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
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
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.
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.
Flow Cytometric Analysis for Ploidy and DNA Content of Banana Variants Induce...paperpublications3
Abstract: Nuclear DNA content of mutated banana plants was determined by using flow cytometric techniques. It is a powerful tool for large scale screening of ploidy levels. Nuclei were isolated from young leaves from (banana mutants & Glycine plants) supplemented with Propidium- iodide (PI) and RNAse. "Glycine max" used as internal reference standard for identifying the nuclear DNA content by FCM. For ploidy estimation DAPI was used. The results showed differences in DNA content between variants indicating the effect of gamma-irradiation on the genotype of these plants. Variants of short plant stature or stunted growth showed great differences in DNA content compared to control (non-irradiated). The phenotypic variations observed at high doses were likely due to changes in the DNA sequences at the chromosomal level. Nuclear DNA contents decreased with an increase of gamma-dose from 20 Gy to 60 Gy. However, there were no significant differences between DNA content at 20 Gy and 30 Gy and also between 40 Gy and 60 Gy, while they were differed significantly from the control. The results showed no significant differences in ploidy level between all samples used (3n); while all selected mutants (variants) showed differences in DNA content.
Tumour Hypoxia - detection and prognostic significanceMAASTRO clinic
Lecture by Dr. Heidi Lyng in the context of the Course: "Tumour Hypoxia: From Biology to Therapy III".
For the complete e-Course see http://www.myhaikuclass.com/MaastroClinic/metoxia
Austin Journal of Nanomedicine & Nanotechnology is an open access, peer reviewed, scholarly journal dedicated to publish innovative research works carried out in the fields of Nanomedicine & Nanotechnology.
Austin Journal of Nanomedicine & Nanotechnology aims to serve health care professionals, medical practitioners and innovative researchers by providing a forum to find most recent advances in the areas Nanomedicine & Nanotechnology.
Austin Journal of Nanomedicine & Nanotechnology accepts original research articles, review articles and short communication on all the aspects of Nanomedicine & Nanotechnology for review and possible publication.
Austin Journal of Nanomedicine & Nanotechnology is an open access, peer reviewed, scholarly journal dedicated to publish innovative research works carried out in the fields of Nanomedicine & Nanotechnology.
Universal and rapid salt extraction of high quality genomic dna for pcr-based...CAS0609
This document describes a simple and universal method for extracting high-quality genomic DNA from a variety of organisms including plants, fungi, insects, and shrimp. The method uses a salt-based homogenizing buffer and SDS to extract DNA from as little as 50mg of fresh tissue. The extracted DNA is of sufficient quality and quantity to be used in PCR, restriction digestion, and other molecular techniques. The method is fast, inexpensive, and does not require expensive equipment, making it suitable for laboratories with limited resources. Test results demonstrated the method successfully extracted high molecular weight DNA from many diverse organisms without modification, indicating its universal applicability.
The document summarizes research characterizing newly isolated bacteriophages (viruses that infect bacteria) that prey on Mycobacterium smegmatis bacteria. Twelve bacteriophages were found and nine were analyzed by electron microscopy, showing a tailed "siphoviridae" structure. The genome of one phage, Bipolar, was fully sequenced and found to be similar to the F1 subcluster. The document then analyzes whether two genes, Tape Measure Protein (TMP) and Lysin A, can accurately predict phage cluster relationships on their own. Results showed that TMP was highly accurate, while Lysin A was less so, supporting the hypothesis that Lysin A is more diverse
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
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.
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.
Flow Cytometric Analysis for Ploidy and DNA Content of Banana Variants Induce...paperpublications3
Abstract: Nuclear DNA content of mutated banana plants was determined by using flow cytometric techniques. It is a powerful tool for large scale screening of ploidy levels. Nuclei were isolated from young leaves from (banana mutants & Glycine plants) supplemented with Propidium- iodide (PI) and RNAse. "Glycine max" used as internal reference standard for identifying the nuclear DNA content by FCM. For ploidy estimation DAPI was used. The results showed differences in DNA content between variants indicating the effect of gamma-irradiation on the genotype of these plants. Variants of short plant stature or stunted growth showed great differences in DNA content compared to control (non-irradiated). The phenotypic variations observed at high doses were likely due to changes in the DNA sequences at the chromosomal level. Nuclear DNA contents decreased with an increase of gamma-dose from 20 Gy to 60 Gy. However, there were no significant differences between DNA content at 20 Gy and 30 Gy and also between 40 Gy and 60 Gy, while they were differed significantly from the control. The results showed no significant differences in ploidy level between all samples used (3n); while all selected mutants (variants) showed differences in DNA content.
Tumour Hypoxia - detection and prognostic significanceMAASTRO clinic
Lecture by Dr. Heidi Lyng in the context of the Course: "Tumour Hypoxia: From Biology to Therapy III".
For the complete e-Course see http://www.myhaikuclass.com/MaastroClinic/metoxia
Austin Journal of Nanomedicine & Nanotechnology is an open access, peer reviewed, scholarly journal dedicated to publish innovative research works carried out in the fields of Nanomedicine & Nanotechnology.
Austin Journal of Nanomedicine & Nanotechnology aims to serve health care professionals, medical practitioners and innovative researchers by providing a forum to find most recent advances in the areas Nanomedicine & Nanotechnology.
Austin Journal of Nanomedicine & Nanotechnology accepts original research articles, review articles and short communication on all the aspects of Nanomedicine & Nanotechnology for review and possible publication.
Austin Journal of Nanomedicine & Nanotechnology is an open access, peer reviewed, scholarly journal dedicated to publish innovative research works carried out in the fields of Nanomedicine & Nanotechnology.
Universal and rapid salt extraction of high quality genomic dna for pcr-based...CAS0609
This document describes a simple and universal method for extracting high-quality genomic DNA from a variety of organisms including plants, fungi, insects, and shrimp. The method uses a salt-based homogenizing buffer and SDS to extract DNA from as little as 50mg of fresh tissue. The extracted DNA is of sufficient quality and quantity to be used in PCR, restriction digestion, and other molecular techniques. The method is fast, inexpensive, and does not require expensive equipment, making it suitable for laboratories with limited resources. Test results demonstrated the method successfully extracted high molecular weight DNA from many diverse organisms without modification, indicating its universal applicability.
The document summarizes research characterizing newly isolated bacteriophages (viruses that infect bacteria) that prey on Mycobacterium smegmatis bacteria. Twelve bacteriophages were found and nine were analyzed by electron microscopy, showing a tailed "siphoviridae" structure. The genome of one phage, Bipolar, was fully sequenced and found to be similar to the F1 subcluster. The document then analyzes whether two genes, Tape Measure Protein (TMP) and Lysin A, can accurately predict phage cluster relationships on their own. Results showed that TMP was highly accurate, while Lysin A was less so, supporting the hypothesis that Lysin A is more diverse
Recent advances in antisense drugs like morpholino oligonucleotides have broadened their therapeutic potential. Morpholinos can specifically block gene expression through steric blocking of translation or splicing. They are currently under clinical investigation for genetic disorders, viral infections, and cancers. Key challenges include improving delivery into tissues and reducing potential toxicity at high doses for clinical use.
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
Site-directed mutagenesis is a technique used to introduce specific changes to the DNA sequence of a gene by altering the nucleotide sequence. It allows researchers to study the impact of mutations by changing individual bases, deleting bases, or inserting new bases. There are different methods of site-directed mutagenesis including oligonucleotide-based methods and PCR-based methods. Site-directed mutagenesis has applications in research, production of desired proteins, and development of engineered proteins for commercial uses like detergents.
Plasma Proteomics: The Next Frontier of Biomarker Discovery in the Precision ...InsideScientific
Prof. Manuel Mayr and Dr. Marco Tognetti discussed how plasma proteomics is increasingly recognized as a fundamental approach to accelerate biomarker discovery and drug development, taking precision medicine to the next level.
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 describes a study that analyzed the chloroplast DNA (cpDNA) in the bamboo species Gigantochloa scortechinii found in Peninsular Malaysia. The researchers developed a PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) marker to detect two distinct cpDNA lineages, called the Gombak- and Langat-types. They analyzed cpDNA from G. scortechinii samples collected from four locations. Most samples (60.7%) had the Gombak-type cpDNA, suggesting it is the dominant type in Peninsular Malaysia. The existence of the two cpDNA types indicates chloroplast capture likely due to past hybridization and introgression among
Circular RNAs (circRNAs) are a class of non-coding RNAs that can regulate gene expression by interacting with microRNAs (miRNAs). This document reviews the roles of circRNAs in human disorders through circRNA-miRNA interactions. It discusses how specific circRNAs like CDR1as have been found to be dysregulated in neurological disorders, cancers, and cardiovascular diseases and can contribute to disease by sponging up certain miRNAs. The prospect of using circRNAs as biomarkers for disease diagnosis and prognosis is also mentioned.
Optimization of experimental protocols for cellular lysisExpedeon
In this project, we have compared existing sample preparation methods for proteomics studies against newly developed FASP method and our in-house developed SDS-TCA protocol. For our
preliminary studies, we have chosen a very well characterized soil microbe Pseudomonas putida.
Manteia non confidential-presentation 2003-09Pascal Mayer
A non confidential corporate presentation of "Manteia Predictive Médicine" as of September 2003. Présents DNA colony sequencing resutls, instrument, DNA preparation for genotyping.
This document reviews microRNAs (miRNAs) related to the occurrence, diagnosis, and prognosis of non-small cell lung cancer (NSCLC). It discusses how some miRNAs act as oncogenes in NSCLC by promoting proliferation, migration, and invasion through targeting tumor suppressor genes. Other miRNAs act as tumor suppressors by inhibiting oncogenes. The expression levels of certain miRNAs have diagnostic and prognostic value for NSCLC. Some miRNAs show potential as biomarkers for early detection of NSCLC or for distinguishing NSCLC subtypes. Circulating miRNAs may also serve as biomarkers for cancer detection and prognosis. Single nucleotide polymorphisms in miRNA genes have been associated with survival in NSCLC patients.
Assessment of immunomolecular_expression_and_prognostic_role_of_tlr7_among_pa...dr.Ihsan alsaimary
This document summarizes a research study that assessed the immunomolecular expression and prognostic role of Toll-like receptor 7 (TLR7) in patients with prostatitis. The study included 135 confirmed prostatitis patients and 50 control patients. DNA was extracted from blood samples and amplified using PCR to assess TLR7 expression. Results showed the PCR product for TLR7 was 149bp, indicating a high percentage of TLR7 presence. The study suggests TLR alleles may be associated with risk of prostatitis.
Label free and reagentless electrochemical detection of micro rn-as using a c...hbrothers
This document describes a label-free and reagentless electrochemical biosensor for detecting microRNAs (miRNAs). The sensor uses a conducting polymer nanostructured with carbon nanotubes that is electroactive in neutral aqueous solutions. Addition of the target miRNA miR-141, a prostate cancer biomarker, causes a "signal-on" response by increasing the current through the polymer. Non-complementary miRNAs do not change the current. The sensor achieves very low detection of about 8 femtomolar (fM) of miR-141. The conducting polymer-carbon nanotube composite provides a reagentless platform for immobilizing and detecting miRNA sequences with high sensitivity and specificity.
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.
The Thiazolobenzimidazole TBZE-029 Inhibits Enterovirus Replication by Target...degarden
This document summarizes research identifying the viral target of the antiviral compound TBZE-029 against enteroviruses. Through selecting for drug-resistant coxsackievirus B3, the researchers identified three mutations in the nonstructural protein 2C clustered near motif C. Reintroducing the mutations, particularly at positions 227 and 229, conferred drug resistance, demonstrating 2C as the target. Viruses with the mutations also showed cross-resistance to other known 2C-targeting antivirals. The ATPase activity of 2C was unaffected by TBZE-029, suggesting it targets a different function of this essential replication protein.
Molecular quantitative genetics for plant breeding roundtable 2010xFOODCROPS
This document provides an overview of molecular markers and quantitative trait locus (QTL) mapping. It begins with a discussion of different types of genetic variation and how molecular markers can be used to detect variation at the DNA level. The document then describes different types of molecular markers, including restriction fragment length polymorphisms (RFLPs), polymerase chain reaction (PCR)-based markers, simple sequence repeats (SSRs), and single nucleotide polymorphisms (SNPs). It also discusses what a QTL is and how QTL mapping is performed. The document concludes with how molecular markers and QTL mapping can be used to understand the genetic basis of traits and help improve crops.
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.
Next generation sequencing (NGS) has various applications in cancer treatment and research. It can be used to identify novel cancer mutations, detect hereditary cancer syndromes, enable personalized cancer treatment based on a patient's genetic profile, and detect circulating tumor DNA (ctDNA). NGS allows comprehensive analysis of cancer genomes and biomarkers for molecular diagnosis, prognosis, and monitoring treatment response. Challenges include analyzing large amounts of NGS data and accurately interpreting genetic variations, but its clinical utility continues to advance personalized cancer care.
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
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.
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.
Recent advances in antisense drugs like morpholino oligonucleotides have broadened their therapeutic potential. Morpholinos can specifically block gene expression through steric blocking of translation or splicing. They are currently under clinical investigation for genetic disorders, viral infections, and cancers. Key challenges include improving delivery into tissues and reducing potential toxicity at high doses for clinical use.
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
Site-directed mutagenesis is a technique used to introduce specific changes to the DNA sequence of a gene by altering the nucleotide sequence. It allows researchers to study the impact of mutations by changing individual bases, deleting bases, or inserting new bases. There are different methods of site-directed mutagenesis including oligonucleotide-based methods and PCR-based methods. Site-directed mutagenesis has applications in research, production of desired proteins, and development of engineered proteins for commercial uses like detergents.
Plasma Proteomics: The Next Frontier of Biomarker Discovery in the Precision ...InsideScientific
Prof. Manuel Mayr and Dr. Marco Tognetti discussed how plasma proteomics is increasingly recognized as a fundamental approach to accelerate biomarker discovery and drug development, taking precision medicine to the next level.
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 describes a study that analyzed the chloroplast DNA (cpDNA) in the bamboo species Gigantochloa scortechinii found in Peninsular Malaysia. The researchers developed a PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) marker to detect two distinct cpDNA lineages, called the Gombak- and Langat-types. They analyzed cpDNA from G. scortechinii samples collected from four locations. Most samples (60.7%) had the Gombak-type cpDNA, suggesting it is the dominant type in Peninsular Malaysia. The existence of the two cpDNA types indicates chloroplast capture likely due to past hybridization and introgression among
Circular RNAs (circRNAs) are a class of non-coding RNAs that can regulate gene expression by interacting with microRNAs (miRNAs). This document reviews the roles of circRNAs in human disorders through circRNA-miRNA interactions. It discusses how specific circRNAs like CDR1as have been found to be dysregulated in neurological disorders, cancers, and cardiovascular diseases and can contribute to disease by sponging up certain miRNAs. The prospect of using circRNAs as biomarkers for disease diagnosis and prognosis is also mentioned.
Optimization of experimental protocols for cellular lysisExpedeon
In this project, we have compared existing sample preparation methods for proteomics studies against newly developed FASP method and our in-house developed SDS-TCA protocol. For our
preliminary studies, we have chosen a very well characterized soil microbe Pseudomonas putida.
Manteia non confidential-presentation 2003-09Pascal Mayer
A non confidential corporate presentation of "Manteia Predictive Médicine" as of September 2003. Présents DNA colony sequencing resutls, instrument, DNA preparation for genotyping.
This document reviews microRNAs (miRNAs) related to the occurrence, diagnosis, and prognosis of non-small cell lung cancer (NSCLC). It discusses how some miRNAs act as oncogenes in NSCLC by promoting proliferation, migration, and invasion through targeting tumor suppressor genes. Other miRNAs act as tumor suppressors by inhibiting oncogenes. The expression levels of certain miRNAs have diagnostic and prognostic value for NSCLC. Some miRNAs show potential as biomarkers for early detection of NSCLC or for distinguishing NSCLC subtypes. Circulating miRNAs may also serve as biomarkers for cancer detection and prognosis. Single nucleotide polymorphisms in miRNA genes have been associated with survival in NSCLC patients.
Assessment of immunomolecular_expression_and_prognostic_role_of_tlr7_among_pa...dr.Ihsan alsaimary
This document summarizes a research study that assessed the immunomolecular expression and prognostic role of Toll-like receptor 7 (TLR7) in patients with prostatitis. The study included 135 confirmed prostatitis patients and 50 control patients. DNA was extracted from blood samples and amplified using PCR to assess TLR7 expression. Results showed the PCR product for TLR7 was 149bp, indicating a high percentage of TLR7 presence. The study suggests TLR alleles may be associated with risk of prostatitis.
Label free and reagentless electrochemical detection of micro rn-as using a c...hbrothers
This document describes a label-free and reagentless electrochemical biosensor for detecting microRNAs (miRNAs). The sensor uses a conducting polymer nanostructured with carbon nanotubes that is electroactive in neutral aqueous solutions. Addition of the target miRNA miR-141, a prostate cancer biomarker, causes a "signal-on" response by increasing the current through the polymer. Non-complementary miRNAs do not change the current. The sensor achieves very low detection of about 8 femtomolar (fM) of miR-141. The conducting polymer-carbon nanotube composite provides a reagentless platform for immobilizing and detecting miRNA sequences with high sensitivity and specificity.
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.
The Thiazolobenzimidazole TBZE-029 Inhibits Enterovirus Replication by Target...degarden
This document summarizes research identifying the viral target of the antiviral compound TBZE-029 against enteroviruses. Through selecting for drug-resistant coxsackievirus B3, the researchers identified three mutations in the nonstructural protein 2C clustered near motif C. Reintroducing the mutations, particularly at positions 227 and 229, conferred drug resistance, demonstrating 2C as the target. Viruses with the mutations also showed cross-resistance to other known 2C-targeting antivirals. The ATPase activity of 2C was unaffected by TBZE-029, suggesting it targets a different function of this essential replication protein.
Molecular quantitative genetics for plant breeding roundtable 2010xFOODCROPS
This document provides an overview of molecular markers and quantitative trait locus (QTL) mapping. It begins with a discussion of different types of genetic variation and how molecular markers can be used to detect variation at the DNA level. The document then describes different types of molecular markers, including restriction fragment length polymorphisms (RFLPs), polymerase chain reaction (PCR)-based markers, simple sequence repeats (SSRs), and single nucleotide polymorphisms (SNPs). It also discusses what a QTL is and how QTL mapping is performed. The document concludes with how molecular markers and QTL mapping can be used to understand the genetic basis of traits and help improve crops.
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.
Next generation sequencing (NGS) has various applications in cancer treatment and research. It can be used to identify novel cancer mutations, detect hereditary cancer syndromes, enable personalized cancer treatment based on a patient's genetic profile, and detect circulating tumor DNA (ctDNA). NGS allows comprehensive analysis of cancer genomes and biomarkers for molecular diagnosis, prognosis, and monitoring treatment response. Challenges include analyzing large amounts of NGS data and accurately interpreting genetic variations, but its clinical utility continues to advance personalized cancer care.
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
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.
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.
Boronated Monoclonal Antibody LA84 for BNCTkent.riley
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
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.
The document reports on progress made in the second year of research reactor coalitions established with IAEA support. It discusses the activities and results of coalitions in Eastern Europe, Eurasia, the Caribbean, and the Mediterranean region. Upcoming initiatives include new coalitions for Africa, the Baltic region, and the Pacific, as well as continued efforts to strengthen existing coalitions through training, workshops, and business planning to promote self-sufficiency. While successes have been achieved, substantial work remains to fully realize the goal of establishing self-sustaining research reactor coalitions.
Boron neutron capture therapy (BNCT) utilizes boronated agents that preferentially accumulate in tumor tissues. When irradiated with neutrons, boron undergoes a nuclear reaction producing alpha particles that damage nearby tumor cells while sparing normal tissues. The document reviews clinical studies of BNCT for various cancers including glioblastoma, head and neck, and cutaneous melanoma. For glioblastoma, BNCT achieved median survival rates of 10.8-23.5 months in recurrent and newly diagnosed settings. Adverse effects included radiation necrosis and pseudoprogression. Combining BNCT with bevacizumab or proton radiotherapy showed promise for improving outcomes. Overall, the review evaluates the current applications and challenges of BNCT
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus–associated malignancy that is most common in East Asia, Africa, and Alaska. Radiotherapy is the main treatment option; unfortunately, disease response to concurrent radiotherapy and chemotherapy varies among patients with NPC, and in many cases, NPC becomes resistant to radiotherapy. Our previous studies indicated that Jab1/CSN5 was overexpressed and plays a role in the pathogenesis and radiotherapy resistance in NPC. Therefore, it is important to seek for innovative therapeutics targeting Jab1/CSN5 for NPC. In this study, we explored the antitumor effect of a curcumin analogue T83 in NPC, and found T83 exhibits antitumor activity and induces radiosensitivity through inactivation of Jab1 in NPC.
This document describes two new organometallic ruthenium complexes and their ability to inhibit cancer cell growth. The complexes have the general formula [Ru(g5-C5H5)(PP)L][CF3SO3] and differ in their PP and L ligands. Crystal structures of the complexes were determined by X-ray diffraction. The complexes were found to inhibit the growth of human colon and pancreatic cancer cell lines. Atomic force microscopy images suggest the complexes interact with DNA through different mechanisms, such as intercalation or covalent bond formation.
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.
1) NF-kB is constitutively activated in pancreatic cancer cells but not normal pancreatic cells, suggesting it plays a role in pancreatic tumorigenesis.
2) Expressing a mutant IkBa (IkBaM) that inhibits NF-kB suppressed the tumorigenicity of pancreatic cancer cells in a mouse model.
3) Inhibiting NF-kB reduced expression of pro-survival genes like Bcl-xL and Bcl-2, and reduced VEGF and IL-8 expression which are involved in angiogenesis. This suggests NF-kB inhibition can suppress tumorigenesis by reducing pro-survival and angiogenic factors.
Collaborative science to identify novel inhibitors for the pseudokinase TRIB2Morgan Focas
This document summarizes research into developing inhibitors for the pseudokinase TRIB2. It describes synthesizing additional quantities of the compound GW881A, which was identified as a potent hit from screening the Published Kinase Inhibitor Set in a differential scanning fluorimetry assay of TRIB2. The synthesis involved a three-step route to obtain the final product. Additional analogs were screened in the TRIB2 assay to gain insight into structure-activity relationships, with the goal of improving potency. GW881A remained the most potent inhibitor identified.
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.
The document characterizes Te NRs produced by the bacterium Pseudomonas pseudoalcaligenes that ranged in size from 40-200nm and found the biogenic Te NRs to be cytotoxic to PC-12 cells. It assessed the cytotoxicity of the biogenic Te NRs at three doses on PC-12 cells to evaluate cell apoptosis and the expression of caspase-3 protein to confirm apoptosis through flow cytometry and western blot analysis. The study aimed to investigate the underlying mechanisms of cytotoxicity induced by biogenic Te NRs in PC-12 cells.
1. Researchers identified a novel isoform of the tumor suppressor gene DLC1 called DLC1-i4 through 5' RACE. DLC1-i4 encodes a 1125 amino acid protein with a distinct N-terminus compared to other DLC1 isoforms.
2. DLC1-i4 expression is frequently downregulated in multiple carcinoma cell lines, including esophageal, gastric, breast, colorectal, cervical and lung cancers. Its promoter region contains CpG islands that are often methylated, silencing expression.
3. Ectopic expression of DLC1-i4 in silenced tumor cells strongly inhibited their growth and colony formation, demonstrating its tumor suppressive
Combined Analysis of Micro RNA and Proteomic Profiles and Interactions in Pat...daranisaha
Liquid Chromatography Tandem Mass Spectrometry
The Liquid Mass System(LMS) includes an Easy nLC1000 (Thermo Fisher) coupled ultra-high resolution mass spectrometer Orbitrap Fusion Lumos (Thermo Fisher) with a Thermo Fisher electrospray source. Each injection is sent to a preset column (Acclaim PepMap C18, 100 μm x 2 cm, Thermo Scientific) for adsorption at a flow rate of 3 L/min. The sample is then sent to the analyzer column (Acclaim PepMap C18, 75 μm x 15 cm, Thermo Scientific) for separation.
Combined Analysis of Micro RNA and Proteomic Profiles and Interactions in Pat...eshaasini
The Liquid Mass System(LMS) includes an Easy nLC1000 (Thermo Fisher) coupled ultra-high resolution mass spectrometer Orbitrap Fusion Lumos (Thermo Fisher) with a Thermo Fisher electrospray source. Each injection is sent to a preset column (Acclaim PepMap C18, 100 μm x 2 cm, Thermo Scientific) for adsorption at a flow rate of 3 L/min. The sample is then sent to the analyzer column (Acclaim PepMap C18, 75 μm x 15 cm, Thermo Scientific) for separation.
Combined Analysis of Micro RNA and Proteomic Profiles and Interactions in Pat...semualkaira
The Liquid Mass System(LMS) includes an Easy nLC1000 (Thermo Fisher) coupled ultra-high resolution mass spectrometer Orbitrap Fusion Lumos (Thermo Fisher) with a Thermo Fisher electrospray source. Each injection is sent to a preset column (Acclaim PepMap C18, 100 μm x 2 cm, Thermo Scientific) for adsorption at a flow rate of 3 L/min. The sample is then sent to the analyzer column (Acclaim PepMap C18, 75 μm x 15 cm, Thermo Scientific) for separation.
Combined Analysis of Micro RNA and Proteomic Profiles and Interactions in Pat...semualkaira
The Liquid Mass System(LMS) includes an Easy nLC1000 (Thermo Fisher) coupled ultra-high resolution mass spectrometer Orbitrap Fusion Lumos (Thermo Fisher) with a Thermo Fisher electrospray source. Each injection is sent to a preset column (Acclaim PepMap C18, 100 μm x 2 cm, Thermo Scientific) for adsorption at a flow rate of 3 L/min. The sample is then sent to the analyzer column (Acclaim PepMap C18, 75 μm x 15 cm, Thermo Scientific) for separation.
Combined Analysis of Micro RNA and Proteomic Profiles and Interactions in Pat...semualkaira
The Liquid Mass System(LMS) includes an Easy nLC1000 (Thermo Fisher) coupled ultra-high resolution mass spectrometer Orbitrap Fusion Lumos (Thermo Fisher) with a Thermo Fisher electrospray source. Each injection is sent to a preset column (Acclaim PepMap C18, 100 μm x 2 cm, Thermo Scientific) for adsorption at a flow rate of 3 L/min. The sample is then sent to the analyzer column (Acclaim PepMap C18, 75 μm x 15 cm, Thermo Scientific) for separation.
Combined Analysis of Micro RNA and Proteomic Profiles and Interactions in Pat...JohnJulie1
Liquid Chromatography Tandem Mass Spectrometry
The Liquid Mass System(LMS) includes an Easy nLC1000 (Thermo Fisher) coupled ultra-high resolution mass spectrometer Orbitrap Fusion Lumos (Thermo Fisher) with a Thermo Fisher electrospray source. Each injection is sent to a preset column (Acclaim PepMap C18, 100 μm x 2 cm, Thermo Scientific) for adsorption at a flow rate of 3 L/min. The sample is then sent to the analyzer column (Acclaim PepMap C18, 75 μm x 15 cm, Thermo Scientific) for separation.
Combined Analysis of Micro RNA and Proteomic Profiles and Interactions in Pat...EditorSara
1. The study analyzed miRNA and protein expression profiles in tissue samples from patients with primary lung adenocarcinoma (LP group) and lung adenocarcinoma brain metastases (BM group).
2. Sixteen miRNAs were found to be upregulated and four downregulated in the BM group compared to the LP group. Fifty-three proteins were upregulated and thirty-five downregulated in the BM group.
3. Enrichment analysis revealed that the NF-κB signaling pathway and primary immunodeficiency pathway may play critical roles in the occurrence and development of brain metastases in lung adenocarcinoma.
Combined Analysis of Micro RNA and Proteomic Profiles and Interactions in Pat...NainaAnon
The Liquid Mass System(LMS) includes an Easy nLC1000 (Thermo Fisher) coupled ultra-high resolution mass spectrometer Orbitrap Fusion Lumos (Thermo Fisher) with a Thermo Fisher electrospray source. Each injection is sent to a preset column (Acclaim PepMap C18, 100 μm x 2 cm, Thermo Scientific) for adsorption at a flow rate of 3 L/min. The sample is then sent to the analyzer column (Acclaim PepMap C18, 75 μm x 15 cm, Thermo Scientific) for separation
Combined Analysis of Micro RNA and Proteomic Profiles and Interactions in Pat...EditorSara
The Liquid Mass System(LMS) includes an Easy nLC1000 (Thermo Fisher) coupled ultra-high resolution mass spectrometer Orbitrap Fusion Lumos (Thermo Fisher) with a Thermo Fisher electrospray source. Each injection is sent to a preset column (Acclaim PepMap C18, 100 μm x 2 cm, Thermo Scientific) for adsorption at a flow rate of 3 L/min. The sample is then sent to the analyzer column (Acclaim PepMap C18, 75 μm x 15 cm, Thermo Scientific) for separation.
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.
The document summarizes the history and development of Boron Neutron Capture Therapy (BNCT) for cancer treatment. It discusses how boron is used to selectively target cancer cells and how neutron capture by boron leads to high-LET particle production within tumor cells. Key developments include the first studies in the 1930s, clinical trials starting in the 1980s focused on glioblastoma, and ongoing research to develop more effective boron delivery agents and dosimetry techniques. BNCT shows potential for treating cancers like brain tumors but challenges remain around boron delivery and normal tissue toxicity.
Similar to Targeting of TK1 to tumors for BNCT (20)
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.
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.
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.
Must Know Postgres Extension for DBA and Developer during MigrationMydbops
Mydbops Opensource Database Meetup 16
Topic: Must-Know PostgreSQL Extensions for Developers and DBAs During Migration
Speaker: Deepak Mahto, Founder of DataCloudGaze Consulting
Date & Time: 8th June | 10 AM - 1 PM IST
Venue: Bangalore International Centre, Bangalore
Abstract: Discover how PostgreSQL extensions can be your secret weapon! This talk explores how key extensions enhance database capabilities and streamline the migration process for users moving from other relational databases like Oracle.
Key Takeaways:
* Learn about crucial extensions like oracle_fdw, pgtt, and pg_audit that ease migration complexities.
* Gain valuable strategies for implementing these extensions in PostgreSQL to achieve license freedom.
* Discover how these key extensions can empower both developers and DBAs during the migration process.
* Don't miss this chance to gain practical knowledge from an industry expert and stay updated on the latest open-source database trends.
Mydbops Managed Services specializes in taking the pain out of database management while optimizing performance. Since 2015, we have been providing top-notch support and assistance for the top three open-source databases: MySQL, MongoDB, and PostgreSQL.
Our team offers a wide range of services, including assistance, support, consulting, 24/7 operations, and expertise in all relevant technologies. We help organizations improve their database's performance, scalability, efficiency, and availability.
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QA or the Highway - Component Testing: Bridging the gap between frontend appl...zjhamm304
These are the slides for the presentation, "Component Testing: Bridging the gap between frontend applications" that was presented at QA or the Highway 2024 in Columbus, OH by Zachary Hamm.
In our second session, we shall learn all about the main features and fundamentals of UiPath Studio that enable us to use the building blocks for any automation project.
📕 Detailed agenda:
Variables and Datatypes
Workflow Layouts
Arguments
Control Flows and Loops
Conditional Statements
💻 Extra training through UiPath Academy:
Variables, Constants, and Arguments in Studio
Control Flow in Studio
"NATO Hackathon Winner: AI-Powered Drug Search", Taras KlobaFwdays
This is a session that details how PostgreSQL's features and Azure AI Services can be effectively used to significantly enhance the search functionality in any application.
In this session, we'll share insights on how we used PostgreSQL to facilitate precise searches across multiple fields in our mobile application. The techniques include using LIKE and ILIKE operators and integrating a trigram-based search to handle potential misspellings, thereby increasing the search accuracy.
We'll also discuss how the azure_ai extension on PostgreSQL databases in Azure and Azure AI Services were utilized to create vectors from user input, a feature beneficial when users wish to find specific items based on text prompts. While our application's case study involves a drug search, the techniques and principles shared in this session can be adapted to improve search functionality in a wide range of applications. Join us to learn how PostgreSQL and Azure AI can be harnessed to enhance your application's search capability.
ScyllaDB is making a major architecture shift. We’re moving from vNode replication to tablets – fragments of tables that are distributed independently, enabling dynamic data distribution and extreme elasticity. In this keynote, ScyllaDB co-founder and CTO Avi Kivity explains the reason for this shift, provides a look at the implementation and roadmap, and shares how this shift benefits ScyllaDB users.
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.
The Department of Veteran Affairs (VA) invited Taylor Paschal, Knowledge & Information Management Consultant at Enterprise Knowledge, to speak at a Knowledge Management Lunch and Learn hosted on June 12, 2024. All Office of Administration staff were invited to attend and received professional development credit for participating in the voluntary event.
The objectives of the Lunch and Learn presentation were to:
- Review what KM ‘is’ and ‘isn’t’
- Understand the value of KM and the benefits of engaging
- Define and reflect on your “what’s in it for me?”
- Share actionable ways you can participate in Knowledge - - Capture & Transfer
inQuba Webinar Mastering Customer Journey Management with Dr Graham HillLizaNolte
HERE IS YOUR WEBINAR CONTENT! 'Mastering Customer Journey Management with Dr. Graham Hill'. We hope you find the webinar recording both insightful and enjoyable.
In this webinar, we explored essential aspects of Customer Journey Management and personalization. Here’s a summary of the key insights and topics discussed:
Key Takeaways:
Understanding the Customer Journey: Dr. Hill emphasized the importance of mapping and understanding the complete customer journey to identify touchpoints and opportunities for improvement.
Personalization Strategies: We discussed how to leverage data and insights to create personalized experiences that resonate with customers.
Technology Integration: Insights were shared on how inQuba’s advanced technology can streamline customer interactions and drive operational efficiency.
[OReilly Superstream] Occupy the Space: A grassroots guide to engineering (an...Jason Yip
The typical problem in product engineering is not bad strategy, so much as “no strategy”. This leads to confusion, lack of motivation, and incoherent action. The next time you look for a strategy and find an empty space, instead of waiting for it to be filled, I will show you how to fill it in yourself. If you’re wrong, it forces a correction. If you’re right, it helps create focus. I’ll share how I’ve approached this in the past, both what works and lessons for what didn’t work so well.
Freshworks Rethinks NoSQL for Rapid Scaling & Cost-EfficiencyScyllaDB
Freshworks creates AI-boosted business software that helps employees work more efficiently and effectively. Managing data across multiple RDBMS and NoSQL databases was already a challenge at their current scale. To prepare for 10X growth, they knew it was time to rethink their database strategy. Learn how they architected a solution that would simplify scaling while keeping costs under control.
Session 1 - Intro to Robotic Process Automation.pdfUiPathCommunity
👉 Check out our full 'Africa Series - Automation Student Developers (EN)' page to register for the full program:
https://bit.ly/Automation_Student_Kickstart
In this session, we shall introduce you to the world of automation, the UiPath Platform, and guide you on how to install and setup UiPath Studio on your Windows PC.
📕 Detailed agenda:
What is RPA? Benefits of RPA?
RPA Applications
The UiPath End-to-End Automation Platform
UiPath Studio CE Installation and Setup
💻 Extra training through UiPath Academy:
Introduction to Automation
UiPath Business Automation Platform
Explore automation development with UiPath Studio
👉 Register here for our upcoming Session 2 on June 20: Introduction to UiPath Studio Fundamentals: https://community.uipath.com/events/details/uipath-lagos-presents-session-2-introduction-to-uipath-studio-fundamentals/
This talk will cover ScyllaDB Architecture from the cluster-level view and zoom in on data distribution and internal node architecture. In the process, we will learn the secret sauce used to get ScyllaDB's high availability and superior performance. We will also touch on the upcoming changes to ScyllaDB architecture, moving to strongly consistent metadata and tablets.
2. A
Fig. 1. Structure of 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-
yl}pentan-1-yl] thymidine (N5–2OH). Nonenriched and 10B enriched N5–2OH
were synthesized as an epimeric mixture, as previously described by us (17).
B
which resulted in a calculated total absorbed dose (beam only) to
the tumor of 4.50 0.16 Gy. The 10B containing TK1( ) and
TK1( ) tumors received an additional 0.55 0.03 Gy per g 10B
during irradiations (17.0 versus 9.1 Gy, respectively). Animals
bearing TK1( ) tumors, which had received 10B-enriched N5–2OH
by i.t. injection followed by BNCT, had an average 15-fold reduction
in mean tumor volume on day 30 after implantation. This was 247
151 mm3 compared with 3603 1103 mm3 for matched control
animals that did not receive BNCT and 2225 1074 mm3 for
irradiated controls that did not receive N5–2OH (Fig. 2). Animals
bearing L929 TK1( ) tumors showed modest reductions in tumor
volumes, which were not significantly different from those of
irradiated animals bearing TK1( ) tumors that did not receive Fig. 3. Ki67 expression in L929 TK1( ) tumors. (A) A section of L929 tumor
N5–2OH. Because hypothetically N5–2OH preferentially targets from one irradiated animal that did not receive N5–2OH. (B) Section from an
proliferating tumor cells, these reductions in tumor volumes cor- animal that received N5–2OH. (200 magnification).
related with a marked decrease in the number of proliferating cells,
as evidenced by immunostaining for Ki67, which recognizes a
nuclear protein involved in the proliferative phases of the cell cycle cells per hpf, and in both of these groups, there was no evidence of
necrosis.
(Fig. 3). L929 TK1( ) tumors from animals that received N5–2OH,
followed by BNCT, had 1.2 1 Ki67 ( ) cells per high power field
Biodistribution Studies and Dosimetry in Glioma Bearing Rats. To
(hpf) with extensive areas of necrosis. In contrast, tumors from determine whether i.c. delivery of N5–2OH was nontoxic, a
animals that did not receive N5–2OH, but had been irradiated with group of five non-tumor-bearing rats received 500 g of N5–
thermal neutrons, had 154.4 2.8 cells per hpf without any 2OH, administered i.c. by Alzet osmotic pumps over 24 h. These
necrosis, and those from irradiated control mice had 188.8 8.5 animals were followed clinically for 2 weeks and weighed 3 per
week. Initially there was 10% weight loss, but this was regained
within a few days. There was no clinical evidence of neurologic
deficits, and 2 weeks later, the rats were euthanized and their
brains were removed and processed for neuropathologic exam-
ination. This did not reveal any microscopic findings associated
with the i.c. administration of N5–2OH.
Boron concentrations in tumor, brain, and blood of RG2
glioma bearing rats after administration of N5–2OH are sum-
marized in Table 1. The tumor and normal brain boron con-
centrations were 27.6 9.5 g/g and 2.6 2.4 g/g, respectively,
and the blood value was undetectable ( 0.5 g/g). Because it is
unlikely that any single boron delivery agent could target all
tumor cells, a group of RG2 glioma-bearing rats received i.v.
BPA in combination with i.c. administration of N5–2OH to
target cells that had not taken up sufficient quantities N5–2OH.
The corresponding tumor and normal brain boron values for the
combination at 1 h after termination of delivery of N5–2OH and
2.5 h after i.v. injection of BPA were 45.6 14.1 g/g and 7.3
1.0 g/g, respectively. In contrast, the tumor and normal brain
boron values for BPA alone were 14.2 7.7 g/g and 5.0 1.0
g/g, respectively. Tumor to normal brain (T:Br) boron ratios for
Fig. 2. Growth of L929 TK1( ) and TK1( ) tumors after i.t. injection of rats that received either N5–2OH or BPA alone were 10.6:1 and
N5–2OH and BNCT TK1( ) (F); TK1( ) ( ); TK1( ) radiation control (3); 1.9:1, respectively. Based on these boron concentrations, the
TK1( ) untreated control (‚). The vertical lines indicate the standard devia- unweighted, absorbed physical radiation doses were calculated
tions (SD) of the mean tumor volumes. (Table 1). Irradiated control animals received the same physical
17494 www.pnas.org cgi doi 10.1073 pnas.0809569105 Barth et al.
3. Table 1. Boron biodistribution and physical radiation doses delivered to tumor, brain, and blood in RG2 glioma bearing rats
Boron uptake, g/g wt Physical dose, Gy†
Group‡ Tumor Brain§ Blood Tumor/brain conc. ratio Tumor Brain Blood
RG2/CED N5–2OH 27.6 9.5 2.6 2.4 0.5 10.6 8.1 2.3 1.9
RG2/CED N5–2OH i.v. BPA 45.6 14.1 7.3 1.0 7.6 1.9 6.2 12.2 3.4 3.5
RG2/i.v. BPA 14.2 7.7 5.0 1.0 7.5 2.1 1.9 5.0 2.9 3.5
RG2/Irradiation control (CED of DMSO) None None None — 1.8 1.8 1.8
RG2/Untreated control (CED N5–2OH) 17.3 4.3 0.5 0.5 0 0 0
Boron-10 enriched N5–2OH was administered i.c. by means of convection enhanced delivery over 24 h using Alzet pumps at a flow rate of 8.33 l/h. BPA was
administered intravenously 2.5 h prior to BNCT.
*Boron content was quantified by means of direct current plasma-atomic emission spectroscopy (DCP-AES) and has been reported as micrograms per gram of
wt.
†Physical dose estimates include contributions from photons, 14N (n,p)14C, and 10B (n, ) 7Li reactions.
‡RG2 glioma cells were implanted into rats intracerebrally. The rats were irradiated 14 days after implantation.
§Boron concentrations for the tumor bearing cerebral hemisphere after excision of the tumor.
radiation dose as those that received either N5–2OH or BPA delivery agent for NCT. Ki67( ) immunostaining of L929
alone, but in addition they received a dose attributable to the 10B tumors indicated that TK1( ) proliferating cells were the pri-
[n, ]7Li capture reaction. This was 8.1 Gy for rats that received mary targets for N5–2OH based BNCT. The %ILS of BNCT-
N5–2OH, 5.0 Gy for those that received BPA, and 12.2 Gy for treated, RG2 glioma-bearing rats that received N5–2OH was
animals that received the combination. 2.4 greater than in those that received BPA. Kinase mediated
trapping (19) appears to have been an effective mechanism for
Responses After BNCT of RG2 Glioma-Bearing Rats. Survival data are the selective entrapment of N5–2OH in the TK1( ) L929 tumor
summarized in Table 2, and the corresponding Cox survival plots and the RG2 glioma. However, it was less so in the F98 glioma
are shown in Fig. 4. The longest MST standard error (SE) was (20), which possibly might have been due to differences in TK1
52.9 8.9 days for animals that received the combination of activity and/or the expression levels of multidrug resistance
N5–2OH and BPA compared with 45.6 7.2 days for the rats proteins. Because serum concentrations of Thd, which compete
that received N5–2OH alone and 35.9 3.3 d for those that with N5–2OH at the active site of TK1, are at least 10 times lower
received BPA alone. The differences between the Cox survival in humans than in mice and rats (21), N5–2OH might achieve
plots (Fig. 4) of RG2 glioma-bearing rats that received i.c. higher tumor boron concentrations in humans than in rodents.
N5–2OH vs. i.v. BPA were highly significant (P 0.0003) while Schinazi et al. (22) have evaluated the efficacy of a pyrimidine
in contrast, there was only borderline significance in the survival nucleoside analogue, -5-o-carboranyl-2 -deoxyuridine (D-
plots of animals that received i.v. BPA N5–2OH vs. N5–2OH CDU) as a boron delivery agent in 9L gliosarcoma-bearing rats.
alone (P 0.054). The MSTs of irradiated and untreated Non-10B-enriched D-CDU at concentrations of either 30 or 150
controls were 28.1 1.8 d and 23.8 2.3 d, respectively. The mg/kg was administered by either i.p. or i.v. injection, and the
greatest percent increase in life span (%ILS) (122%) was seen measured tumor boron concentrations at 2 h were 2.3 and 7.4
in RG2 glioma-bearing rats that received the combination of g/g of tumor, respectively, with concomitant normal brain
N5–2OH and BPA, and this correlated with the fact that the concentrations of 1.13 and 0.17 g/g. In contrast, by adminis-
tumor in these animals received the highest physical radiation tering N5–2OH at a much lower dose (500 g vs. 30 mg for
doses. The tumor size indices for all experimental and control D-CDU) i.c. over 24 h by Alzet pumps, we have markedly
groups were all almost identical and ranged from 3.3 to 3.6. increased tumor boron uptake (27.6 g/gm tumor) with unde-
Neuropathologic examination of the brains of RG2 glioma- tectable amounts in normal brain and blood. Furthermore, our
bearing rats showed invasive growth of malignant cells and rare survival data demonstrated that N5–2OH can function as an
foci of necrosis and hemorrhage. In some instances, there were effective boron delivery agent, as evidenced by a highly signif-
MEDICAL SCIENCES
central clear zones in which viable tumor cells were dispersed icant improvement in MST compared with that of irradiated
and focal areas of leptomeningeal extension of the tumor. control rats.
There are, however, limitations and problems associated with
Discussion N5–2OH and other currently available 3CTAs. First, the most
The experimental data presented in this study provide proof-of- promising 3CTAs are not water-soluble and require DMSO for
principle that a 3CTA can function as an effective in vivo boron solubilization. This could be obviated by designing 3CTA-
Table 2. Survival times of RG2 glioma bearing rats following CED of N5–2OH with or without i.v. BPA
% Increased life
Survival time, d† span‡
Group* Number of animals Mean SE Median Mean Median
CED of N5–2OH i.v. BPA 10 52.9 8.9 52.5 42–71 122 119
CED of N5–2OH 10 45.6 7.2 45 36–61 92 88
i.v. BPA 8 35.9 3.3 35.5 32–41 51 48
Irradiated controls 8 28.1 1.8 28 26–31 18 17
Untreated controls 10 23.8 2.3 24 20–27 — —
*N5–2OH and BPA were administered as described in a footnote in Table 1.
†Mean and median survival times were determined for each group of 8 –10 rats.
‡Percent increased life span (% ILS) was defined relative to mean and median survival times of untreated controls.
Barth et al. PNAS November 11, 2008 vol. 105 no. 45 17495
4. Materials and Methods
Target Validation Studies Using the L929 Tumor Model. Both unenriched and
10B-enriched N5–2OH were synthesized as epimeric mixtures, as previously
described (17). Because N5–2OH was designed to specifically target cells
producing the TK1 enzyme, its potential to selectively accumulate in tumors
was established using the L929TK1( ) wild-type cell line [American Type
Culture Collection (ATCC) #CCL1, NCTC clone 929] and its L929 TK1( ) mutant
counterpart [ATCC#CCL1.3 L-M (TK-)].
To obtain some estimate of the potential maximum in vivo uptake of
N5–2OH, studies were carried out with TK1( ) and TK1( ) L929 cells, using a
standardized labeling procedure with the Thd analogue, 5-bromo-2-
deoxyuridine (BUdR), which is a TK1 substrate and is incorporated into DNA
during S phase of the cell cycle. All animal studies were carried out in
accordance with National Research Council guidelines (26) and approved by
the Institutional Laboratory Animal Use Committee of The Ohio State Univer-
sity. L929 cells were implanted s.c. into the dorsum of NIH NCr-nu/nu nude
mice, and 2 weeks later, when tumors had attained a sufficient size, the
animals were injected i.p. with a mixture of BUdR and 5 fluorodeoxyuridine
(FUdR) at 2- h intervals for a total of up to 6 injections. FUdR was administered
to suppress the de novo synthesis of thymidylate and, thus, DNA by inhibiting
thymidylate synthetase. Two animals were killed by exposure to halothane
Fig. 4. Cox survival plots for RG2 glioma bearing rats. Survival times have vapor 30 min after each injection. The tumors then were excised, fixed in
been plotted for untreated animals (F), irradiated controls ( ), and animals ethanol, and embedded in paraffin, and then 4- m sections were cut. These
that received i.v. BPA (}) or N5–2OH either alone (Œ) or in combination with were immunostained for BUdR ( ) cells using a commercially available kit
BPA ({). (ZYMED Laboratory, Inc.) and counterstained with hematoxylin and eosin
(H&E), and the percentage of BUdR( ) cells was determined microscopically
by counting 3–5 medium power fields (mpf).
specific drug delivery systems based on lipid nanotechnology or To validate the hypothesis that tumor cells, which constitutively produced
the design and synthesis of water-soluble third generation 3CTA the TK1 enzyme, would be selectively targeted by N5–2OH, an in vivo biodis-
prodrugs. Second, they appear to be significantly less effective tribution study was performed in which 106 TK1( ) or ( ) L929 cells were
than Thd in competing for the substrate binding site of TK1-like implanted s.c. into the flanks of NIH nu/nu mice. Once the tumors had attained
enzymes (19). This is a major limitation of the currently available a size of 0.3– 0.5 cm in diameter, in vivo uptake studies were initiated. Non
10B-enriched N5–2OH (250 g) at a concentration of 31.6 mM (50 g of boron)
3CTAs, and could explain their lack of in vivo tumor selectivity
was solubilized in 70% dimethyl sulfoxide (DMSO). Because it previously was
after i.v. administration (W.Y. and R.F.B., unpublished data) shown by us that systemic injection of N5–2OH resulted in low tumor and high
and the necessity to administer them i.c. by means of Alzet nontumor boron concentrations (W.Y. and R.F.B., unpublished data), this was
osmotic pumps to produce high tumor drug concentrations. administered by direct i.t. injection in a volume of 15 l over 2 min, and again
Third, virtually nothing is known about the metabolism of 2 h later. Animals were killed at 2 h after the second injection; tumors and
3CTAs, including their possible incorporation into DNA. Fourth, samples of skin and blood were taken, and subsequently processed for boron
there is very little information relating to the mechanisms of determination by means of direct current plasma-atomic emission spectros-
cellular influx and efflux of 3CTAs, and their metabolites. copy (DCP-AES), as previously described (27).
On the other hand, the subcellular localization of 3 CTAs
Intracerebral Delivery and Toxicity of N5–2OH in Glioma Bearing Rats. To
after in vivo administration may prove to be a significant determine whether i.c. delivery of N5–2OH was nontoxic, a group of five
advantage in their future development as boron delivery non-tumor-bearing Fischer rats received 500 g of N5–2OH (100 g of B) at a
agents. Using the technique of secondary ion mass spectrom- concentration of 4.7 mM, solubilized in 200 l of 30% DMSO. This was
etry (SIMS), it has been demonstrated that another 3CTA, administered over 24 h by means of Alzet pumps (model #2001D, Durect Corp.,
designated N4 (14, 15), was distributed throughout interphase Cupertino, CA) at a flow rate of 8.33 l/h. After administration of N5–2OH, the
and mitotic T9 glioma cells, including their chromosomes (23). animals were monitored clinically for 2 weeks and weighed three times per
The latter observation suggests that it possibly was incorpo- week, after which they were killed. Their brains were removed, fixed in
formalin, and then cut at 2-mm intervals. Selected sections were processed for
rated into DNA. In contrast, no nuclear localization was seen
microscopic neuropathologic examination and stained with H&E.
in T9 cells that had been exposed to BPA, which is not
incorporated into DNA but whose uptake is increased in BNCT of L929 Tumor-Bearing Nude Mice. One million L929 TK1( ) or TK1( )
metabolically active, proliferating tumor cells. These observa- cells were implanted s.c. into NIH NCr-nu/nu mice. Thirteen days later, the
tions support our hypothesis that the 3CTAs have a propensity tumors had attained a volume of 80 mm3, as determined by measuring the
to deliver boron to the cell nucleus, where the 10B [n, ]7Li greatest length (a) and width (b) [V a b2/2]. The mice then were transported
capture reaction products have a greater likelihood of lethally to the MIT Research Reactor (MITR-II), where BNCT was performed by using
damaging cells. In contrast to N5–2OH, i.c. delivery of BPA the M-011 thermal neutron beam. Anesthetized animals were positioned in a
6Li enriched polyethylene box with a removable lid in which a 13 2 cm2
resulted in transiently high tumor and normal brain boron
aperture had been machined. This served as a beam delimiter and provided
concentrations with rapid clearance, which would have pre- whole body shielding from the thermal neutrons during an irradiation. Four
cluded BNCT (15). The combination of boron delivery agents mice were secured side-by-side, head-to-tail, to the underside of the box lid
that target different subpopulations of tumor cells has been and positioned to align their tumors in the middle of the aperture. 10B-
used by us (24) and others (25). In future studies, it would be enriched N5–2OH was administered as previously described. Four hours after
of interest to evaluate 3CTAs in combination with BSH, which the first dose, the animals were irradiated with a collimated beam of thermal
is taken up passively by nonproliferating (quiescent) cells (25), neutrons at a reactor power of 4.8 megawatts (MW). To determine the
as well as with BPA. In conclusion, our data have demon- response to BNCT, tumors were removed from L929 TK1( ) tumor bearing
animals, two of which had received N5–2OH followed by BNCT and two of
strated that a carboranyl nucleoside, N5–2OH, can function as
which did not, but had been similarly irradiated. The tumors were fixed in
boron delivery agent for NCT of a rat glioma. Based on this, formalin, processed for histology, and then immunostained with Ki67 mAb,
we plan to move forward with the design and synthesis of which recognizes a nuclear antigen expressed during cell proliferation. Re-
3CTAs with improved physico-chemical and biological prop- ductions in Ki67 expression have been correlated with the radiochemothera-
erties and therapeutic effectiveness. peutic response of some neoplasms (28).
17496 www.pnas.org cgi doi 10.1073 pnas.0809569105 Barth et al.
5. RG2 Brain Tumor Model, Biodistribution, and BNCT Studies. The RG2 (CRL-2433, allow induced radioactivity to decay before they were returned to Columbus,
ATCC, Manassus, VA) rat glioma, which in vitro expressed TK1, was used to OH. All animals were weighed three times per week, and their clinical status
assess the response to BNCT. This was carried out 14 d after stereotactic was evaluated at the same time. Once the animals had progressively growing
implantation of 103 glioma cells (29). One week before irradiation, the rats tumors, they were euthanized to minimize discomfort. The brains of all
were shipped by air to the MIT Nuclear Reactor Laboratory for irradiation at animals in the therapy studies were removed after death, fixed in 10%
the MITR-II facility. They were randomized into experimental groups of 8 –10 buffered formalin, and then cut coronally at the level of the optic chiasm and
animals each as follows: (1) i.c. delivery of N5–2OH plus i.v. BPA and BNCT; (2) 2 mm anterior and posterior to it. Representative brains from each group were
i.c. delivery of N5–2OH and BNCT; (3) i.v. BPA and BNCT; (4) i.c. delivery of processed for neuropathologic examination. The tumor size index was deter-
DMSO and BNCT; and (5) untreated controls. Animals in Groups 1 and 2 mined by measuring with calipers the tumor’s greatest cross-sectional diam-
received 500 g of 10B-enriched N5–2OH at the same concentration as that eter in 2-mm coronal sections of brain under a dissecting microscope. As
used in the biodistribution studies. It contained 100 g of boron, solubilized previously described (30), a semiquantitative grading scale ranging from 0 to
in 35% DMSO in a volume of 200 l, and was administered by means of Alzet 4 was used. The mean survival time (MST), standard error (SE), and median
osmotic pumps (model #2001D) over 24 h at a flow rate of 8.33 l/h, after survival times (MeST) were calculated for each group by using the Kaplan–
which BNCT was carried out. Animals in Groups 1 and 3 received 500 mg of
10B-enriched BPA (Katchem), formulated as a fructose complex (29), and
Meier method, and simultaneous Cox survival plots also were plotted (31). The
latter performs a simultaneous fit of the survival plots by using all of the data
administered i.v. via the penile vein 2.5 h. before neutron irradiation. All
points using a partial likelihood approach. Therefore, the number of data
irradiated rats were anesthetized with a mixture of ketamine and xylazine,
points in each plot includes all of the death times, rather than only those
after which they were irradiated at the MITR-II reactor, as previously described
animals in a specific group. Because proportional hazards were satisfied,
by us (11, 30).
pairwise Wald log rank tests were performed comparing the Cox survival plots
of the groups by using a Bonferroni method of adjustment for multiple
Dosimetry and Clinical Monitoring. Dosimetric measurements were performed,
comparisons (32).
as previously described (11, 30). The measured absorbed dose rates in mice
(muscle 3.5% nitrogen by weight) at the position of the tumor and normal-
ized to the reactor operating at 5 MW were 0.20 .01 Gy min 1 for photons, ACKNOWLEDGMENTS. This work was supported in part by National Institutes
of Health Grant 1R01 CA09845 (to R.F.B.); the Dardinger Neuro-Oncology
0.13 0.01 Gy min 1 for thermal neutrons (principally capture in nitrogen 14N
Center Endowment of The Ohio State University (R.F.B.); Unites States De-
[n, p] 14C), and 0.04 Gy min 1 for neutron capture per g of 10B in tissue. The
partment of Energy through the program of Innovations in Nuclear Infra-
measured dose rates in rats (brain 2.2% nitrogen by weight), normalized to structure and Education, Office of Nuclear Energy, Science and Technology
the reactor operating at a power of 5 MW, were 0.185 Gy min 1 for photons, [contract no. DE-FG07-02ID14420DE-FG07– 02 (K14420)] (to P.J.B. and K.J.R.);
0.08 Gy min 1 for thermal neutrons, and 0.034 Gy min 1 per g 10B in tissues, Office of Environmental and Biological Research (contract nos. DE-FG02-
which was based on 10B concentrations determined in the biodistribution 02ER63358 (to R.F.B.) and DE-FG02-90ER60972 (to W.T.); and the Swedish
studies. After completion of BNCT, the animals were held at MIT for 3 d to Research Council (S.E.).
1. Barth RF, Coderre JA, Vicente MG, Blue TE (2005) Boron neutron capture therapy of 18. Johansson NG, Eriksson S (1996) Structure-activity relationships for phosphorylation of
cancer: Current status and future prospects. Clin Cancer Res 11:3987– 4002. nucleoside analogs to monophosphates by nucleoside kinases. Acta Biochim Pol
2. Barth RF, Joensuu H (2007) Boron neutron capture therapy for the treatment of 43:143–160.
glioblastomas and extracranial tumours: As effective, more effective or less effective 19. Tjarks W, Tiwari R, Byun J, Naranyanasamy S, Barth RF (2007) Carboranyl nucleoside
than photon irradiation? Radiother Oncol 82:119 –122. analogues for neutron capture therapy. Chem Comm (London) 47:4978 – 4991.
3. Miyatake S-I, et al. (2007) Boron neutron capture therapy for malignant tumors related 20. Barth RF, et al. (2006) In vivo evaluation of the 3-carboranyl thymidine analogue
to meningiomas. Neurosurg 60:1–11. (3-CTA), N5–2OH, for neutron capture therapy. Proc. 12th International Congress on
4. Kankaanranta L, et al. (2007) Boron neutron capture therapy in the treatment of locally Neutron Capture Therapy, eds Nakagawa Y, Kobayashi T, Fukada H, pp 109 –112.
recurred head and neck cancer. Int J Rad Oncol Biol Phys 69:475– 482. 21. Nottebrock H, Then R (1977) Thymidine concentrations in serum and urine of different
5. Zonta A, et al. (2006) Clinical lessons from the first applications of BNCT on unresect- animal species and man. Biochem Pharmacol 26:2175–2179.
able liver metastases. J Physics: Conference series 41:484 – 495. 22. Schinazi RF, et al. (2000) Treatment of isografted 9L rat brain tumors with -5-o-
6. Zamenhof RG, Coderre JA, Rivard MJ, Patel H (2004) Topics in Neutron Capture carboranyl-2 -deoxyuridine neutron capture therapy. Clin Cancer Res 6:725–730.
Therapy. Proceedings of the Eleventh World Congress on Neutron Capture Therapy. 23. Chandra S, Tjarks W, Lorey DR, Barth RF (2008) Quantitative subcellular imaging of
Appl Radiat Isotop 61:731–1130. boron compounds in individual mitotic and interphase human glioblastoma cells with
7. Vicente MGH (2006) Boron in medicinal chemistry. Anti-Cancer Agents Med Chem imaging secondary ion mass spectrometry (SIMS). J Microscopy 229:92–103.
6:73–181.
24. Barth RF, et al. (2000) Boron neutron capture therapy of brain tumors: Enhanced
8. Soloway AH, et al. (1998) The chemistry of neutron capture therapy. Chem Rev
survival and cure following blood-brain barrier disruption and intracarotid injection of
98:1515–1562.
sodium borocaptate and boronophenylalanine. Int J Radiat Oncol Biol Phys 47:209 –
9. Mendelsohn J, Baselga J (2006) Epidermal growth factor receptor targeting in cancer.
218.
Semin Oncol 33:369 –385.
25. Ono K, et al. (1999) The combined effect of boronphenylalanine and borocaptate in
10. Wu G, et al. (2006) Boron containing macromolecules and nanovehicles as delivery
MEDICAL SCIENCES
boron neutron capture therapy for SccVII tumors in mice. Int J Rad Oncol Biol Phys
agents for neutron capture therapy. Anti-Cancer Agents Med Chem 6:167–184.
43:431– 436.
11. Wu G, et al. (2007) Molecular targeting and treatment of an epidermal growth factor
26. Anonymous (1996) Guide for the Care and Use of Lab Anim (National Academy Press,
receptor-positive glioma using boronated cetuximab. Clin Cancer Res 13:1260 –1268.
Washington, DC).
12. Yang W, Barth RF, Wu G, et al. (2006) Molecular targeting and treatment of EGFRvIII-
27. Barth RF, et al. (1991) Determination of boron in tissues and cells using direct-current
positive gliomas using boronated monoclonal antibody L8A4. Clin Cancer Res 12:3792–
3802. plasma atomic emission spectroscopy. Anal Chem 63:890 – 893.
13. Arner ES, Eriksson S (1995) Mammalian deoxyribonucleoside kinases. Pharmacol Thera- 28. Rodel C, et al. (2000) Apoptosis, p53, bcl-2, and Ki-67 in invasive bladder carcinoma:
peut 67:155–186. Possible predictors for response to radiochemotherapy and successful bladder preser-
14. Al-Madhoun AS, Johnsamuel J, Barth RF, Tjarks W, Eriksson S (2004) Evaluation of vation. Intl J Rad Oncol Bio Phys 46:1213–1221.
human thymidine kinase 1 substrates as new candidates for boron neutron capture 29. Yang W, Barth RF, Carpenter DE, Moeschberger ML, Goodman JH (1996) Enhanced
therapy. Cancer Res 64:6280 – 6286. delivery of boronophenylalanine for neutron capture therapy by means of intracarotid
15. Barth RF, et al. (2004) Boron-containing nucleosides as potential delivery agents for injection and blood-brain barrier disruption. Neurosurg 38:985–992.
neutron capture therapy of brain tumors. Cancer Res 64:6287– 6295. 30. Yang W, et al. (2008) Molecular targeting and treatment of composite EGFRvIII and
16. Byun Y, et al. (2006) 3-carboranyl thymidine derivatives and other boronated nucleo- EGFR-positive gliomas using boronated monoclonal antibodies. Clin Cancer Res
sides for neutron capture. Curr Med Chem Anti-Cancer Agents 6:127–144. 14:883– 891.
17. Byun Y, et al. (2006) Preparation and biological evaluation of 10B-enriched 3-[5-{2- 31. Klein JP, Moeschberger ML (2003) Survival analysis: Techniques for censored and
(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5–2OH), a new bo- truncated data, 2nd ed. Springer, New York), pp 92–104, 205–221, 276 –283.
ron delivery agent for boron neutron capture therapy of brain tumors. J Med Chem 32. Madsen RW, Moeschberger ML (1986) Statistical concepts. (Prentice-Hall, Englewood
49:5513–5523. Cliffs, New Jersey), pp 538 –541, 583.
Barth et al. PNAS November 11, 2008 vol. 105 no. 45 17497