc.edu.
reaction. Two low molecular weight boron delivery agents,
F 2006 American Association for Cancer Research. sodium borocaptate (BSH) and boronophenylalanine (BPA),
doi:10.1158/1078-0432.CCR-06-0141 have been used in both experimental animal and clinical
Clin Cancer Res 2006;12(12) June 15, 2006 3792 www.aacrjournals.org
2. Molecular Targeting of EGFRvIII-Positive Gliomas
studies. Several recent reviews and monographs are available heterobifunctional reagent N-(k-maleimidoundecanoic acid)hydrazide
for those readers interested in more detailed information (Pierce) and then linked to the sulfhydryl-containing BD to yield the
relating to these studies and BNCT in general (1 – 3). bioconjugate BD-L8A4 (15). This was purified by column chromatog-
raphy using a Sephadex-G50 column (Amersham Pharmacia Biotech,
The gene encoding epidermal growth factor receptor (EGFR)
Piscataway, NJ) and eluted with 0.1 mol/L Tris and 0.2 mol/L NaCl
often is amplified or mutated in human gliomas (4), but its
buffer (pH 8.5). Fractions (1 mL) were collected and protein
expression is low or undetectable in normal brain (5). Based on concentrations were determined spectrophotometrically by measuring
this, EGFR and its mutant isoform, EGFRvIII, are under absorbance at 280 nm using a Beckman DU-6 spectrophotometer
intensive investigation as molecular targets for the specific (Beckman Instruments, Inc., Irvine CA). Boron was quantified by direct
delivery of diagnostic and therapeutic agents to brain tumors current plasma-atomic emission spectroscopy using a Spectraspan VB
(6 – 8). We have been interested in the possibility of using either spectrometer (Applied Research Laboratories, La Brea, CA) as described
EGF itself (9 – 13) or anti-EGFR monoclonal antibodies (mAb; previously (33). Fractions containing the highest concentrations of
refs. 14, 15) as boron delivery agents for NCT of high-grade both protein and boron were pooled and used in the studies described
gliomas. To fully evaluate this approach, we initially produced in the following section.
Radioiodination of BD-L8A4. BD-L8A4 bioconjugates were reacted
a series of transfectants of the F98 rat glioma, which expressed
with Bolton-Hunter reagent (Pierce) to introduce an aromatic ring for
wild-type human EGFR (11, 12). Using the F98EGFR glioma
radioiodination. A 10-fold molar excess of Bolton-Hunter reagent was
model, we evaluated boronated EGF as a delivery agent for NCT added to BD-L8A4 and cooled on ice for 1 hour following which
and established proof-of-principle that there was a significant unreacted reagent was removed using a Bio-Spin P-6 column (Bio-Rad
therapeutic response following BNCT (13). However, although Laboratories, Hercules, CA). BD-L8A4 and BD then were radioiodinated
wild-type EGFR is overexpressed in a variety of human with [125I]NaI by the procedure described by us (12) using chloramine-T
malignancies, it also is expressed in normal liver and spleen, (ICN Biomedicals, Inc., Costa Mesa, CA) at a concentration of 2 mg/mL
which can take up significant amounts of either anti-EGFR mAb in 0.5 mol/L phosphate buffer (pH 7.5). [125I]BD-L8A4 was shown
(16) or EGF ligand (17 – 19) following systemic administration. to be stable and was not dehalogenated for at least 1 week when kept
On the other hand, EGFRvIII, which has an in-frame deletion at 4jC.
In vitro receptor-binding assay. The F98 glioma cell line (CRL-2397,
of exons 2 to 7 of the extracellular domain (7, 20), is expressed
American Type Culture Collection, Manassas, VA) was derived from a
and amplified in up to 54% of human glioblastomas and 75%
CD-Fischer rat whose mother had received N-ethyl-N-nitrosourea
of anaplastic astrocytomas (21). Because EGFRvIII seems to be during pregnancy and it has been described in detail elsewhere (34).
a truly tumor-specific target, several mAbs directed against this F98 wild-type (F98WT) cells and F98npEGFRvIII cells (31, 32) were used in
receptor have been produced for diagnostic and therapeutic the studies described in the following sections. All cells were grown in
purposes (6, 22). These include DH8.3 (23), 806 (24 – 26), DMEM containing glucose, L-glutamine, and 10% fetal bovine serum.
and, the subject of the present report, L8A4 (27 – 31). Receptor-binding activity of 125I-labeled, boronated, and native L8A4
We recently have described an EGFRvIII-expressing variant of with F98npEGFRvIII cells was studied by a competitive binding assay.
the F98 rat glioma, designated F98npEGFRvIII, which is syngeneic F98npEGFRvIII cells (f3 Â 104 per well) were seeded into 24-well flat-
to Fischer rats. This was produced by transfecting wild-type F98 bottomed plates (Corning, Inc., Corning, NY) and allowed to attach
glioma cells with the gene encoding human EGFRvIII, and one overnight. Medium was replaced with DMEM containing 10% fetal
bovine serum and 1 Amol/L dexamethasone (Sigma) and incubated
of the transfectants stably expressed a mutant, nonphosphory-
overnight at 37jC. This was replaced with serum-free DMEM and
lated form of the protein. This tumor model recently has been
incubated for 2 hours following which the cells were washed with PBS
described by us in detail elsewhere (31, 32). Using this model, (pH 7.2). Varying concentrations of native and boronated L8A4 were
we evaluated the biodistribution of [125I]L8A4 in F98npEGFRvIII added to triplicate wells and incubated at ambient temperature in an
glioma-bearing rats following i.v. or i.t. injection or convection atmosphere containing 5% CO2 for 2 hours. The cells then were
enhanced delivery (CED) and showed specific molecular washed, and medium containing [125I]L8A4 at a concentration of
targeting of the receptor (31). In the present study, we initially 0.18 nmol/L was added. They were incubated for an additional 2 hours
evaluated the biodistribution of boronated L8A4 in both non- at ambient temperature, washed three times with PBS, and harvested
tumor-bearing and F98npEGFRvIII glioma-bearing rats. Based on using 0.5 mmol/L EDTA in PBS, and cell-associated radioactivity was
favorable biodistribution data, we then initiated therapy studies determined by g-scintillation counting (model 1185, Tm Analytic, Elk
using BD-L8A4, given by either i.t. injection or CED, alone or in Grove Village, IL). F98WT and F98npEGFRvIII cells were seeded into T-150
flasks and cultured for 3 days to establish a confluent monolayer. Cells
combination with i.v. BPA. As described in detail in this report,
were washed twice with PBS and then harvested by incubating them
CED of BD-L8A4 followed by BNCT resulted in a significant with 0.5 mmol/L EDTA at 37jC for 10 minutes. Following removal of
prolongation in the survival times of F98npEGFRvIII glioma- EDTA, 106 cells were added to 1.5 mL tubes to which varying amounts
bearing rats with a subset of cured animals. of [125I]L8A4 in 0.1% bovine serum albumin had been added, and
these were incubated at 4jC for 90 minutes. The cells then were washed
three times with PBS, cell-bound and free radiolabeled antibody or
Materials and Methods bioconjugate were separated by centrifugation, and radioactivity was
quantified by g-scintillation counting. The K a and the number of
Preparation and purification of boronated L8A4 bioconjugate. Either receptor sites were derived by nonlinear regression analysis.
fourth- or fifth-generation polyamido amine (PAMAM) dendrimers Tumor implantation and CED of BD-L8A4. All animals studies were
(Sigma, St. Louis, MO) were boronated with the methylisocyanato done in accordance with the Guide for the Care and Use of Laboratory
polyhedral borane anion Na(CH3)3NB10H8NCO, which was synthe- Animals (National Academy Press, Washington, DC, 1996) and the
sized by us, to yield a boronated dendrimer (BD) using a procedure protocol was approved by the Institutional Laboratory Care and Use
described previously by us (15). The BD was reacted with Committee of The Ohio State University (Columbus, OH). CD-Fischer
N-succinimidyl 3-(2-pyridyldithio)propionate (Pierce Chemical Corp., rats (Charles River Laboratories, Wilmington, MA), weighing 200 to
Rockford, IL) and the resulting product was cleaved with DTT to yield a 220 g, were anesthetized with a 1.2:1 mixture of ketamine/xylazine.
SH-containing BD. mAb L8A4 was derivatized at the Fc region with the Following this, tumor cells were implanted stereotactically as described
www.aacrjournals.org 3793 Clin Cancer Res 2006;12(12) June 15, 2006
3. Cancer Therapy: Preclinical
previously (35). A small plastic screw (Arrow Machine Manufacturing, autoradiography were prepared from homogenized brain at concen-
Inc., Richmond, VA) with an entry port, which allowed insertion of a trations ranging from 0.01 to 0.8 relative to the 125I concentration of
27-gauge needle, was embedded into the calvarium before implanta- the infusate (12).
tion. For CED, a plastic cannula was inserted into the entry port and The autoradiographs subsequently were analyzed by quantitative
then advanced 5 mm below the dura into the right caudate nucleus of densitometry using a Macintosh-based computer image analysis system
non-tumor-bearing animals or into the tumor of glioma-bearing rats. (Image 1.5, kindly provided by the NIH, Bethesda, MD, via the
CED of BD-L8A4 was carried out using a syringe pump (Harvard Internet). The absorbances of the radioactivity standards were fit to
Apparatus Co., Cambridge, MA) as described previously by us (12). The known tissue equivalents using a Rodbard function as described
bioconjugate was diluted with PBS to yield a concentration of 5 ACi/50 previously by us (12). The Wilcoxon rank-sum test in SAS version 8-02
Ag BD-L8A4/10 AL. Evans blue dye (3 AL) was added to every 100 AL (SAS Institute, Cary NC) was used to calculate exact Ps for tumor uptake
[125I]BD-L8A4 solution, so that the site of infusion subsequently could of [125I]BD-L8A4. The V d was defined as the tissue volume whose local
be visualized grossly within the brain parenchyma following termina- concentration of the infused (V i) [125I]BD-L8A4 relative to the
tion of the study. Initially, studies were carried out in non-tumor- concentration of the infusate uniformly equaled or exceeded an
bearing rats to define the relationships among the volume of infusion arbitrary fraction (>1%) of the concentration of the infusate. To define
(V i), the volume of distribution (V d), and the rate of infusion. These the boundaries of infusion, a threshold equal to f15% of the
were divided into four groups of eight animals each as follows: group 1 maximum tissue equivalent was used. The V d was estimated by
received an i.c. injection of 5 ACi/50 Ag BD-L8A4/10 AL and groups 2 to multiplying the area of perfusion, as measured by computer analysis,
4 received BD-L8A4 by CED at a rate of 0.33 AL/min for 15, 30, or 60 by the distance between sections and summing across all slices. The
minutes with corresponding injection volumes of 5, 10, and 20 AL, percent recovery was determined by obtaining the counts/min of 125I in
respectively. The infusion rates and injection volumes in the brains of the tissue sample using a Tm Analytic g-scintillation counter. The total
non-tumor-bearing rats are summarized in Table 1. amount of radioactivity in the five coronal sections and the percent
Following completion of these studies, biodistribution studies were recovery were determined as described previously (12). Homogeneity of
carried out in tumor-bearing animals 12 to 14 days following tumor delivery was determined from autoradiographs made from coronal
implantation. Animals were divided into four experimental groups of sections of the brains of animals that had received [125I]BD-L8A4, and
10 to 16 rats each. Animals in groups 1 and 2 had F98npEGFRvIII gliomas cross-sectional concentration profiles were generated. The tissue
and those in groups 3 and 4 had F98WT tumors. Rats in groups 2 and 4 concentrations of [125I]BD-L8A4, in sequential 0.1-mm increments,
received an i.t. injection of [125I]BD-L8A4 (5 ACi/50 Ag L8A4/10 AL) were determined by converting the optical densities of the infused
and those in groups 1 and 3 received an equal volume of [125I]BD-L8A4 regions of the autoradiographs to tissue equivalents (ACi/g tissue) by
delivered by CED over 30 minutes at a rate of 0.33 AL/min. The appropriate 125I standards and image analysis software. Tissue uptake of
biodistribution of [125I]BD-L8A4 in tumor-bearing animals was [125I]BD-L8A4 was determined by g-counting of weighed samples of
determined at 6, 12, 24, and 48 hours after administration. Animals blood, liver, kidney, muscle, and skin from each animal.
were euthanized by an overdose of halothane following which tumors Therapy experiments and dosimetry. BNCT was done 14 days
and normal tissues, consisting of brain, blood, liver, kidney, and following stereotactic implantation of 103 F98npEGFRvIII glioma cells.
muscle, were removed and weighed. Uptake of 125I was determined by Rats were transported to the Nuclear Reactor Laboratory at the
g-scintillation counting for [125I]BD-L8A4. Massachusetts Institute of Technology and then randomized based on
Quantitative autoradiographic analysis of distribution of [125I]BD- weight into experimental groups of 7 to 11 animals each as follows:
L8A4 in non-tumor-bearing rats. Rats were euthanized either imme- group 1, CED of BD-L8A4 and BNCT; group 2, CED of BD-L8A4 plus
diately following or 12 hours after CED and their brains were removed i.v. BPA and BNCT; group 3, i.v. BPA and BNCT; group 4, CED of L8A4
and frozen in isopentane (2-methylbutane), which had been cooled to and neutron irradiation; and group 5, CED of BD-L8A4. BNCT was
À150jC in liquid nitrogen, and they were stored at À70jC until initiated 24 hours after CED of 10 AL BD-L8A4 (40 Ag 10B/750 Ag L8A4)
sectioning. Brains were cut coronally at 1-mm intervals rostral and and 2.5 hours after i.v. administration of BPA (500 mg/kg body
caudal to the point of insertion of the cannula. Five serial sections from weight). All irradiated rats were anesthetized with a mixture of ketamine
each coronal slice were cut on a cryostat (Miles Scientific, Naperville, and xylazine. BNCT was carried out at the Massachusetts Institute of
IL) at a thickness of 20 Am each. One of the five sections was stained Technology Research Reactor-II nuclear reactor in the M011 irradiation
with H&E for histologic examination. The percent uptake of facility, which produces a beam of thermal neutrons of high purity and
radioactivity was quantified in two sections by g-scintillation counting intensity with no measurable fast neutron component. Two rats at a
for 125I using a well counter (model 1185, Tm Analytic). The remaining time were positioned in a 6Li-enriched polyethylene box that provided
two sections were processed for quantitative autoradiography by whole-body shielding from the thermal neutrons during irradiation.
exposing them to either NTB-2 dipping emulsion or X-ray stripping The animals’ heads were aligned in the middle of a 13 Â 2 cm2 aperture,
film (Eastman Kodak, Rochester, NY). Following a 16-hour exposure, machined in the box lid, which served as the beam delimiter. Four
the autoradiographs were developed. 125I standards for quantitative fission counters, located at the periphery of the 15-cm circular field,
Table 1. V d of [125I]BD-L8A4 following i.c. injection or CED in non-tumor-bearing rats
Group Route Infusion V d (mm3) V d/V i ratio Recovery of infusate
3 3
Time (min) Volume (mm ) Rate (mm /min)
1 i.c. 2 10.0 5.0 10.8 F 3.1 1.1 F 0.3. 87.1 F 6.8
2 CED 15 5.0 0.33 31.6 F 5.8 6.3 F 1.2 90.1 F 8.2
3 CED 30 10.0 0.33 60.8 F11.4 6.1 F 1.3 88.3 F 5.6
4 CED 60 20.0 0.33 118.5 F 19.2 5.9 F 0.6 85.9 F 4.3
NOTE: V d was determined by quantitative autoradiography, and percentage recovery was determined by g-scintillation in groups of four animals each. Means and
SDs ofV d,V d/V i ratios, and percentage recovery were calculated.
Clin Cancer Res 2006;12(12) June 15, 2006 3794 www.aacrjournals.org
4. Molecular Targeting of EGFRvIII-Positive Gliomas
automatically controlled beam delivery and provided real-time data on Fig. 1B, based on the radioactivity bound to F98EGFRvIII cells,
the relative neutron fluence during an irradiation. it was found that the bioconjugate and unmodified antibody
Dosimetric measurements were done using bare gold foils and a both inhibited binding of [125I]BD-L8A4 in a concentration-
graphite-walled ionization chamber (V = 0.1 cm3) flushed with reagent-
dependent manner. The IC50 of boronated and native L8A4
grade CO2 on both dead rats and phantoms made from type 6 nylon
were 27.2 and 16.7 nmol/L, respectively, indicating that the
(36). The measured dose rates in brain (2.2% nitrogen by weight),
normalized to the reactor operating at a power of 5 MW, were 18.5 cGy/
bioconjugate had 60% binding activity compared with that of
min for photons, 7.7 cGy/min for thermal neutrons from the nitrogen the native antibody.
capture reaction, and 3.4 cGy/min/Ag 10B in tissues. For dosimetric Intracerebral distribution of [125I]BD-L8A4 in non-tumor-
calculations, boron concentrations were determined in tumor, normal bearing rats. The V d of [125I]BD-L8A4 following either i.c.
brain, liver, and blood in a separate group of animals 24 hours after injection or CED in normal (i.e., non-tumor-bearing) rat brains
CED of BD-L8A4 and 2.5 hours after i.v. injection of BPA. Animal are summarized in Table 1. The V d that contained >1% of the
irradiations were done with the reactor operating at a power between amount of the bioconjugate that was infused were 31.6, 60.8,
4.0 and 4.8 MW. These took between 6.9 and 8.6 minutes to deliver a and 118.5 AL, respectively, following CED of 5, 10, and 20 AL
thermal neutron fluence of 2.64 Â 1012 nÁcmÀ2 to complement
of bioconjugate. The calculated V d, following i.c. injection
previous dose prescriptions (13, 14). After completion of BNCT,
of 10 AL, was 10.8 AL and the V d/V i ratio was 1.1 compared
the animals were held at Massachusetts Institute of Technology for
f3 days to allow induced radioactivity to decay before they were
with 6.3, 6.1, and 5.9 for CED. CED resulted in f6-fold
returned to The Ohio State University for clinical monitoring.
Monitoring of clinical status and neuropathologic evaluation. All
animals were weighed three times per week and their clinical status was
evaluated at the same time. Once the animals had progressively growing
tumors, as evidenced by the combination of sustained weight loss,
ataxia, and periorbital hemorrhage, they were euthanized to minimize
discomfort. Survival times were determined by adding 1 day to the time
between tumor implantation and euthanization. Rats surviving >180
days were designated long-term survivors and were euthanized. The
brains of all animals in the therapy studies were removed after death,
fixed in 10% buffered formalin, and then cut coronally at the level of
the optic chiasma and 2 mm anterior and posterior to it. Tissue sections
through the tumor were embedded in paraffin, cut at 4 Am, stained with
H&E, and examined microscopically to assess the histopathologic
changes. The tumor size index was determined from H&E-stained
coronal sections of brain using a semiquantitative grading scale ranging
from 0 to 4. Each section was scored as follows: 0, no tumor; 1, very
small (i.e., microscopic, <1 mm); 2, small (f1-3 mm); 3, large (f4-7
mm); and 4, massive (>8 mm).
Statistical evaluation of survival data. The mean survival time
(MST), SE, and median survival time were calculated for each group
using the Kaplan-Meier method (37). The Kaplan-Meier curves and Cox
survival curves also were plotted. The hypotheses involved comparing
each L8A4 animal to each irradiated control. A log-rank test was used
for these comparisons, with a Bonferroni method of adjustment for the
multiple comparisons (38). Because five comparisons were tested for
statistical significance within the L8A4 tests, a = 0.0125 was used.
Results
In vitro receptor-binding activity of BD-L8A4. To determine if
the immunoreactivity of L8A4 was retained following borona-
tion, BD-L8A4 and unmodified antibody were compared for
their binding affinity to F98npEGFRvIII cells. After incubation with
either BD-L8A4 or unmodified antibody, F98npEGFRvIII cells were
then exposed to [125I]BD-L8A4 for an additional 2 hours.
The binding of mAb L8A4 to EGFRvIII was determined by
incubating F98EGFRvIII cells, with varying amounts of [125I]L8A4,
and data from these experiments are shown in Fig. 1A.
[125I]L8A4 had a very low binding affinity with F98WT cells,
Fig. 1. A, cellular binding of mAb L8A4 to EGFRvIII-positive (F98npEGFRvIII) and
indicating that nonspecific binding was negligible. In contrast, EGFRvIII-negative (F98WT) expressing glioma cells.Varying amounts of [125I]L8A4
as determined by binding of [125I]L8A4 to F98npEGFRvIII cells, ranging from 0 to 100 nmol/L were incubated at 4jC for 90 minutes with cells
expressing mutant EGFRvIII receptors (F98npEGFRvIII; E) and receptor-negative
the affinity constant (K a) was 4.85 F 0.40 Â 107 mol/LÀ1 and parental cells (F98WT; n). Cell-bound radioactivity was determined by g-scintillation
receptor site density was 7.34 F 0.61 Â 105 sites per cell. counting. B, competitive binding assay using 125I-labeled bioconjugate. Cells were
These numbers are somewhat higher than the K a of 6.62 F 0.8 Â incubated at ambient temperature for 2 hours with medium containing 0.185 nmol/L
[125I]BD-L8A4 and varying concentrations (0-500 nM) of either native L8A4 (4)
108 mol/LÀ1 and a receptor site density of 1.20 F 0.08 Â 105 or BD-L8A4 (n) following which cell-associated radioactivity was determined by
per cell that were reported previously by us (31). As shown in g-scintillation counting. Each point represents the mean of six replicates.
www.aacrjournals.org 3795 Clin Cancer Res 2006;12(12) June 15, 2006
5. Cancer Therapy: Preclinical
either i.t. injection or CED into glioma-bearing rats is
summarized in Fig. 2 and Table 2. As determined by g-
scintillation counting, between 1 and 6 hours following i.t.
injection or CED, 60% to 80% ID/g of BD-L8A4 was
nonspecifically localized in F98npEGFRvIII gliomas and the
differences between the two groups were not statistically
significant (Fig. 2). However, by 12 hours following i.t.
injection, retention of BD-L8A4 in F98npEGFRvIII gliomas was
higher than that of F98WT tumors (58.5% versus 41.3% ID/g)
and these differences became larger at 24 hours (43.7% versus
15.2% ID/g) and 48 hours (31.3% versus 8.5% ID/g; P < 0.01).
In contrast, there were no significant differences in the amount
of the bioconjugate retained in normal brain (Fig. 2). Similar
differences were noted in animals that received BD-L8A4 by
CED. At 24 hours following CED, 60.1% ID/g was localized in
F98npEGFRvIII gliomas compared with 43.7% ID/g after i.t.
injection and 14.6% ID/g after CED in F98WT gliomas (Table 2).
Using the Wilcoxon rank-sum test to calculate exact P values,
Fig. 2. Tumor and normal brain uptake of 125I-labeled bioconjugate. F98npEGFRvIII the differences between the CED and i.t. groups were highly
(.) or F98WT (o) glioma-bearing rats were injected i.t. with [125I]BD-LA84 and
euthanized 6, 12, 24, and 48 hours later. Normal brain uptake in F98npEGFRvIII (!) significant (P = 0.008) as were differences between the
and F98WT (4) tumor-bearing rats was determined following excision of the tumor. F98npEGFRvIII and F98WT groups. The amounts of radioactivity
Points, mean of four rats; bars, SD. in muscle, liver, skin, and kidney after CED were all <1% of the
injected dose for all infusion volumes and times after infusion.
increase in the V d/V i ratio compared with that attained Autoradiographs clearly showed that CED was far superior to
following i.c. injection. These differences were clearly evident i.t. injection as a means to disperse [125I]BD-L8A4 within the
in a series of autoradiographs (data not shown) that were made tumor. Although the brains of glioma-bearing rats showed
from coronal sections of brains from non-tumor-bearing rats. significant tumor-related neuropathologic changes, none
As determined by quantitative densitometry, immediately after seemed to be related specifically to insertion of the cannula.
completion of CED of 20 AL [125I]BD-L8A4 for 60 minutes, Tumor weights ranged from 160 to 300 mg, and as determined
f80% of the rat gray matter or f25% of the infused from H&E-stained coronal sections, tumor diameters ranged
hemisphere had received >1% of the infusion concentration. from f3 to 7 mm.
The mean percent radioactivity recovered from the brain were Tissue boron concentrations and dosimetry. Boron concen-
90.1%, 88.3%, and 85.9%, respectively, for V i of 5, 10, and 20 trations in tumor and selected normal tissues and the calculated
AL (Table 1). The V d of animals euthanized 12 hours after CED physical doses delivered to them are summarized in Table 3.
or i.c. injection were slightly increased over those determined The tumor boron concentration in rats that received CED of
immediately after CED or i.c. injection (data not shown). The BD-L8A4 was 32.7 F 3.6 Ag/g compared with 10.7 F 1.7 Ag/g
concentration of the bioconjugate in normal brain, as following i.v. injection of BPA. Boron levels in normal tissues
determined by quantitative autoradiography, was homogenous. were in the undetectable range (<0.5 Ag/g) in rats that received
Microscopic examination of the brains of non-tumor-bearing CED of BD-L8A4. Dosimetric calculations were based on mean
rats, which had undergone CED, showed minimal hemorrhage boron concentrations of tumor, brain, and blood at 24 hours
along the path of the infusion cannula but no other following CED of BD-L8A4 and 2.5 hours after i.v. adminis-
neuropathologic changes in the remainder of the infused tration of BPA in a separate group of untreated animals. Based
cerebral hemisphere. on these total boron concentrations, the mean absorbed dose
Biodistribution of [125I]BD-L8A4 in glioma-bearing rats. delivered to F98npEGFRvIII tumors was 9.2 Gy following CED of
Tumor and normal tissue uptake of the bioconjugate following L8A4, 4.2 Gy following i.v. administration of BPA alone, and
Table 2. Radiolocalization of [125I]BD-L8A4 in F98 glioma-bearing rats at 24 hours following either i.t. injection
or CED
Tumor/route %ID/g Tumor/brain ratio
Tumor Brain ipsilateral Brain contralateral Liver Blood
F98npEGFRvIII/CED 60.1 F10.8 6.2 F 1.2 2.0 F 0.5 0.19 F 0.05 0.05 F 0.01 9.5 F 2.6
F98npEGFRvIII/i.t. 43.7 F 6 .1 5.6 F 1.1 2.9 F 1.1 0.19 F 0.05 0.06 F 0.03 6.9 F 1.3
F98 WT/CED 14.6 F 2.7 2.9 F 1.2 1.2 F 0.5 0.22 F 0.08 0.05 F 0.01 5.6 F 2.6
F98WT/i.t. 15.2 F 3.4 3.2 F 1.0 1.0 F 0.5 0.34 F 0.06 0.10 F 0.02 4.9 F 1.0
NOTE: Each animal received 5 ACi [125I]BD-L8A4 (50 Ag L8A4) by either i.t. or CED. %ID/g was based on the amount recovered relative to that given. The tumor/brain
ratio was based on tumor uptake versus ipsilateral (tumor-bearing) cerebral hemisphere.
Clin Cancer Res 2006;12(12) June 15, 2006 3796 www.aacrjournals.org
6. Molecular Targeting of EGFRvIII-Positive Gliomas
Table 3. Boron concentrations and radiation absorbed dose to tumor, brain, and blood
Group Boron concentrations (Mg/g)* Absorbed dose (Gy)c
b
Tumor Brain Blood Tumor Brain Blood
CED BD-L8A4 32.7 F 3.6 <0.5 <0.5 9.2 1.9 1.9
i.v. BPA 10.7 F 1.7 3.8 F 1.1 5.2 F 1.3 4.2 2.6 2.9
CED BD-L8A4 i.v. BPA 44.5 F 11.1 4.2 F 0.5 4.0 F 1.2 12.0 2.7 2.7
*Boron content was quantified by means of direct current plasma-atomic emission spectroscopy. These values were obtained from rats that had received CED of
BD-L8A4 (40 Ag 10B/750 mg L8A4) alone 24 hours earlier or in combination with i.v. BPA (500 mg/kg body weight equivalent to 27 mg 10B/kg body weight), which
was given 2.5 hours before euthanization.
cAbsorbed dose determinations include contributions from g-photons, 14N(n,p)14C and 10B(n,a) 7Li reactions.
bBoron concentrations were determined in the tumor-bearing cerebral hemisphere after excision of the tumor.
12.0 Gy in combination with CED of BD-L8A4 (Table 3). The for the irradiated controls (Table 4). Animals bearing
normal brain doses ranged from 1.9 to 2.7 Gy. All doses in this F98npEGFRvIII gliomas, which had received CED of BD-L8A4
report were expressed as the physical absorbed dose and no and BNCT, had a MST of 70.4 F 11.1 days (range, 41->180
attempt was made to apply biological weighting factors. days), with one animal surviving 180 days. Animals that
Therapeutic response of glioma-bearing rats following received CED of BD-L8A4 in combination with i.v. BPA had a
BNCT. All animals in a pilot study to determine tolerance to MST of 85.5 F 15.5 days (range, 42 to >180 days) with two rats
BNCT following CED of BD-L8A4 lost weight within 7 to 10 surviving >180 days compared with 40.1 F 2.2 days (range,
days after treatment. Rats that received CED of f40 Ag 10B/ 32-52 days) for animals that received i.v. BPA alone. The
f750 Ag BD-L8A4 and 500 mg/kg body weight of BPA i.v. lost corresponding percent increased life span were 225.1% for the
<10% of their body weight but regained it within 2 weeks. combination versus 168% for CED of BD-L8A4 and 54% for
Based on these results, CED of f40 Ag 10B/f750 Ag L8A4 i.v. BPA (Table 4). The results from these comparisons indicate
alone or in combination with i.v. BPA was used. BNCT was that CED of BD-L8A4 either alone or in combination with
initiated at the Massachusetts Institute of Technology Research i.v. BPA was significantly different from the i.v. BPA group
Reactor-II 14 days following i.c. implantation of 103 F98npEGFR- (P = 0.02) and the untreated and irradiated control groups
vIII glioma cells. All rats tolerated BNCT without any untoward (P = 0.002). However, the difference in MSTs between the
effects, and 3 to 7 days later, they were returned to Columbus, groups that received BD-L8A4 either alone or combination
OH. A Cox proportional hazards regression model was fit to the with BPA was not significant (P = 0.15). This lack of statistical
data and the proportional hazards assumption was checked. significance was attributable to the overlapping ranges in
Because this was met, the log-rank test was used to test for survival times of animals that received CED of BD-L8A4 alone
significance between survival curves, and the survival data of (41-180 days) versus those that received it in combination with
the groups were significantly different overall (P < 0.0001), i.v. BPA (42-180 days).
indicating that not all of the Kaplan-Meier survival plots were Neuropathologic findings. The brains of all animals were
equal. Survival data following BNCT are summarized in Table 4 subjected to histopathologic examination. Animals that re-
and Kaplan-Meier and Cox survival plots for BNCT-treated ceived boronated L8A4 either alone or in combination with
animals and irradiated controls are shown in Figs. 3 and 4, BPA had almost identical tumor size indices (3.6, 3.8, and 3.8).
respectively. Untreated control rats had a MST F SE of 26.3 F Control animals that received either non-BD, which had been
1.6 days compared with a modest increase of 30.3 F 1.6 days conjugated to L8A4, or BD-L8A4 without neutron irradiation
Table 4. Survival times of F98npEGFRvIII glioma-bearing rats following CED or i.t. injection of BD-L8A4 with or
without i.v. BPA and BNCT
Group Route/agent Survival times (d) % Increased life span*
c
Range Mean F SE Median Mean Median
1 CED/BD-L8A4 (n = 11) 41to >180 (n = 1) 70.4 F 11.1 58 168 123
2 CED/BD-L8A4 + i.v./BPA (n = 10) 42 to >180 (n = 2) 85.5 F 15.5 65.5 225 152
3 i.v./BPA (n = 8) 32-52 40.1 F2.2 40 52 54
4 CED/L8A4 + irradiation (n = 7) 24-37 30.3 F 1.6 30 15 15
5 CED/BD-L8A4 (n = 7) 21-34 26.3 F 1.6 26 ö ö
*Percentage of increased life span was defined relative to MSTand median survival time of untreated controls.
cn is the number of rats surviving >180 days.
www.aacrjournals.org 3797 Clin Cancer Res 2006;12(12) June 15, 2006
7. Cancer Therapy: Preclinical
these most likely were the result of an acute inflammatory
response that may have been evoked by bacteria that were
inadvertently introduced into the brain at the time of tumor cell
implantation due to bacterial contamination of the syringe
needle. Choroidal epithelial cells, which are especially sensitive
to radiation injury, appeared to be normal. In summary, these
histopathologic changes were similar to those that we have seen
in long-term survivors from other studies (41) and showed that
tumor cells could be selectively killed without damage to
adjacent normal brain.
Discussion
In the present study, we have evaluated the efficacy of the
anti-EGFRvIII mAb L8A4 as a boron delivery agent for NCT in
rats bearing i.c. implants of the F98npEGFRvIIII glioma. We first
established that CED more efficiently delivered BD-L8A4 to the
Fig. 3. Kaplan-Meier survival plots for F98npEGFRvIII glioma-bearing rats. Survival
times in days after implantation have been plotted for untreated animals (.), tumor compared with direct i.t. injection (60.1% versus 43.7%
irradiation + L8A4 (o), i.v. BPA + BNCT (E), and CED of BD-L8A4 alone ( w ) or in ID/g). Based on these observations, CED was used to
combination with i.v. BPA (5) followed by BNCT. The differences in MSTs of those
animals that received BD-L8A4 either alone or in combination with BPA were
administer the bioconjugate in our therapy experiments.
significantly different (P < 0.01) from those of untreated or irradiated control animals Boronated L8A4 was given either alone or in combination
or BPA alone (P < 0.02). However, they were not different from each other with i.v. injection of BPA, and 24 hours later, BNCT was carried
(P = 0.16).
out. The MST of animals that received the bioconjugate in
combination with BPA was 85.5 days compared with 70.4 days
had smaller tumor size indices (3.4 and 3.0, respectively). The for those that received it alone, 40.1 days for BPA alone, and
fact that these animals died with smaller tumors than those that 30.3 days for irradiated controls. Among the treated animals,
had received BNCT suggests that they may have had more there was a subset of rats that survived >180 days, which
cerebral edema, which invariably is associated with brain clinically were regarded as cured, and this was confirmed by
tumors (39). histopathologic examination. These survival data were superior
Although there was considerable variability in the histopath- to those that we have obtained using BPA in combination with
ologic appearance of the tumors at the time of the animal’s BSH following i.v. or intra-arterial administration (41, 42). The
death or euthanization, there were certain constant features present data, and those recently reported by us in a preliminary
irrespective of the treatment that they had received (Fig. 5A study using boronated cetuximab (14), establish proof-of-
and B). Almost all of the tumors were highly infiltrative of principle that gliomas expressing either EGFR or EGFRvIII can
surrounding white matter with islands of malignant cells at be selectively targeted with boronated mAbs, given by either i.t.
some distance from the main tumor mass. There were only injection or CED, and that a significant gain in survival time
small zones of necrosis either located centrally or in the can be obtained following NCT.
periphery. There was variability in cellular morphology, ranging To date, only two drugs have been used in clinical BNCT
from spindle-shaped cells showing a storiform pattern of trials, BSH and BPA (1). The potential use of high molecular
growth to contiguous sheets or clusters of small, round cells
showing a highly infiltrative pattern of growth (Fig. 5B), which
is characteristic of malignant gliomas (40). In addition, rare
tumor giant cells and occasional mitotic figures were seen
(Fig. 5B). This cellular pleiomorphism resembled that seen in
human high-grade gliomas (40). Immunostaining revealed that
the tumor cells were glial fibrillary acidic protein negative and
S100 negative. Rare CD3+ T lymphocytes were seen within the
tumor and scattered CD68+ macrophages were seen in the
periphery. In contrast to these findings, the brain of one long-
term survivor (i.e., >180 days), which had received BD-L8A4
plus BPA, showed no evidence of residual tumor, necrosis, or
inflammatory cell infiltrates. The brains of two other long-term
survivors showed focal fibrosis, with small (<1 mm) central
cavities (Fig. 5C and E). There were CD3+, CD20+, CD68+, and
glial fibrillary acidic protein-positive cells and hemosiderin
laden macrophages interspersed in the fibrous tissue compo-
nent (Fig. 5D and E). In the brain of one of these animals,
there was a dense infiltrate of polymorphonuclear leukocytes Fig. 4. Cox survival plots for F98npEGFRvIII glioma-bearing rats. Survival times in
days after implantation have been plotted for untreated animals (.), irradiation +
adjacent to the fibrous tissue (Fig. 5F). Because a tumor-asso- L8A4 (o), i.v. BPA + BNCT (E), and CED of BD-L8A4 alone ( w ) or in combination
ciated immune response would have a lymphocytic infiltrate, with i.v. BPA (5) followed by BNCT.
Clin Cancer Res 2006;12(12) June 15, 2006 3798 www.aacrjournals.org
8. Molecular Targeting of EGFRvIII-Positive Gliomas
Fig. 5. Neuropathologic findings in untreated and BNCT-treated rats bearing i.c. implants of the F98npEGFRvIII glioma. A, tumor in an untreated rat. This was composed
predominantly of spindle-shaped cells showing a storiform pattern of growth. Magnification, Â200. B, tumor from a rat that had received i.v. BPA. There was considerable
cellular pleiomorphism ranging from spindle-shaped cells in the main tumor mass to small round cells and occasional multinucleate tumor giant cells in the periphery.
Magnification, Â200. C, brain of a long-term survivor (180 days) showing a small central cavity (<1mm) surrounded by fibrotic tissue (magnification, Â100), in which (D)
there were lymphocytes and macrophages, some of which were hemosiderin laden but no residual tumor cells (magnification, Â600). E, the brain of another long-term
survivor showed a circumscribed area of fibrosis with scattered macrophages and rare lymphocytes. Magnification, Â400. F, in another area of this same tumor, there was a
focal infiltrate of polymorphonuclear leukocytes. Magnification, Â200.
weight boron delivery agents recently has been reviewed by us The F98npEGFRvIII glioma, used in this study, expressed
(43), but none of these have as yet been evaluated clinically. human EGFRvIII at a density of >105 receptor sites per cell.
Studies previously carried out by us have shown that the i.v. Another cell line, designated F98EGFRvIII, which has been
route of administration was unsuitable for the delivery of produced for us by Drs. Frank Furnari and Webster Cavenee
boronated EGF (10, 19) and L8A4 (31) in glioma-bearing rats. (Ludwig Institute for Cancer Research, University of California
One way to overcome the blood-brain barrier is to administer at San Diego, San Diego, CA), expressed >106 receptor sites
the high molecular weight agents directly into the brain by CED per cell. Furthermore, this receptor was constitutively phos-
(44 – 46). This approach has been used by us in the present phorylated compared with the nonphosphorylated receptor of
study, and as recently reported, it has been used clinically to the F98npEGFRvIII cell line that we have used in the present
administer the anti-tenascin mAb 81C6 into the cavity created study. However, the former cell line, when implanted i.c. with
following surgical resection of gliomas (47). The efficacy and logarithmically incremental numbers of tumor cells, did not
toxicity of [131I]81C6 was evaluated in a group of 43 patients produce survival times that were a linear function of the
with recurrent high-grade gliomas. The mAb was given by tumor cell dose, and unexpectedly, animals that received 105
Rickham reservoirs and cannulas that had been placed into the tumor cells i.c. had longer survival times than those that
resection cavity. The median overall survival of patients with received 103 cells.9 Based on these observations, and our
glioblastoma multiforme and anaplastic astrocytomas were 64 previous studies with another EGFR transfectant model, the
and 99 weeks, respectively, which were greater than those of C6 glioma, which had been transfected with the human EGFR
historical controls at the same institution (Duke University gene (48), we have concluded that the cell line expressing 106
Medical Center, Durham, NC) for patients that had been EGFRvIII sites per cell can evoke an immune response directed
treated with surgery plus 125I brachytherapy. These studies have against the human receptor, whereas the F98npEGFRvIII cell line
established the feasibility of using direct i.c. delivery of a mAb does not. Although it would be advantageous to have a cell
directed against a tumor-associated antigen, and based on these line that had a functional (i.e., phosphorylated) receptor
favorable results, a phase III multicenter trial is planned (47). expressing 106 receptor sites per cell, it would not be possible
Our own data suggest that the use of boronated antibodies is to use the one that Furnari and Cavenee have produced for
feasible for NCT. A significant advantage of a boronated experimental therapy studies in syngeneic Fischer rats because
delivery agent over the direct administration of a radiolabeled the ensuing immune response would confound the effects of
mAb is that one can wait until the 10B has cleared from normal
tissues before BNCT is carried out, thereby eliminating or
minimizing damage to normal brain. 9
W. Yang and R.F. Barth, unpublished data.
www.aacrjournals.org 3799 Clin Cancer Res 2006;12(12) June 15, 2006
9. Cancer Therapy: Preclinical
the therapeutic agent. To prevent this, it would be necessary to less than that of L8A4.10 What are the advantages of each? EGF
use immunologically deficient nude rats to obviate the bioconjugates have better diffusion properties within the tumor
immune response that would occur in immunocompetent by virtue of their lower molecular weight. L8A4 bioconjugates
animals. have specificity only for EGFRvIII and not wild-type EGFR,
We would like to make several comments relating to the which is expressed on many different types of cells, and this
neuropathologic findings in those rats that clinically were could be of importance if it were given systemically. However,
cured and relate them to BNCT. First, it is noteworthy that only cetuximab (Erbitux) has met rigorous Food and Drug
there was no evidence of normal brain necrosis or small Administration requirements for biologics and is now being
blood vessel injury at the site of infusion of the boronated widely used clinically (55 – 58), whereas L8A4 and EGF only
L8A4. This indicated that the 10B levels in normal brain at 24 have been evaluated in experimental animals studies, have not
hours following CED had fallen below the threshold amounts been prepared in good manufacturing practice (GMP) facilities,
that would have been required to produce radiation injury and are very costly to produce. The conclusion at this time,
(49). Second, the very fact that we had a subset of animals therefore, is that boronated cetuximab (14, 15), which will be
that were histopathologically free of tumor strongly suggests the subject of another report, would be the agent of choice.
that all or almost all of the tumor cells had been killed by the We would like to conclude with some comments relating to
a-particles and recoiling 7Li particles that were produced in the clinical trials that have been carried out with BSH (59) and
the 10B(n,a)7Li capture reaction. Bystander effects following BPA (60 – 63) as single agents, the results of which have been
a-particle irradiation have been described by several inves- reported and discussed in several recent reviews and mono-
tigators (50 – 53) and we believe that our data show that graphs (1 – 3). In the clinical trials carried out with BPA at the
following BNCT molecular targeting of a tumor cell surface Brookhaven National Laboratory in the United States (60),
receptor with a boronated mAb was tumoricidal either directly there were not only regions of frank tumor necrosis but also
or via bystander effects. The challenge is to develop other evidence of tumor progression in the high-dose target volume,
molecular targeting agents that can selectively deliver 10B to suggesting that there was nonuniform distribution of boron to
tumor cells. the tumor cells. Longer infusions of BPA, carried out in Sweden
The data that we have obtained with the mAbs L8A4 and (63), may marginally have increased the median survival time,
cetuximab define two characteristics of EGFR targeting but the dose escalation studies with BPA have reached the
bioconjugates that make them promising boron delivery point where normal brain tolerance has become the limiting
agents for use in combination with either BPA alone or with factor. The occurrence of the somnolence syndrome in patients
BPA and BSH as is currently being evaluated in Japan (54). treated with the higher radiation doses has been reported (64),
The data shown in Tables 3 and 4 indicate that CED of which indicates that dose escalation trials with BPA as the
BD-L8A4 was more effective than i.v. administration of BPA single boron delivery agent, have reached a limit both in terms
for BNCT of the F98npEGFRvIII glioma. When the MSTs of of the doses of BPA and neutrons. With BPA, there was a
animals in the experimental and control groups were plotted significant amount of boron in normal brain, and this
versus the 10B concentrations in the tumor, there was a linear undoubtedly contributed to the brain dose and the occurrence
relationship (r 2 = 0.998). This indicated that the MST was of the somnolence syndrome. Further progress in clinical
directly related to the total cell-associated boron in the tumor studies of BNCT for high-grade gliomas will require significant
and that the radiobiological effectiveness of the 10B contrib- improvements in the methods used to administer BPA and
uted by the bioconjugate was additive to that of BPA. BSH, as well as the use of combinations of agents, which is
However, use of the boronated conjugate allowed us to based on the premise that two or more boron delivery agents
escalate the tumor 10B concentration without significantly would target different subpopulations of tumor cells. We have
increasing the blood and normal brain concentrations. In shown that the combination of BPA and BSH was more
contrast, when combinations of BPA and BSH were used, effective than either one alone in BNCT of the rat F98 glioma
there always was an increased amount of 10B in the blood and (41, 42). Ono et al. have reported similar data for BNCT of the
normal tissues (41, 42), which limited the neutron dose that SCCVII rat squamous cell carcinoma (65). However, although
could be delivered to the target volume. BPA results in tumor- BPA and BSH have been shown to be clinically safe, their
to-normal brain boron concentration ratios that may be as therapeutic efficacy, at least as they are currently being used, is
high as 3:1 or 4:1, but the boron concentration in normal less than ideal (66). The time has come to move on to new
brain is still significant, which limits the neutron dose that boron delivery agents (67), among which high molecular
can be delivered to the tumor (2). Because BSH does not cross weight targeting bioconjugates (68) may be particularly
the intact blood-brain barrier, it may contribute additional 10B promising candidates. Because it is highly unlikely that all
to the tumor, but the tumor-to-blood boron concentrations tumor cells within a glioblastoma multiforme would express
ratios with BSH are f1:1, thereby limiting the neutron dose either EGFR or EGFRvIII, the bioconjugate would have to be
in clinical irradiations (2). used in combination with BPA alone or with BSH.
We now have evaluated three boronated EGFR targeting
agents, the ligand itself, EGF (11, 13), cetuximab (14), and, as Acknowledgments
reported in the present study, L8A4. Based on all of our data,
what can we conclude about these three different targeting We thank Dr. Darrell Bigner for a generous gift of L8A4 to carry out these studies,
Dianne Adams, Joan Rotaru, and Michele Swindall for technical assistance, and
agents? EGF bioconjugates only can target the wild-type
Beth Kahl for secretarial assistance in the preparation of this article.
receptor, and the L8A4 bioconjugate only can target EGFRvIII.
Cetuximab, on the other hand, can target both wild-type EGFR
and EGFRvIII, although its binding affinity for the latter was 10
G.Wu and R.F. Barth, unpublished data.
Clin Cancer Res 2006;12(12) June 15, 2006 3800 www.aacrjournals.org
10. Molecular Targeting of EGFRvIII-Positive Gliomas
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