1) A team at Scripps Research Institute proposes permanently suppressing latent HIV rather than trying to eliminate all viral reservoirs through "shock and kill" strategies, which have not worked.
2) The team used a derivative of cortistatin to inhibit the HIV transcription factor tat and suppress viral replication in cells from HIV patients on antiretroviral therapy (ART). When ART was withdrawn, viral rebound was reduced by over 90% compared to without the inhibitor.
3) This approach aims to accumulate repressive epigenetic marks at the HIV promoter through tat inhibition, preventing viral reactivation even when strong inducers are used. If successful in further tests, it could lead to a functional cure for HIV
Hasil Uji Klinis I dan II Vaksin Coronavac dari SinovacCIkumparan
This clinical trial evaluated the safety, tolerability, and immunogenicity of CoronaVac, an inactivated SARS-CoV-2 vaccine candidate, in healthy adults. In phase 1, participants received either a low dose (3 μg) or high dose (6 μg) vaccine or placebo on a 0-14 day or 0-28 day schedule. In phase 2, participants received low dose vaccine, high dose vaccine, or placebo on a 0-14 day or 0-28 day schedule. The vaccine was found to have a good safety profile with mostly mild adverse reactions. Seroconversion of neutralizing antibodies was seen in 46-83% of participants in phase 1 and 92-100% of participants in phase 2
This document describes the development of a new diagnostic method called ProteAl for the rapid detection of Proteus bacteria. 2-methylbutanal was identified as a volatile organic compound biomarker specifically produced by Proteus. A fluorescent assay was developed using the reagent 5-dimethylaminonaphthalene-1-sulfonylhydrazine to detect 2-methylbutanal. This ProteAl assay could identify Proteus within 7 hours of growth and differentiated it from other common uropathogens. The production of 2-methylbutanal by Proteus was found to be regulated by the isoleucine metabolic pathway. Rational design of growth medium with increased isoleucine enhanced the yield of
Advances in diagnostic technology allow for more sensitive, specific, rapid and cost-effective diagnosis of diseases. New methods like PCR, real-time PCR, in situ hybridization, biosensors, infrared thermography, and ELISA have improved on classical diagnostic approaches by being able to detect minute amounts of pathogens, identify pathogens rapidly, and differentiate between field strains and vaccine strains. These advanced diagnostic techniques are important for disease control, treatment, and surveillance.
The study found that Ivermectin, an FDA-approved drug used to treat parasites, inhibited the replication of SARS-CoV-2, the virus that causes COVID-19, in vitro. A single dose of Ivermectin resulted in a 5000-fold reduction in viral RNA at 48 hours in infected cells. The authors hypothesize this is likely through inhibiting the nuclear import of viral proteins. They conclude Ivermectin warrants further investigation for possible benefits in humans and could help limit viral load and prevent severe disease if given early in infection.
The study found that Ivermectin, an FDA-approved anti-parasitic drug, is able to inhibit the replication of SARS-CoV-2, the virus that causes COVID-19, in vitro. A single dose of Ivermectin resulted in a ~5000-fold reduction in viral RNA at 48 hours when added to infected cells. Ivermectin is believed to work by inhibiting the nuclear import of viral proteins through interaction with importin proteins. The study suggests Ivermectin warrants further investigation for potential benefits against COVID-19 in humans.
Molecular biomarkers can be used for several purposes in infectious disease research and clinical practice. These include detecting pathogens, measuring antibody responses, identifying markers of virulence, resistance, and disease severity, and understanding human immune responses and genetic susceptibility. Challenges include lack of sensitivity, mobile genetic elements, and changes in RNA sequences. Whole genome sequencing allows investigation of microbial phylogeny, evolution, and virulence factors.
Using Multi-Scale Modeling to Support Preclinical DevelopmentsTao You
The document describes how multi-scale modeling can support preclinical drug development. It provides an example of developing a systems pharmacology model to integrate in vitro biomarker and cell cycle data with in vivo efficacy studies of a combination therapy. The model was able to recapitulate multiple datasets and validate dosing schedules. Lessons learned include the importance of practical yet mechanistic models, consistency, precision, collaboration, and validation.
In-vitro Correlates of Heterologous Protection using Avidity and IgG-Subtypin...EuFMD
The 2018 Open Session of the EuFMD Standing Technical Committee was held in Borgo Egnazia - Italy, 29-31 October 2018 . The session theme was on global vaccine security
The European Commission for the Control of Foot-and-Mouth Disease (EuFMD), one of FAO’s oldest Commissions, came into being on the 12th June 1954, with the pledge of the sixth founding member state to the principles of a coordinated and common action against Foot-and-mouth Disease.
Hasil Uji Klinis I dan II Vaksin Coronavac dari SinovacCIkumparan
This clinical trial evaluated the safety, tolerability, and immunogenicity of CoronaVac, an inactivated SARS-CoV-2 vaccine candidate, in healthy adults. In phase 1, participants received either a low dose (3 μg) or high dose (6 μg) vaccine or placebo on a 0-14 day or 0-28 day schedule. In phase 2, participants received low dose vaccine, high dose vaccine, or placebo on a 0-14 day or 0-28 day schedule. The vaccine was found to have a good safety profile with mostly mild adverse reactions. Seroconversion of neutralizing antibodies was seen in 46-83% of participants in phase 1 and 92-100% of participants in phase 2
This document describes the development of a new diagnostic method called ProteAl for the rapid detection of Proteus bacteria. 2-methylbutanal was identified as a volatile organic compound biomarker specifically produced by Proteus. A fluorescent assay was developed using the reagent 5-dimethylaminonaphthalene-1-sulfonylhydrazine to detect 2-methylbutanal. This ProteAl assay could identify Proteus within 7 hours of growth and differentiated it from other common uropathogens. The production of 2-methylbutanal by Proteus was found to be regulated by the isoleucine metabolic pathway. Rational design of growth medium with increased isoleucine enhanced the yield of
Advances in diagnostic technology allow for more sensitive, specific, rapid and cost-effective diagnosis of diseases. New methods like PCR, real-time PCR, in situ hybridization, biosensors, infrared thermography, and ELISA have improved on classical diagnostic approaches by being able to detect minute amounts of pathogens, identify pathogens rapidly, and differentiate between field strains and vaccine strains. These advanced diagnostic techniques are important for disease control, treatment, and surveillance.
The study found that Ivermectin, an FDA-approved drug used to treat parasites, inhibited the replication of SARS-CoV-2, the virus that causes COVID-19, in vitro. A single dose of Ivermectin resulted in a 5000-fold reduction in viral RNA at 48 hours in infected cells. The authors hypothesize this is likely through inhibiting the nuclear import of viral proteins. They conclude Ivermectin warrants further investigation for possible benefits in humans and could help limit viral load and prevent severe disease if given early in infection.
The study found that Ivermectin, an FDA-approved anti-parasitic drug, is able to inhibit the replication of SARS-CoV-2, the virus that causes COVID-19, in vitro. A single dose of Ivermectin resulted in a ~5000-fold reduction in viral RNA at 48 hours when added to infected cells. Ivermectin is believed to work by inhibiting the nuclear import of viral proteins through interaction with importin proteins. The study suggests Ivermectin warrants further investigation for potential benefits against COVID-19 in humans.
Molecular biomarkers can be used for several purposes in infectious disease research and clinical practice. These include detecting pathogens, measuring antibody responses, identifying markers of virulence, resistance, and disease severity, and understanding human immune responses and genetic susceptibility. Challenges include lack of sensitivity, mobile genetic elements, and changes in RNA sequences. Whole genome sequencing allows investigation of microbial phylogeny, evolution, and virulence factors.
Using Multi-Scale Modeling to Support Preclinical DevelopmentsTao You
The document describes how multi-scale modeling can support preclinical drug development. It provides an example of developing a systems pharmacology model to integrate in vitro biomarker and cell cycle data with in vivo efficacy studies of a combination therapy. The model was able to recapitulate multiple datasets and validate dosing schedules. Lessons learned include the importance of practical yet mechanistic models, consistency, precision, collaboration, and validation.
In-vitro Correlates of Heterologous Protection using Avidity and IgG-Subtypin...EuFMD
The 2018 Open Session of the EuFMD Standing Technical Committee was held in Borgo Egnazia - Italy, 29-31 October 2018 . The session theme was on global vaccine security
The European Commission for the Control of Foot-and-Mouth Disease (EuFMD), one of FAO’s oldest Commissions, came into being on the 12th June 1954, with the pledge of the sixth founding member state to the principles of a coordinated and common action against Foot-and-mouth Disease.
The document discusses Robert Koch's postulates for determining if a microorganism causes a disease and Thomas Rivers' alternative criteria. It analyzes several key studies on SARS and COVID-19 that claimed the viruses met Koch's postulates or Rivers' criteria. However, the document finds that none of the studies actually fulfilled the first three criteria of isolating the virus, cultivating it in host cells, or demonstrating filterability. The conclusions that the viruses cause the diseases appear to be unsupported and based primarily on genetic similarities rather than direct evidence from Koch's postulates or Rivers' criteria.
Real-Time Genome Sequencing of Resistant Bacteria Provides Precision Infectio...ExternalEvents
http://www.fao.org/about/meetings/wgs-on-food-safety-management/en/
Real-Time Genome Sequencing of Resistant Bacteria Provides Precision Infection Control in an Institutional Setting. Presentation from the Technical Meeting on the impact of Whole Genome Sequencing (WGS) on food safety management and GMI-9, 23-25 May 2016, Rome, Italy.
Web applications for rapid microbial taxonomy identification ExternalEvents
http://www.fao.org/about/meetings/wgs-on-food-safety-management/en/
Web applications for rapid microbial taxonomy identification. Presentation from the Technical Meeting on the impact of Whole Genome Sequencing (WGS) on food safety management -23-25 May 2016, Rome, Italy.
T cell recall response of two hypothetical proteins (Rv2251 and Rv2721c) from...Santhi Devasundaram
The demonstrated variable efficacy of the only licensed TB vaccine Mycobacterium
bovis bacillus CalmetteeGue´rin (M. bovis BCG) encourages the need for new vaccine candidates
against TB. Antigen specific cellular immune response is often considered imperative
during Mycobacterium tuberculosis (M. tuberculosis) infection and antigens that are strongly
associated with the latent phase of infection are drawing increasing attention for anti-TB vaccine
development. Here, we investigated the phenotypic and functional profiles of two novel
mycobacterial antigens Rv2251 and Rv2721c during T cell recall response via multi-color flow
cytometry.
The document describes a study that used MALDI-TOF MS to identify mycobacterial isolates. It compared two protein extraction protocols (A and B) on reference strains and clinical isolates, finding protocol A identified 92.1% of isolates to the species level compared to 50% for protocol B. Protocol A was then used to identify 27 environmental mycobacterial isolates, with two isolates misidentified by PRA-hsp65 but correctly identified by MALDI-TOF MS. Sequencing of the hsp65 and 16S rRNA genes confirmed the MALDI-TOF MS identifications. The results support the use of MALDI-TOF MS as a rapid and valuable tool for identifying
Profiling Hospital-Acquired Pathogens and Antibiotic Resistance Genes WebinarQIAGEN
Hospital-acquired infections (HAIs) are caused by bacterial, viral and fungal pathogens that easily spread through the body. The most common HAIs include urinary tract infections, bloodstream infections and pneumonia. HAIs are becoming more virulent and more resistant to the antibiotics typically used to fight them, making antibiotic resistance a serious public health concern. In this webinar, we will provide an overview of hospital-acquired pathogens and antibiotic resistance. We will also present tools to help you identify and characterize hospital-acquired bacterial species and antibiotic resistance genes in your research samples.
This document summarizes Lauren Cowley's second year PhD review. It discusses her recent work deploying to Sierra Leone to help with Ebola testing, extending her PhD, and her main achievements over the past year. This includes publishing a paper on typing phage sequencing, making progress on a TraDIS library to study phage susceptibility genes, and planning two additional papers on long read vs short read outbreak analysis and the role of Stx2a prophages in phage type switching.
Added Value of Open data sharing using examples from GenomeTrakrExternalEvents
http://www.fao.org/about/meetings/wgs-on-food-safety-management/en/
Added Value of Open data sharing using examples from GenomeTrakr. Presentation from the Technical Meeting on the impact of Whole Genome Sequencing (WGS) on food safety management and GMI-9, 23-25 May 2016, Rome, Italy.
The document describes the development of multiplex qPCR assays that can rapidly and reliably detect Bacillus anthracis, Francisella tularensis, and Yersinia pestis. The assays target pathogen-specific DNA sequences and include an internal control (B. thuringiensis cry1 gene) to control for DNA extraction and amplification. Validation showed the assays can simultaneously detect 3 pathogen targets with high sensitivity and specificity, and that inclusion of the internal control reduces the risk of false negatives. The assays provide a useful tool for the detection of these high-risk pathogens.
Antibiotic resistance is increasing in Gram Negative organisms. It is important to know the antibiogram of the hospital to start empirical therapy. It can serve as a reference to clinician looking for information on antibiotic resistance. A retrospective analysis of the isolates obtained from January 2016 to December 2016 was performed. Samples were processed as per CLSI guideline. A total of 718 isolates were obtained. These were analysed for the prevalence
of MDR/XDR/PDR. It was found that XDR isolates are prevalent in our teaching hospital. The study showed an emergence in pan drug resistant isolates. The knowledge of local antibiogram
along with strong antibiotic stewardship program can help in guiding antibiotic therapy.This reduces antibiotic pressure among organisms and hence development of resistance.
The document summarizes research that aimed to validate a mouse model for studying Hepatitis A Virus (HAV) by quantifying the expression of interferon-stimulated genes (ISGs) in mouse livers infected with HAV. The researcher found elevated levels of ISG20, ISG15, ISG56, IP10, interferon alpha/beta, and interferon gamma in infected mice, similar to levels found in infected humans and chimpanzees. This supported the mouse model and showed its ability to accurately represent the human immune response to HAV infection. Further research using this model may help develop treatments and further understanding of HAV.
This document summarizes the key findings of a study analyzing samples from 9 COVID-19 patients:
- Active virus replication was detected in the upper respiratory tract, especially in the throat during the first week of symptoms based on high viral loads, successful virus isolation, and detection of viral RNA intermediates.
- Infectious virus was isolated from throat and lung samples but not stool samples, despite high viral loads in stool. Virus was not isolated from blood or urine.
- Distinct virus populations were found in throat and lung samples from the same patient, providing evidence of independent virus replication in these sites.
- Shedding of viral RNA outlasted the end of symptoms in some cases. Seroconversion
Medical microbiology deals with infection from initial diagnosis through treatment. It involves both laboratory work and close involvement with clinical staff to manage infections and ensure effective surveillance. Unlike other specialties, microbiology departments are often neglected. Upcoming microbiologists must adapt to changing environments and utilize available resources optimally, such as improving sterilization practices, specimen collection techniques, updating bacteriology departments, and exploring anaerobic bacteriology. They should also seek to implement molecular diagnostic methods and utilize data management programs to monitor antimicrobial resistance trends.
A single infusion of the monoclonal antibody 3BNC117 was found to be safe and effective at reducing HIV-1 viraemia in infected individuals. At doses of 10-30 mg/kg, 3BNC117 reduced viral loads by up to 2.5 log10 and viraemia remained significantly reduced for 28 days in some individuals. However, HIV-1 was able to develop resistance to 3BNC117 in some individuals by 28 days, as shown by increased IC50 values and emergence of envelope mutations associated with resistance. The antibody was generally well-tolerated with no serious safety issues observed.
MVPK cell cultures showed cytopathic effect when inoculated with the virus. Animals inoculated with the virus showed increased rectal temperatures within 24 hours and vesicular lesions at inoculation sites by 48 hours, preceded by fever. Complement fixation and serum neutralization tests were performed on convalescent sera to identify virus neutralizing antibodies against vesicular exanthema virus. References included literature on the pathogenesis and identification of vesicular exanthema virus.
Este manual presenta las políticas y procedimientos de Ponce Paramedical College relacionados a la prevención del uso de sustancias controladas y alcohol. Describe las leyes aplicables como la Ley de Escuelas y Comunidades Libres de Drogas de 1989. Explica que se debe distribuir información anualmente a estudiantes y empleados sobre los riesgos a la salud de drogas, alcohol y tabaco, y las sanciones por su uso. También establece protocolos de intervención, estrategias de prevención y las consecuencias disciplinarias y legales por
El documento analiza las redes sociales más utilizadas, con el objetivo de compararlas y conocer su uso. Facebook, YouTube y WhatsApp son las tres redes más populares según las estadísticas, con porcentajes de uso de 85%, 56% y 64% respectivamente. El documento concluye que las redes sociales son importantes herramientas de comunicación cuando se usan de forma responsable.
This study analyzed news articles published by BuzzFeed from 2007 to 2015 to examine how the organization adapted its news production over time. The findings show that after 2012, BuzzFeed increased the number of news stories and sources per story, shifted to producing more hard news and political coverage, and relied more on official sources. This demonstrates that BuzzFeed gradually adopted news routines expected of traditional news organizations and transitioned from primarily spreading viral content to original reporting, positioning itself as a legitimate news source for digital natives.
Hay dos tipos de empresas según su finalidad: las lucrativas, que buscan beneficios económicos produciendo bienes y servicios rentables para multiplicar el capital y obtener dividendos; y las no lucrativas, cuyo fin no es económico sino asistencial, educativo, cultural, intelectual, social o recreativo, manejan recursos pero no obtienen utilidades ni su finalidad es lucrativa.
The document discusses Robert Koch's postulates for determining if a microorganism causes a disease and Thomas Rivers' alternative criteria. It analyzes several key studies on SARS and COVID-19 that claimed the viruses met Koch's postulates or Rivers' criteria. However, the document finds that none of the studies actually fulfilled the first three criteria of isolating the virus, cultivating it in host cells, or demonstrating filterability. The conclusions that the viruses cause the diseases appear to be unsupported and based primarily on genetic similarities rather than direct evidence from Koch's postulates or Rivers' criteria.
Real-Time Genome Sequencing of Resistant Bacteria Provides Precision Infectio...ExternalEvents
http://www.fao.org/about/meetings/wgs-on-food-safety-management/en/
Real-Time Genome Sequencing of Resistant Bacteria Provides Precision Infection Control in an Institutional Setting. Presentation from the Technical Meeting on the impact of Whole Genome Sequencing (WGS) on food safety management and GMI-9, 23-25 May 2016, Rome, Italy.
Web applications for rapid microbial taxonomy identification ExternalEvents
http://www.fao.org/about/meetings/wgs-on-food-safety-management/en/
Web applications for rapid microbial taxonomy identification. Presentation from the Technical Meeting on the impact of Whole Genome Sequencing (WGS) on food safety management -23-25 May 2016, Rome, Italy.
T cell recall response of two hypothetical proteins (Rv2251 and Rv2721c) from...Santhi Devasundaram
The demonstrated variable efficacy of the only licensed TB vaccine Mycobacterium
bovis bacillus CalmetteeGue´rin (M. bovis BCG) encourages the need for new vaccine candidates
against TB. Antigen specific cellular immune response is often considered imperative
during Mycobacterium tuberculosis (M. tuberculosis) infection and antigens that are strongly
associated with the latent phase of infection are drawing increasing attention for anti-TB vaccine
development. Here, we investigated the phenotypic and functional profiles of two novel
mycobacterial antigens Rv2251 and Rv2721c during T cell recall response via multi-color flow
cytometry.
The document describes a study that used MALDI-TOF MS to identify mycobacterial isolates. It compared two protein extraction protocols (A and B) on reference strains and clinical isolates, finding protocol A identified 92.1% of isolates to the species level compared to 50% for protocol B. Protocol A was then used to identify 27 environmental mycobacterial isolates, with two isolates misidentified by PRA-hsp65 but correctly identified by MALDI-TOF MS. Sequencing of the hsp65 and 16S rRNA genes confirmed the MALDI-TOF MS identifications. The results support the use of MALDI-TOF MS as a rapid and valuable tool for identifying
Profiling Hospital-Acquired Pathogens and Antibiotic Resistance Genes WebinarQIAGEN
Hospital-acquired infections (HAIs) are caused by bacterial, viral and fungal pathogens that easily spread through the body. The most common HAIs include urinary tract infections, bloodstream infections and pneumonia. HAIs are becoming more virulent and more resistant to the antibiotics typically used to fight them, making antibiotic resistance a serious public health concern. In this webinar, we will provide an overview of hospital-acquired pathogens and antibiotic resistance. We will also present tools to help you identify and characterize hospital-acquired bacterial species and antibiotic resistance genes in your research samples.
This document summarizes Lauren Cowley's second year PhD review. It discusses her recent work deploying to Sierra Leone to help with Ebola testing, extending her PhD, and her main achievements over the past year. This includes publishing a paper on typing phage sequencing, making progress on a TraDIS library to study phage susceptibility genes, and planning two additional papers on long read vs short read outbreak analysis and the role of Stx2a prophages in phage type switching.
Added Value of Open data sharing using examples from GenomeTrakrExternalEvents
http://www.fao.org/about/meetings/wgs-on-food-safety-management/en/
Added Value of Open data sharing using examples from GenomeTrakr. Presentation from the Technical Meeting on the impact of Whole Genome Sequencing (WGS) on food safety management and GMI-9, 23-25 May 2016, Rome, Italy.
The document describes the development of multiplex qPCR assays that can rapidly and reliably detect Bacillus anthracis, Francisella tularensis, and Yersinia pestis. The assays target pathogen-specific DNA sequences and include an internal control (B. thuringiensis cry1 gene) to control for DNA extraction and amplification. Validation showed the assays can simultaneously detect 3 pathogen targets with high sensitivity and specificity, and that inclusion of the internal control reduces the risk of false negatives. The assays provide a useful tool for the detection of these high-risk pathogens.
Antibiotic resistance is increasing in Gram Negative organisms. It is important to know the antibiogram of the hospital to start empirical therapy. It can serve as a reference to clinician looking for information on antibiotic resistance. A retrospective analysis of the isolates obtained from January 2016 to December 2016 was performed. Samples were processed as per CLSI guideline. A total of 718 isolates were obtained. These were analysed for the prevalence
of MDR/XDR/PDR. It was found that XDR isolates are prevalent in our teaching hospital. The study showed an emergence in pan drug resistant isolates. The knowledge of local antibiogram
along with strong antibiotic stewardship program can help in guiding antibiotic therapy.This reduces antibiotic pressure among organisms and hence development of resistance.
The document summarizes research that aimed to validate a mouse model for studying Hepatitis A Virus (HAV) by quantifying the expression of interferon-stimulated genes (ISGs) in mouse livers infected with HAV. The researcher found elevated levels of ISG20, ISG15, ISG56, IP10, interferon alpha/beta, and interferon gamma in infected mice, similar to levels found in infected humans and chimpanzees. This supported the mouse model and showed its ability to accurately represent the human immune response to HAV infection. Further research using this model may help develop treatments and further understanding of HAV.
This document summarizes the key findings of a study analyzing samples from 9 COVID-19 patients:
- Active virus replication was detected in the upper respiratory tract, especially in the throat during the first week of symptoms based on high viral loads, successful virus isolation, and detection of viral RNA intermediates.
- Infectious virus was isolated from throat and lung samples but not stool samples, despite high viral loads in stool. Virus was not isolated from blood or urine.
- Distinct virus populations were found in throat and lung samples from the same patient, providing evidence of independent virus replication in these sites.
- Shedding of viral RNA outlasted the end of symptoms in some cases. Seroconversion
Medical microbiology deals with infection from initial diagnosis through treatment. It involves both laboratory work and close involvement with clinical staff to manage infections and ensure effective surveillance. Unlike other specialties, microbiology departments are often neglected. Upcoming microbiologists must adapt to changing environments and utilize available resources optimally, such as improving sterilization practices, specimen collection techniques, updating bacteriology departments, and exploring anaerobic bacteriology. They should also seek to implement molecular diagnostic methods and utilize data management programs to monitor antimicrobial resistance trends.
A single infusion of the monoclonal antibody 3BNC117 was found to be safe and effective at reducing HIV-1 viraemia in infected individuals. At doses of 10-30 mg/kg, 3BNC117 reduced viral loads by up to 2.5 log10 and viraemia remained significantly reduced for 28 days in some individuals. However, HIV-1 was able to develop resistance to 3BNC117 in some individuals by 28 days, as shown by increased IC50 values and emergence of envelope mutations associated with resistance. The antibody was generally well-tolerated with no serious safety issues observed.
MVPK cell cultures showed cytopathic effect when inoculated with the virus. Animals inoculated with the virus showed increased rectal temperatures within 24 hours and vesicular lesions at inoculation sites by 48 hours, preceded by fever. Complement fixation and serum neutralization tests were performed on convalescent sera to identify virus neutralizing antibodies against vesicular exanthema virus. References included literature on the pathogenesis and identification of vesicular exanthema virus.
Este manual presenta las políticas y procedimientos de Ponce Paramedical College relacionados a la prevención del uso de sustancias controladas y alcohol. Describe las leyes aplicables como la Ley de Escuelas y Comunidades Libres de Drogas de 1989. Explica que se debe distribuir información anualmente a estudiantes y empleados sobre los riesgos a la salud de drogas, alcohol y tabaco, y las sanciones por su uso. También establece protocolos de intervención, estrategias de prevención y las consecuencias disciplinarias y legales por
El documento analiza las redes sociales más utilizadas, con el objetivo de compararlas y conocer su uso. Facebook, YouTube y WhatsApp son las tres redes más populares según las estadísticas, con porcentajes de uso de 85%, 56% y 64% respectivamente. El documento concluye que las redes sociales son importantes herramientas de comunicación cuando se usan de forma responsable.
This study analyzed news articles published by BuzzFeed from 2007 to 2015 to examine how the organization adapted its news production over time. The findings show that after 2012, BuzzFeed increased the number of news stories and sources per story, shifted to producing more hard news and political coverage, and relied more on official sources. This demonstrates that BuzzFeed gradually adopted news routines expected of traditional news organizations and transitioned from primarily spreading viral content to original reporting, positioning itself as a legitimate news source for digital natives.
Hay dos tipos de empresas según su finalidad: las lucrativas, que buscan beneficios económicos produciendo bienes y servicios rentables para multiplicar el capital y obtener dividendos; y las no lucrativas, cuyo fin no es económico sino asistencial, educativo, cultural, intelectual, social o recreativo, manejan recursos pero no obtienen utilidades ni su finalidad es lucrativa.
This newsletter from the City of Manhattan Beach features two upcoming art exhibitions at the Manhattan Beach Art Center. The first exhibition features kinetic sculptures by William Sandell and oil paintings by Cynda Valle, running from January 13th to March 12th. The second is a community art exhibition called "I <3 MB" inviting local residents to submit artwork depicting what they love about Manhattan Beach, with a submission deadline of January 24th. The newsletter also discusses the legacy of historic ceramics manufacturer Metlox in inspiring the city's ceramics education program. It concludes with an invitation to view the sunset through the Light Gate sculpture on January 27th.
This document outlines the Vietnam Oregon Initiative (VOI) investment strategy for spring 2016. It discusses VOI's mission and values, key accomplishments to date, competitive advantages, and plans to transition VOI from an initiative to a sustainable institute. VOI aims to foster partnerships across government, business, education, and other sectors between Vietnam and Oregon. It has relationships with stakeholders in both countries and plans to expand innovation labs, provincial impacts, and transition to dedicated staff and funding through Portland State University.
Este documento discute el derecho a la libertad de enseñanza en España. Aborda la libertad religiosa en el contexto de la libertad de enseñanza según la Constitución Española, que garantiza el derecho de los padres a elegir la formación religiosa y moral de sus hijos. También analiza la diferencia entre enseñanza pública y privada, y cómo la existencia de escuelas privadas permite ofrecer una educación acorde a las convicciones de los padres.
Silicon Valley Bank’s annual Startup Outlook survey provides insight into how startups in the US, UK and China are feeling about the year ahead. The 2016 report finds that while startups across the globe are eternally optimistic, they are preparing for a new reality.
Learn more about the Startup Outlook Report and view the UK and China reports at www.svb.com/IEO.
The document provides details about a final project report on an automatic spray painter using a 2-DOF robotic arm. It includes the names and enrollment numbers of the 4 students on the project team. It discusses the external and internal project supervisors. It also includes acknowledgments thanking various people who provided guidance and support. The document is divided into multiple chapters that discuss processes automation, analysis and simulation, implementation proposals, the mechanical structure, and conclusions from the project.
How to measure frequency and duty cycle using arduinoSagar Srivastav
Source - http://www.engineersgarage.com
Arduino has several applications. We may find its application in many different fields and areas. It can be used in measurement field also to measure electrical quantities (like voltage, current, power etc) or physical quantities (like temperature, moisture, light intensity, humidity etc) or electronic component values etc.
This article summarizes a study that found cowpea mosaic virus nanoparticles can induce an immune response against tumors when administered to mice. The nanoparticles activated neutrophils in the tumor which secreted chemokines recruiting more immune cells to the tumor. This led to activation of T lymphocytes and destruction of tumor cells, delaying tumor growth. The nanoparticles offer a simple, scalable approach to cancer immunotherapy without targeting a specific antigen, and induce localized immune responses without toxicity to normal tissues. However, questions remain about how such a specific anti-tumor response occurs and why neutrophils rather than lymphocytes are the primary responders. Answering these questions could advance cancer immunotherapy.
In a week when the coronavirus closures and quarantines hit like falling dominoes – the lockdown in Italy, the empty workplaces and college campuses in the U.S., suspended sports seasons, canceled festivals – far less attention fell on the global scientific community's drive to find treatments for the new virus.
The document provides information about HIV/AIDS, including:
1) It describes what HIV and AIDS are, how HIV causes AIDS by compromising the immune system over time.
2) It provides statistics on HIV infections in the US since 1981, including that 1 in 5 people living with HIV are unaware of their status.
3) It summarizes research showing that HIV likely originated from transmission from chimpanzees to humans in the early 20th century.
4) It lists symptoms that can emerge when HIV progresses to AIDS and compromises the immune system.
This document summarizes research on the use of adeno-associated virus (AAV) as a vector for gene therapy. AAV is a promising delivery method due to its low immunogenicity, ability to target specific cell types, and lack of pathogenicity. The document discusses how AAV is being used experimentally to treat diseases like cystic fibrosis, cancer, and heart disease by delivering therapeutic genes. While challenges remain, AAV vectors appear safer than other methods and have the potential to treat many currently incurable diseases.
Aa Vin The Treatment Of Human DiseasesReginaDGates
This document discusses the use of adeno-associated virus (AAV) as a vector for gene therapy. AAV is a promising delivery method due to its low immunogenicity, ability to target specific cell types, and lack of pathogenicity. The document focuses on how AAV may be used as a therapy for cystic fibrosis, cancer, and heart disease. It summarizes challenges with AAV therapy but concludes that AAV vectors appear to be among the safest methodologies for further developing therapies for many currently incurable diseases.
Bionanotechnology and its applications rita martin
Bionanotechnology combination of biotechnology and nanotechnology. Find its applications in various fields Nanotherapeutics, Gene therapy , Immunotherapy, Harmless Viruses, stem cells
This document provides information about malaria vaccines. It discusses the context of malaria globally and the need for a vaccine. Several potential vaccine candidates target different stages of the malaria parasite's lifecycle, including sporozoites, infected hepatocytes, and erythrocytic stages. Developing an effective vaccine is challenging due to the parasite's diversity and complexity. The most promising current candidate is RTS,S, which provides some protection against malaria in clinical trials but is not fully effective.
Novel research aimed at finding a cure for AIDS requires animal models responding to human antiretroviral drugs. However, there have been few antiretrovirals cross-active against the simian viruses. In this study, we expanded the arsenal of drugs active against the simian retrovirus SIVmac251 and showed that this virus is inhibited by the protease inhibitor, darunavir, and the CCR5 blocker, maraviroc. Administration of these two drugs in combination with the reverse transcriptase inhibitors, tenofovir and emtricitabine, and the integrase inhibitor, raltegravir, resulted in prolonged plasma viral loads below assay detection limits, and, surprisingly, restricted the viral reservoir, a marker of which is viral DNA. We then decided to employ this multidrug regimen (termed “highly intensified ART”) in order to increase the potency of a previous strategy based on the gold drug auranofin, which recently proved able to restrict the viral reservoir in vivo. A short course of highly intensified ART following the previous treatment resulted, upon therapy suspension, in a remarkably spontaneous control of the infection, that may pave the way to a persistent suppression of viremia in the absence of ART. These results corroborate the robustness of the macaque AIDS model as a vanguard for potentially future treatments for HIV in humans.
Revolutionary new antibiotic kills drug resistant germs and growingYeison Rodriguez
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Raltegravir not better than nrt is for refractory HIVYael Waknine
Raltegravir offers no benefits over nucleoside reverse-transcriptase inhibitors (NRTIs) when used in combination with a protease inhibitor (PI) as second-line HIV therapy. A study of over 1,200 patients found that ritonavir-boosted PI plus 2 NRTIs was as effective at controlling HIV as PI plus raltegravir at 96 weeks. Using a PI alone after initial raltegravir induction therapy was less effective. The findings suggest that NRTIs retain sufficient activity for use in second-line regimens when combined with a boosted PI.
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1. TARGETS & MECHANISMS
RETHINKING THE
RESERVOIR
By Selina Koch, Staff Writer
It’s time to rethink using “shock and kill” in HIV - a strategy that has
made no serious progress in the last 16 years towards its goal of getting
patients permanently off antiretroviral therapy (ART) - according to a
group at The Scripps Research Institute. Rather than trying to flush out
the last traces of infection from all the viral reservoirs, the researchers
believe a better approach might be to put the latent virus to sleep
permanently.
Using cells from HIV patients treated with ART, a team led by Susana
Valente showed that by inhibiting the transcription factor HIV tat,
it could suppress viral replication and prevent viral rebound after
withdrawal of ART.
“We are targeting suppression of the virus to such a point that no virus
will be expressed in cells,” said Valente, an associate professor in the
Department of Immunology and Microbial Sciences at Scripps.
Despite the success of ART in suppressing HIV to the point where no
virus is detectable in the blood, the virus inevitably rebounds within
just a few weeks of withdrawing treatment. And while many infected
patients have lived for decades on the therapy, researchers are still
trying to find a way to eliminate the virus completely because lifelong
treatment is costly, makes patient adherence more difficult, and results
in accumulating toxicities, said Anthony Fauci, director of NIH’s
National Institute of Allergy and Infectious Diseases (NIAID).
“The trouble is ‘shock and kill’ has been totally unsuccessful thus far,
no matter what method we’ve tried,” Fauci told BioCentury. “I think
suppressing the viral reservoir and not allowing it to reactivate is a
fresh new approach that should be pursued.”
Fauci said the concept behind “shock and kill” has been to pair a
chemical agent that can induce viral reactivation in quiescent cells
with ART to prevent the newly generated viruses from infecting other
cells, “and hope that the cells that are spitting out the virus get sick and
die or are eliminated by an immune response.”
But two key issues have prevented “shock and kill” from working, he
said.
AUGUST 6, 2015
COVER STORY
1 RETHINKING THE RESERVOIR
A Scripps team proposes a method to put latent HIV
to bed permanently that might yield a functional cure
for the disease where “shock and kill” has failed.
PRODUCT R&D
5 IMPEDE A FEVER
An antibody against all serotypes of dengue could
address the danger of second-time infections that is
one of the disease’s biggest problems.
TARGETS & MECHANISMS
8 CAVEAT INHIBITOR
Two groups have identified metabolic changes
caused by therapies targeting the PI3K pathway that
could both explain and provide a solution for the
compounds’ poor performance in the clinic.
TOOLS & TECHNIQUES
12 SILICON FLEXIBILITY
Cyclica’s algorithms model the flexibility around
protein binding sites to flag potential safety issues for
compounds in discovery.
DISTILLERY
14 THERAPEUTICS
Progesterone or progestins for breast cancer; broadly
neutralizing mAbs for Chikungunya viral infection;
inhibiting IL-34 for ischemia/reperfusion-induced
kidney damage; and more...
19 TECHNIQUES
Signaling protein signature for AML prognosis;
telomere-dysfunctional mouse models of IPF; modified
sgRNAs to improve efficiency of CRISPR-Cas9 gene
editing; and more...
2. DISTILLERY
PRODUCT R&D
TOOLS & TECHNIQUES
2 August 6, 2015 TOC
TARGETS & MECHANISMS
First, the existing methods of stimulating viral transcription
only reactivate a small fraction of the reservoir, leaving most
latently infected T cells untouched.
Second, HIV patients often have compromised immune systems
that fail to attack T cells in which the virus has been reactivated.
Instead, he said, “the cells spit out some virus and then go back
into their latent state.”
Andrew Rice, a professor in the Department of Molecular
Virology & Microbiology at Baylor College of Medicine,
told BioCentury that because of the low efficiency rates of
reactivation and elimination, the strategy could only work with
multiple rounds of “shocking” to empty all of the reservoir,
and that treatments would likely need to be paired with an
immunotherapy to boost immune-mediated clearance of the
infected cells.
The reason ART can’t eradicate the virus is that HIV inserts
itself into the genome of the host cell and remains there for as
long as the cell is alive.
While ARTs are very good at inhibiting certain viral functions,
including entry into cells and reverse transcription, Valente
said, “once the virus is in the host gene there are no drugs that
have any ability to eliminate it; the viral genome becomes like a
cellular gene.”
She and her colleagues reasoned it might make more sense to
drive the latent virus underground permanently by blocking the
ability of tat to ramp up DNA replication — a virtually essential
step in reactivating the dormant virus.
In a study published in July in the American Society for
Microbiology’s journal mBio, the team used a derivative of
the steroidal alkaloid cortistatin to inhibit tat, and showed the
compound could suppress both viral replication and rebound
after ART removal. (See Distillery, page 18)
“Cortistatin offers a really nice combination of targeting a viral
protein that targets viral RNA, is not related to a human protein,
and is one that the virus depends on,” said Valente.
TAT-TLE TALE
Valente told BioCentury that the team targeted tat because the
proteinisakeytranscriptionalregulatorthatactsatanearlystage
in the process, and without it, Pol II-mediated transcription is
“incredibly inefficient.”
She said tat acts after integration of the viral genome into host
DNA to jump-start viral transcription by recruiting a protein
complex to the viral promoter that activates Pol II and releases
inhibition from negative elongation factors. Tat also brings
in histone acetylases to allow unwinding of the chromatin,
increasing elongation efficiency. According to Valente, the tat-
driven process is a feedback loop that “amplifies transcription
by several logs.”
To suppress the transcription factor, the group used didehydro-
cortistatin A (dCA) — a cortistatin analog the researchers
had previously shown binds tat and inhibits tat-induced
transcription from the viral promoter.
In a cell-based model of HIV infection, dCA suppressed viral
replication below detectable levels by day 82. When treatment
was discontinued on day 103, viral replication did not restart
during four months of subsequent monitoring.
In addition, the team tested the effect of dCA on viral rebound
after ART withdrawal, using T cells harboring latent virus from
HIV patients on ART.
First, the researchers incubated the cells in vitro with an
antiretroviral cocktail containing Sustiva efavirenz, Retrovir
zidovudine and Isentress raltegravir for 22 days, and then
withdrew the treatment. Within six days, the virus was
reactivated.
When they incubated cells with dCA in addition to the cocktail,
the subsequent viral rebound was reduced by 93.5% and 93.1%
“The trouble is ‘shock and kill’ has been totally
unsuccessful thus far, no matter what method
we’ve tried.”
Anthony Fauci, NIAID
3. DISTILLERY
PRODUCT R&D
TOOLS & TECHNIQUES
3 August 6, 2015 TOC
TARGETS & MECHANISMS
in cells from the two patients respectively, compared with the
rebound seen in the absence of dCA.
Merck & Co. Inc. markets the HIV integrase inhibitor Isentress
and the non-nucleoside reverse transcriptase inhibitor (NNRTI)
Sustiva. GlaxoSmithKline plc markets the nucleoside reverse
transcriptase inhibitor (NRTI) Retrovir.
Valente’s group then tried to chemically induce viral replication
in the quiescent patient cells using the PKC activator prostratin,
which is commonly used to kick-start viral transcription in
“shock and kill” experiments. However, cells treated with the
ART cocktail plus dCA showed 99.9% less prostratin-mediated
reactivation than cells that had received only the HIV drugs.
That suggested viral transcription had been fully suppressed and
had become refractory to viral rebound even in the face of a
strong inducing stimulus.
Valente thinks the persistent viral suppression that occurs after
dCA is removed is likely mediated by epigenetic mechanisms.
“What we think is happening is that the HIV promoter
accumulates very strong repressive epigenetic marks in the
presence of this drug that are somewhat different than what
you would get under normal latency and so we don’t see viral
rebound,” she said.
While the group didn’t find changes in methylation at the viral
promoter in the study, she said the researchers are investigating
other epigenetic modifications such as citrullination to get a
handle on the molecular mechanisms by which dCA persistently
suppresses viral transcription.
ALL OR SOME
Although Fauci noted that it’s early days, he told BioCentury
that given “shock and kill” is not working out, “the opposite
approach is worth pursuing,” and the study is based on good
logic.
“There’s no doubt that is a good in vitro study,” said Fauci. “The
real question is whether this will be translatable in vivo.”
Paul Wender, a professor of chemistry at Stanford University,
told BioCentury that although the “shock and kill” strategy
“clearly has the head start” and will remain an active area of
research, he thinks “viral silencing is an approach that merits
attention.”
Wender, whose lab developed the synthetic method for
prostratin, said his lab and others have since developed
reactivating agents that are more potent than prostratin and he
would like to see if dCA could suppress viral rebound in the
face of those.
He also wants to see how effective the compound is in vivo, and
said that in order for the approach to work, dCA would have
to prevent 100% of the reservoir from reactivating after ART is
discontinued.
“They’re not yet in the position where they can say this is
permanent or that it eliminates reactivation,” said Wender.
“Nearly permanent silencing just isn’t going to be good enough”
because the infection could return.
Wender also noted that the half-life of CD4+
T cells is about
44 months. At that rate, he said, and assuming even a modest
reservoir size of one million cells, it would take about 70 years
to eliminate the reservoir in most patients on ART.
Valente told BioCentury that her lab is synthesizing dCA analogs
to optimize the compound’s effects and safety but that the team
will take dCA forward into proof-of-concept experiments
in animals. She said her group has already begun studies in
humanized mice and hopes to start experiments in non-human
primates next year.
In addition, she noted that a recently publicized case of a
French teenage patient suggests that it might not be necessary
to completely eliminate or suppress the reservoir to achieve a
functional cure.
The girl, who is now 18, was infected from birth and was treated
immediately and aggressively with ART until she was six years
old but was then lost to follow-up and has been off ART for the
past 12 years without significant viral rebound. “She still has the
virus in her,” said Valente, “but she has no detectable viremia.”
“We are targeting suppression of the
virus to such a point that no virus will
be expressed in cells.”
Susana Valente, Scripps
“What we think is happening is that
the HIV promoter accumulates very
strong repressive epigenetic marks in
the presence of this drug.”
Susana Valente, Scripps
4. DISTILLERY
PRODUCT R&D
TOOLS & TECHNIQUES
4 August 6, 2015 TOC
TARGETS & MECHANISMS
What’s of particular interest in that case, said Valente, is that
the girl tried stopping ART twice during her first six years and
each time the virus rebounded, indicating that she was not an
“elite controller”. Elite controllers represent a small subset of
patients who are genetically predisposed to be able to control
HIV infection without drugs. Despite the initial inability to
control her infection, Valente said six years of ART made the girl
competent to suppress her infection on her own, presumably
because her reservoir had shrunk over time as the latently
infected cells died.
Rice agreed that reaching every infected cell might not be
necessary, and noted that theoretical estimates suggest about
90% of cells would need to be eliminated or suppressed. He also
noted that the French girl started treatment earlier than most
patients and may have had a smaller reservoir, suggesting it
could take longer to repeat the result in other patients.
“Maybe a viral suppressor like this HIV tat inhibitor could drive
a lot of the reservoir into some kind of deep latency so that
you wouldn’t have to reduce reservoir size to such an extent,”
Rice said. If so, “the tat inhibitor approach has the potential to
contribute to a functional cure for HIV infection.”
COMPANIES AND INSTITUTIONS MENTIONED
American Society for Microbiology, Washington, D.C.
Baylor College of Medicine, Houston, Texas
GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.
Merck & Co. Inc. (NYSE:MRK), Kenilworth, N.J.
National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Md.
National Institutes of Health (NIH), Bethesda, Md.
The Scripps Research Institute, La Jolla, Calif.
Stanford University, Stanford, Calif.
TARGETS AND COMPOUNDS
HIV tat - HIV tat protein
PKC - Protein kinase C
Pol II - RNA polymerase II
REFERENCES
Mousseau, G., et al. “The tat inhibitor didehydro-cortistatin A prevents HIV-1 reactivation from
latency.” mBio (2015)
5. DISTILLERY
TARGETS & MECHANISMS
TOOLS & TECHNIQUES
5 August 6, 2015 TOC
PRODUCT R&D
PRODUCT R&D
IMPEDE A FEVER
By Stephen Parmley, Senior Writer
A team at the Massachusetts Institute of Technology has
developed an antibody that could treat dengue infections
caused by all four serotypes of the virus, and might be able to
prevent the disease as well. While most companies are focusing
on vaccines for dengue, Visterra Inc. has licensed the mAb and
believes that an immunotherapy could produce a better and
more lasting way to treat and prevent infection.
Researchers have struggled to generate treatments or vaccines
that work broadly in dengue fever because antibodies against
one dengue serotype rarely induce long-term protection against
the others. On top of that, when patients recover from dengue
infection, the antibodies they develop against the first serotype
can exacerbate a second infection by enhancing viral uptake
into host cells.
The most advanced products in the clinic are tetravalent vaccines
that include a mixture of antigens from all four serotypes.
However, according to Visterra COO and CFO David Arkowitz,
vaccine data so far have shown inconsistent protection across
the different serotypes after three doses, and disease worsening
has been observed in some of the younger vaccinated patients.
Although the field is dominated by strategies to prevent
the disease, some of which use small molecule antivirals as
alternatives to the tetravalent vaccines, some groups are trying
to create cross-reactive antibodies that can treat active infections
by any serotype. (See “Delving Into Dengue”, page 6)
Now, the MIT team has described in Cell a strategy that involves
targeting a conserved patch within a region of the dengue viral
envelope not recognized as a dominant epitope by the immune
system during the normal course of an infection. The mAb,
dubbed VIS513, binds residues in domain III of the dengue
surface protein DENV_gp1, neutralizes all four serotypes, and
rapidly treated mice with severe dengue fever after a single dose.
“We believe that VIS513 can be a highly effective therapy to
rapidly clear infection with a single administration,” Arkowitz
told BioCentury.
DOMAIN SEARCH
Because the first attempt to target the patch yielded a mAb
that bound domain III but showed low affinity to serotypes 3
and 4, the group used structure-guided antibody engineering
to improve and equalize the compound’s affinity for all four
serotypes.
The researchers introduced amino acid changes in the
antibody’s binding region that would create better contacts with
matching residues of the bound DENV_gp1. For example, they
reasoned a hydrophobic T33V mutation would improve the
antibody’s interaction with a hydrophobic valine 364 in domain
III. In addition, the group introduced changes and amino acid
deletions to alter the shape of the mAb’s recognition site.
“We predicted a deletion in the antibody that would increase
the contact with the antigen such that it was able to provide a
much broader specificity and that has never been done before,”
said Ram Sasisekharan, principal investigator on the study and
a professor of biological engineering and health sciences and
technology at MIT.
VIS513 bound domain III of dengue serotypes 1-4 with Kd
values of 0.1-4.3 nM, and its affinity for serotypes 3 and 4 was
about 10-fold higher than that of the parent mAb.
The team tested the mAb’s ability to treat infection using mice
engineered to produce human platelets. Treatment with VIS513
following infection with any of the four dengue serotypes
increased platelet counts compared with a control antibody,
which suggested the mAb could treat the infection-induced
thrombocytopenia that is one of the hallmarks of severe dengue
fever.
“We believe that VIS513 can
be a highly effective therapy to
rapidly clear infection with a single
administration.”
David Arkowitz, Visterra Inc.
6. DISTILLERY
TARGETS & MECHANISMS
TOOLS & TECHNIQUES
6 August 6, 2015 TOC
PRODUCT R&D
Next, the team tested in vitro the mAb’s ability to block the
phenomenon in which anti-dengue antibodies enhance
infection, by comparing the activity of VIS513 with that of a
different dengue mAb known to facilitate viral uptake into host
cells expressing the antibody receptor FCGR. In human FCGR-
positive monocytes, VIS513 decreased infection by all four
serotypes compared with the control antibody.
To demonstrate in vivo efficacy against exacerbated disease,
the team tested whether VIS513 could treat dengue serotype
2 infections in newborn mice that had maternally transferred
antibodies against serotype 1. In these mouse pups challenged
with dengue serotype 2, VIS513 decreased clinical scores within
a few days and increased survival compared with an unrelated
isotype-matched mAb. VIS513 also decreased vascular leakage
to levels similar to those seen in uninfected animals.
The authors concluded that the data support the idea that, unlike
previous anti-dengue mAbs, VIS513 would not exacerbate
infections, and could be used to treat active dengue serotype
2 infections even after a previous infection with a different
serotype.
Finally, the team tested the antibody’s efficacy in preventing
infection in a mouse model of dengue serotype 2 infection,
which is one of the more virulent serotypes. Pretreatment with
VIS513 increased survival compared with a control antibody.
DELVING INTO DENGUE
Dengue preventive vaccines and therapeutics in development. At least eight preventive vaccines, four therapeutic antivirals, one anti-infective nanoparticle and one
therapeutic antibody against dengue virus are in development by biotech and pharma companies. The vaccines in development include components from dengue
virus serotypes 1-4 (tetravalent vaccines). The four antivirals treat dengue fever by blocking viral replication. NanoViricides Inc.’s (NYSE-M:NNVC) nanoviricide
micelles treat dengue fever by engulfing and dismantling the virus. Visterra Inc.’s mAb VIS513 treats dengue fever by blocking host cell infection by all dengue
serotypes. Sources: BCIQ: BioCentury Online Intelligence; www.clinicaltrials.gov; company websites
COMPANY PRODUCT DESCRIPTION STATUS
Sanofi (Euronext:SAN; NYSE: SNY) ChimeriVax Chimeric tetravalent dengue vaccine consisting of live
attenuated yellow fever virus 17D strain with structural genes
replaced with the corresponding dengue structural genes
Phase III
Takeda Pharmaceutical Co. Ltd.
(Tokyo:4502)
TAK-003 (Dengue fever vaccine) Recombinant tetravalent attenuated live dengue vaccine Phase II
Globavir Biosciences Inc. GBV006 Combination of two previously FDA-approved anti-infective
drugs
Phase I
Merck Sharp and Dohme Corp.
subsidary of Merck & Co. Inc.
(NYSE:MRK)
V180 Tetravalent recombinant subunit vaccine against dengue fever Phase I
United Therapeutics Corp.
(NASDAQ:UTHR)
UV-4B α-glucosidase inhibitor Phase I
Vical Inc. (NASDAQ:VICL) Vaxfectin-formulated tetravalent
dengue DNA vaccine
Tetravalent vaccine containing genes encoding pre-
membrane and envelope proteins for four dengue virus
serotypes formulated with the Vaxfectin adjuvant
Phase I
Altravax Inc. Dengue virus vaccine Chimeric tetravalent vaccine against dengue virus envelope
protein E (DENV_gp1)
Preclinical
NanoViricides Inc. Anti-dengue nanoviricides
(DengiCide, DengueCide)
Nanoviricides targeting certain regions of the dengue
envelope protein structure
Preclinical
PaxVax Inc. Dengue vaccine Two-dose, whole-virus inactivated vaccine Preclinical
Sarepta Therapeutics Inc.
(NASDAQ:SRPT)
Viral PMO-X RNA-based antiviral based on morpholino-modified
phosphorodiamidate oligomers (PMO) antisense chemistry
Preclinical
Siga Technologies Inc. (Pink:SIGAQ) Dengue antiviral Orally bioavailable antiviral dengue fever compound Preclinical
Themis Bioscience GmbH Dengue fever vaccine Tetravalent vaccine developed using Thermaxyn technology
that uses a single measles viral vector expressing the
conserved EDIII domain of DENV_gp1
Preclinical
Visterra Inc. VIS513 Humanized mAb targeting a conserved region DENV_gp1 Preclinical
7. DISTILLERY
TARGETS & MECHANISMS
TOOLS & TECHNIQUES
7 August 6, 2015 TOC
PRODUCT R&D
PROPHYLACTIC PRACTICALITIES
Visterra has partnered with the Agency for Science Technology
and Research (A*STAR) and plans to take VIS513 into the clinic
next year to treat acute dengue infections. But it’s not clear how
practical an antibody-based prophylactic therapy could be for a
developing world disease.
“Prophylaxis with an antibody might not be very effective
because the antibody has a limited half-life, you can’t predict
when you’re going to get an infection, and it is not feasible to
inject large amounts of the antibody on a weekly basis,” said
Sean Du, COO of infectious disease company Altravax Inc.
He noted that the mAb’s prospects could be better if it works at
low doses.
Arkowitz countered, “There is a long history of the use of
monoclonal and polyclonal antibodies to protect against
infection and we believe that passive prophylaxis could be an
important use for VIS513.”
He added: “We believe that the prophylactic dose will be
meaningfully lower than a curative therapeutic, further reducing
the cost from already affordable mAb ranges.”
Although last week a group at Inovio Pharmaceuticals Inc.
published a study in Scientific Reports about a DNA-based
approach for reducing the cost of a prophylactic dengue
immunotherapy, Arkowitz told BioCentury that Visterra plans
to validate the therapeutic utility of VIS513 in the clinic before
exploring other modalities.
Inovio’s method uses a DNA vector encoding a neutralizing
dengue antibody that generates the mAb when injected into
mouse muscle. A DNA vector would be less expensive to
manufacture than a protein and could require fewer doses if it
elicits sustained expression of the anti-dengue mAb.
Arkowitz said, “Alternative vehicles and strategies, such as DNA
vector electroporation for delivery, are welcome and needed,
[but] we believe that the cost of goods for mAbs will continue
to drop.”
The MIT team has a pending patent on the mAb for the
treatment of dengue fever and has used a similar structure-
guided engineering approach to develop neutralizing mAbs for
additional undisclosed infectious agents.
COMPANIES AND INSTITUTIONS MENTIONED
Agency for Science Technology and Research (A*STAR), Singapore
Altravax Inc., Fargo, N.D.
Inovio Pharmaceuticals Inc. (NASDAQ:INO), Blue Bell, Pa.
Massachusetts Institute of Technology (MIT), Cambridge, Mass.
Visterra Inc., Cambridge, Mass.
TARGETS AND COMPOUNDS
DENV_gp1 - Dengue virus envelope protein E
FCGR - Fcγ receptor
REFERENCES
Flingai, S., et al. “Protection against dengue disease by synthetic nucleic acid antibody prophy-
laxis/immunotherapy.” Scientific Reports (2015)
Robinson, L., et al. “Structure-guided design of an anti-dengue antibody directed to a non-immu-
nodominant epitope.” Cell (2015)
“We predicted a deletion in the
antibody that would increase the
contact with the antigen such that it
was able to provide a much broader
specificity and that has never been
done before.”
Ram Sasisekharan, MIT
8. DISTILLERY
PRODUCT R&D
TOOLS & TECHNIQUES
8 August 6, 2015 TOC
TARGETS & MECHANISMS
TARGETS & MECHANISMS
CAVEAT INHIBITOR
By Karen Tkach, Staff Writer
Two studies have shown that metabolic adaptations can allow
some cancer cells to thrive in response to therapies that inhibit
the PI3K pathway. The results could explain the poor clinical
performance of the inhibitors, but might also open the door to
rescuing or reviving the compounds by combining them with a
molecule that blocks the cells’ ability to adapt.
“What has been perhaps underestimated is that tumors adapt,”
said Dario Altieri, principal investigator of one study. “And
unfortunately, attached to the adaptation phase is the acquisition
of traits that make them more aggressive.” Altieri is president,
CEO and director of the Wistar Institute Cancer Center.
Craig Thompson, president and CEO of Memorial Sloan
Kettering Cancer Center (MSKCC) and principal investigator
of the second study, said both his and Altieri’s results show
ways that some cancer cells can evade or feed off PI3K pathway
inhibitors, and point to new therapeutic options.
“You have to understand how the tumor cell gets away from
that, and build into your first therapy the prevention of that
being an escape strategy,” he said. “So increasingly people are
looking for rational combinations of therapies rather than single
pathway inhibitors.”
In July, Thompson’s group published a study in Cell showing
inhibitors of mTORC1 unexpectedly increased rather than
decreased cancer growth in amino acid-poor tumors containing
KRAS mutations that promote consumption of extracellular
proteins. mTORC1 is a protein complex activated by PI3K
signaling.
The same week, Altieri’s team published in Proceedings of
the National Academy of Sciences a study showing that PI3K
inhibitors can promote cellular energy production that fuels
cancer cell motility and invasiveness.
“The scientific story was that all cells grow by activating mTOR,
and that mTOR was critical to the ability of cells to grow and
proliferate,” Thompson said. “That made the argument that if the
cells were treated with an mTOR inhibitor, at the very worst they
wouldn’t be able to grow anymore” even if they didn’t actively
kill tumor cells. “So a lot of industry effort went into this.”
But both Thompson and Altieri noted that despite over 15 years
of investigation, drugs targeting the PI3K pathway have not
lived up to expectations in the clinic.
“The surprising fact was that an awful lot of studies across a large
number of tumor types were done on the theory that this should
at least impair growth, and therefore might make a registratable
drug, and by and large all those studies failed,” said Thompson.
Although there are derivatives of rapamycin on the market that
inhibit mTOR, and Gilead Sciences Inc. markets the PI3Kδ
inhibitor Zydelig idelalisib, many compounds targeting the
PI3K pathway have failed in development.
For example, Oncothyreon Inc.’s PI3K inhibitor PX-866 was
discontinued in 2013 after failing to meet endpoints in Phase
II trials.
In 2013, Stuart Lutzker, VP of Biooncology Exploratory Clinical
Development at Roche’s Genentech Inc. unit, told BioCentury
that the high potency of the dual PI3K and mTOR inhibitor
GDC-0980 made it the company’s most likely candidate for a
PI3K pathway-targeting monotherapy. Yet last year, a Phase II
trial of GDC-0980 in endometrial cancer showed an unfavorable
safety profile and limited anti-tumor activity.
Thompson said there are two main hypotheses to explain why
PI3K pathway inhibitors have had so little success.
“One explanation was that rapamycin and its derivatives just
weren’t very good mTOR inhibitors,” he said. “So the industry
went back to work to find more complete mTOR inhibitors,
which are coming online now.”
Despite over 15 years of
investigation, drugs targeting the
PI3K pathway have not lived up to
expectations in the clinic.
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The second possibility, he said, was that the compounds might
activate other pathways that oppose tumor suppression.
“There was another possibility that cancer cells have alternative
ways when you turn off mTOR to actually take up nutrients and
grow,” said Thompson. That’s the mechanism he thinks is most
likely in play.
“What we were able to show was that rapamycin actually made
the mouse model tumors grow faster.”
Altieri said that he too favors the hypothesis that cellular
adaptation underlies the poor performance of these drugs. “The
problem is that they put the tumor under tremendous selective
pressure,” he said.
ADAPTATION THROUGH METABOLISM
While Altieri’s group showed that PI3K inhibitors caused tumor
cells to adapt through mitochondrial fueling of cell movement,
Thompson’s team demonstrated that mTOR inhibitors cause the
cells to adapt because of lysosomal consumption of extracellular
proteins. (See “Inhibitable Adaptations”)
Altieri and colleagues demonstrated that PI3K inhibition by
compounds used in the clinic increased invasion of glioblastoma
multiforme (GBM) cells across an in vitro matrix of extracellular
proteins and in 3D tumor spheroids compared with vehicle.
In addition, inhibitors of PI3K increased the size and
persistence of movement-promoting membrane ruffles in a
non-polarized manner. As a result, cells with suppressed PI3K
displayed random motility instead of directional movement in a
chemotactic gradient.
“This is thought to be a very unfavorable circumstance of
tumors, because random cell motility is the one that has been
traditionally associated with metastatic potential,” said Altieri.
INHIBITABLE ADAPTATIONS
Two studies have identified mechanisms by
which therapeutics that inhibit the PI3K pathway
promote tumorigenesis in cancer cells. The cellular
adaptations to the inhibitors increased tumor cell
migration in one study, and growth in low-nutrient
conditions in the other. Blocking the adaptations
by inhibiting mitochondrial energy production or
lysosomal protein degradation, respectively, might
provide a handle to improve the efficacy of PI3K
pathway inhibitors in cancer.
In a report in the Proceedings of the National Academy
of Sciences USA, a group at the Wistar Institute
showed that PI3K inhibitors increased tumor
cell invasiveness by recruiting energy-producing
mitochondria to membrane protrusions. (1) When
localized at the membrane, the mitochondria
supplied energy that drives invasive migration.
Inhibitors of oxidative phosphorylation, which
decrease mitochondrial energy output, decreased
cell migration during PI3K inhibition.
In a report in Cell, a group at Memorial Sloan
Kettering Cancer Center showed that inhibitors
of mTOR, and particularly of mTORC1 complexes,
decreased cell growth in nutrient-rich conditions
with high levels of free amino acids, but increased
growth in cells lacking access to free amino acids.
(2a) Under normal conditions in which cells can
take up free amino acids, mTORC1 promoted
cell growth, and therefore inhibitors of mTOR
or mTORC1 decreased cell growth under these
nutrient-high conditions. (2b) In the absence of free
amino acids, a nutrient-low condition that occurs
inside solid tumors, cells take up and break down
entire proteins through macropinocytosis, and
mTORC1 signaling decreased tumor cell growth.
Consequently, inhibiting mTOR or mTORC1 could
have the unintended effect of increasing tumor
cell growth under nutrient-low conditions, and
the group also found that cancer-associated Ras
mutations exacerbated this unintended effect of
mTOR inhibition. Inhibition of lysosomal protein
degradation decreased macropinocytosis-driven
proliferation in nutrient-low conditions.
mTOR (FRAP; RAFT1) – Mammalian target of
rapamycin; mTORC1 – Mammalian target of
rapamycin complex 1; PI3K – Phosphoinositide
3-kinase
ATPATP
ATP
ATP
ATP
Uptake of free amino
acids in normal
conditions
High
am
ino
acids
Lowaminoacids
Uptake, breakdown of
proteins in amino-acid
poor conditions
PI3K
inhibitor
PI3K
mTOR
mTOR
mTORC1
mTOR
inhibitor
Cell
growth
Cell
migration
1
2a
2b
Growth
inhibition
Oxidation
phosphorylation
inhibitor
Mitochondria
Lysosomal
inhibitor
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Using imaging experiments, Altieri’s team found that PI3K
inhibitors caused mitochondria to elongate and infiltrate areas
close to membrane ruffles and focal adhesions. In addition,
the compounds increased focal adhesion turnover, resulting in
fewer stable adhesions and more motility.
Finally, the team showed that the motility effects of PI3K
inhibitors could be countered by suppressing oxidative
phosphorylation with gamitrinib, a mitochondrially targeted
Hsp90 inhibitor that Altieri’s lab is developing. In a previous
study, his group showed co-treatment with PI3K inhibitors
and gamitrinib also improved survival in an in vivo model of
glioblastoma.
Altieri thinks these studies show gamitrinib or other
mitochondrial modulators could improve the efficacy of PI3K
inhibitors. “It makes perfect sense to target the PI3K/Akt
pathway, but it is less intuitive to combine these agents with an
inhibitor of mitochondrial bioenergetics, and yet this is what
seems to emerge consistently from the studies that we have
conducted,” he said.
In its study, Thompson’s team showed that mTOR inhibitors
could allow tumor cell growth under low-nutrient conditions
via lysosomal uptake of extracellular proteins.
Cells typically rely on the uptake of free amino acids for growth.
However, in conditions with low amino acid availability such
as the interiors of tumors, cells can internalize and consume
whole extracellular proteins, a phenomenon known as
macropinocytosis.
Thompson and colleagues showed KRAS mutations increase
macropinocytosis in mouse embryonic fibroblasts. The increase
in protein uptake allowed cells to proliferate in media that
contained whole albumin protein but lacked free leucine — an
essential amino acid.
To investigate how KRAS promotes cell proliferation via
macropinocytosis, Thompson’s team inhibited several of the
protein’s downstream mediators, including members of the
PI3K pathway. In media that contained albumin but not leucine,
PI3K pathway inhibitors promoted proliferation, whereas in
leucine-rich media, the same inhibitors suppressed cell growth.
Thompson noted the effect centered on mTORC1. “As we went
farther upstream, we still saw effects of enhancing growth when
we used PI3K or combined PI3K/mTOR inhibitors,” including
the Genentech compound GDC-0980. “But it was clearest the
closer we got to inhibiting mTORC1,” he said.
The team believes that mTORC1 might be acting to promote
growth when amino acids are plentiful, but prevent proliferation
in nutrient-poor conditions. When mTORC1 is inhibited,
starved cells can disregard this checkpoint and proliferate using
extracellular proteins as fuel.
According to Thompson, the hypothesis that the poor
performance of mTOR inhibitors in the clinic could be explained
by their promotion of cell growth in low-nutrient conditions
was triggered by trials in pancreatic cancer, a disease in which
95% of patients have KRAS mutations.
“There were two trials that were done in pancreatic cancer
with mTOR inhibitors in which it became apparent early on
that the drug wasn’t, in a randomized trial, making patients
better,” Thompson said. “And if anything, the patients on mTOR
inhibitors were doing worse.”
In a mouse model of KRAS-driven pancreatic cancer, the
authors showed that despite inhibiting proliferation in outer
tumor regions, rapamycin increased overall tumor volume and
proliferation in the tumor’s nutrient-deficient core.
Thompson thinks the tumor-promoting effects of mTOR
inhibition could be opposed by co-treatment with inhibitors
that block the uptake or lysosomal degradation of extracellular
proteins. Alternatively, he thinks the enhanced rates of
macropinocytosis in tumors could be used against them by
providing an extracellular poison.
FROM CAVEAT TO CLINIC
Both Altieri and Thompson believe PI3K pathway inhibitors
could be rescued by rational drug combinations that take the
pathway’s complex biology into account.
“We think that the future of these agents is in combination
therapy, and it’s something that the field I think is appreciating,”
said Altieri.
“It makes perfect sense to target
the PI3K/Akt pathway, but it is less
intuitive to combine these agents
with an inhibitor of mitochondrial
bioenergetics.”
Dario Altieri, Wistar Institute
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Thompson agreed, but noted that drug combinations have a
downside. “You end up with combined toxicities as well in these
combinations, and that’s what makes people hesitant to take
them on until they’re sure that there’s a reason to do that.”
He added that more evidence is needed before the caveats these
two studies raise change the course of drug development.” Our
experience in dealing with those types of concepts is they’re best
to put into the literature, let others evaluate and see if they can
confirm them, and then the weight of the evidence will be on
people to actually design their trials to address that issue,” he
said.
“Our results don’t excite people that have worked long and hard
on developing even better and more effective mTOR inhibitors,”
Thompson said. “You’re not going to get people to change the
dogma by which they’re doing drug discovery until there’s a
validation of that, and I think that’s an absolutely fair standard. I
think the community has done a very good job of that.”
If his teams’ results are verified, Thompson thinks also they
might influence patient selection in clinical trials.
“We would hope in some of the trials of the new generation
of mTOR inhibitors that they’ll exclude patients with Ras”
mutations, he said. “That’ll be the first immediate impact that
would benefit patients.” If those efforts succeed, he hopes
researchers will start clinical trials to test the ideas his team has
put forward, in the appropriate settings.
He added: “Our results don’t apply to all cancers. We suspect
there will be a good role for mTOR inhibitors in certain other
forms of cancer. It’s a cautionary tale to be careful about specific
circumstances in which you investigate mTOR inhibitors as an
effective therapeutic against growth.”
COMPANIES AND INSTITUTIONS MENTIONED
Genentech Inc., South San Francisco, Calif.
Gilead Sciences Inc. (NASDAQ:GILD), Foster City, Calif.
Memorial Sloan Kettering Cancer Center (MSKCC), New York, N.Y.
Oncothyreon Inc. (NASDAQ:ONTY), Seattle, Wash.
Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland
Wistar Institute, Philadelphia, Pa.
Wistar Institute Cancer Center, Philadelphia, Pa.
TARGETS AND COMPOUNDS
Hsp90 – Heat shock protein 90
mTOR (FRAP; RAFT1) – Mammalian target of rapamycin
mTORC1 – Mammalian target of rapamycin complex 1
PI3K – Phosphoinositide 3-kinase
PI3Kδ – Phosphoinositide 3-kinase δ
REFERENCES
Caino, M., et al. “PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion.”
Proceedings of the National Academy of Sciences USA (2015)
Fulmer, T, “Genentech’s PI3K arsenal.” BioCentury (2013)
Palm, W., et al. “The utilization of extracellular proteins as nutrients is suppressed by mTORC1.”
Cell (2015)
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SILICON FLEXIBILITY
By Mark Zipkin, Staff Writer
While companies and academics are chasing proteomics to find
new targets for drug discovery, Cyclica Inc. thinks the field is
limited by the fact that most of the data derive from static 3D
crystal structures that don’t represent how proteins behave when
they bind other molecules. The company has developed an in
silico platform to model the flexibility around protein binding
sites and is using the system to predict protein-drug interactions
and flag possible toxicities.
But because its algorithms draw on large databases in the public
domain, it’s not clear whether its predictions will fall foul of the
inaccuracies in experimental design and reporting that underlie
much of the reproducibility crisis.
Jason Mitakidis, founder and CEO of Cyclica, told BioCentury
that he became interested in using “all the data that’s available” for
drug discovery, while an undergraduate at McMaster University.
He noted that one of the key problems with using proteomic
data in public databases is that, because the protein structures
are in the lowest energy state, researchers can lose sight of the
conformational dynamics that take place inside a cell.
Heandhiscolleaguesthoughtthatproteomicsdatacouldbebetter
exploited by merging them with results from drug information
and systems biology databases, and created algorithms for
predicting how proteins will alter their shape when they bind
different compounds.
The central idea was to break the information down into what
the company calls “fingerprints” through a process that takes into
account changes that occur in proteins upon binding, something
not typically evident from the static structures captured in the 3D
representations available in most databases.
“We have billions of records, we’ve indexed those, we’re able to
account now for flexibility around binding sites,” said Mitakidis.
“So if we want to look at how a certain drug candidate will interact
with the entire structural proteome that’s available, we can do that
and we can in many cases predict, for example, side effects and
toxicity.”
To create its Ligand Express platform, Cyclica used IBM Corp.’s
Blue Gene supercomputer to run simulations of protein-drug
interactions on FDA-approved drugs as well as millions of
compounds from public databases, such as compounds in
development, and research probes.
“We’ve now integrated various other databases into our platform
that allow us to look at the systems biology to identify new
targets,” as well as side effects and toxicity, said Mitakidis.
The system involves an initial pass of the digitized molecules to
scan for new targets with which the molecules might interact that
could either represent new drug discovery opportunities or could
highlight potential problems. “Once we get that information, we
look at certain other types of information — systems biology
information and research literature — and give you predictions
about possible clinical outcomes,” said Mitakidis.
However, the reliance on the large amounts of published research
could present as many problems as solutions, according to some
experts who spoke with BioCentury.
Derek Lowe, a medicinal chemist and author of a widely read blog
on drug research, said that although there’s support for harnessing
the power of big data to help with drug design, there’s also cause
for caution because “large databases get unwieldy because of
curation.”
“Anyone who’s gone through the big databases in the field knows
thatthere’sanot-insignificantamountofgarbageinthem,”hesaid.
“You have to find a way to seek that stuff out, to recognize it when
you see it, and if possible, to not let it send you to conclusions that
look convincing but are wrong,” he told BioCentury.
GARBAGE DISPOSAL
The problem is not Cyclica’s alone. Several other companies are
building predictive software tools to help with drug design or
selection to speed the process from discovery to lead selection.
“We have billions of records, we’ve
indexed those, we’re able to account
now for flexibility around binding
sites.”
Jason Mitakidis, Cyclica
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Biovista Inc. and NuMedii Inc. also have algorithms that parse
large amounts of publicly available data, although unlike Cyclica,
their focus is on predicting efficacy rather than side effects.
ArisPersidis,presidentandco-founderofBiovista,toldBioCentury
that Biovista’s approach is to make predictions for how compounds
will work in different pathways or clinical outcomes, to allow
approved drugs to be repurposed for new indications.
“We take existing drugs as starting points because we know so
much about them,” said Persidis. “We think of drugs not simply
as drugs, but as probes of function of the disease. A drug can help
me understand how a disease works.”
In 2013, Biovista collaborated with the CFIDS Association of
Americatorepurposetwopotentialtreatmentsforchronicfatigue
syndrome (CFS). “We went from nothing to pre-IND meeting
with FDA in about a year,” he told BioCentury. “In normal drug
development, you should expect that could take something like
two to three years, if not more.”
NuMedii founder and CEO Gini Deshpande said her company
was spun out of Stanford University to use data in public
databases to reclassify diseases by genomic signatures, then match
them with therapies that might work on all diseases sharing that
signature. The goal is to find new drug candidates and biomarkers
that can predict efficacy in a disease.
“We look at connecting drugs and diseases at a network level as
opposed to a single target level,” said Deshpande.
She said the company spends considerable effort on quality
checks of the data it uses. She added that in addition to NuMedii’s
internal controls to ensure data quality, the large quantity of data
involved provides some protection from false positives.
“If you’ve got vast amounts of data for a given disease condition,
you can filter the signal from the noise because you have many
data subsets that are being deposited,” she said. She added that
because the lab that deposited the data is disclosed with the entry,
it’s possible to compare information from one group to another
and identify data sets that have good quality.
“It’s not trivial, but certainly it’s a very important process we
go through because there’s a lot of noisy data that’s out there,”
Deshpande said.
Persidis agreed, noting, “If the good information exceeds the bad
information, and if you normalize this across enormous data sets,
then you get valid signals. While you can’t stop garbage from
being generated, you can certainly put systems and processes in
place to identify it,” and understand what needs to be done to end
up with a valid signal.
He said that because Biovista’s system involves multiple inputs —
including disease indications, unique clinical outcomes, unique
adverse events, marketed drugs and compounds that are or have
been in development — it has an advantage in reducing the noise
of false associations.
“A byproduct of our approach is that it has helped us identify
garbage going in a lot more effectively,” he said. “When you watch
the weather, you see the radar picture and the barometer and the
rain index and all those different sensors give you different types
of information. All those measurements are valid when standing
on their own, but you really have to combine them to get a valid
picture of the weather.”
For safety issues such as those Cyclica wants to address, data
qualitycanbeanevenbiggerissuethanforefficacy,saidMitakidis,
because gaps in knowledge about certain pathways can reduce the
reliability of the company’s analyses.
“In cases like those, we’re able to inform our partners and clients
that there’s a certain degree of reliability for the results that we
generate,” he said.
For now, Cyclica’s focus is on helping companies select the
optimal candidates to take into the clinic, said Mitakidis. He
added that the company has started working with a number of
pharmaceutical companies as clients and has done work for an
undisclosed government agency.
To date, Cyclica has raised C$2 million ($1.5 million) and is in the
process of raising another C$1 million ($760,000). In the coming
months he hopes to raise “in the C$15-C$20 million [$11-$15
million] range.”
COMPANIES AND INSTITUTIONS MENTIONED
Biovista Inc., Charlottesville, Va.
CFIDS Association of America, Charlotte, N.C.
Cyclica Inc., Toronto, Ontario
IBM Corp. (NYSE:IBM), Armonk, N.Y.
McMaster University, Hamilton, Ontario
NuMedii Inc., Palo Alto, Calif.
Stanford University, Stanford, Calif.
“Anyone who’s gone through the big
databases in the field knows that
there’s a not-insignificant amount of
garbage in them.”
Derek Lowe, industry blogger
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DISTILLERY
INDICATION: Breast cancer
Mouse and patient sample studies suggest progesterone or progestins could
help treat breast cancer. In cultured tumor explants derived from patients with
estrogen receptor α- and progesterone receptor-positive breast cancer, a progestin
decreased estrogen-dependent proliferation compared with vehicle. In a mouse
xenograft model of estrogen receptor α- and progesterone receptor-positive breast
cancer, progesterone decreased tumor growth compared with no treatment, and
progesterone plus the generic estrogen receptor inhibitor tamoxifen decreased
tumor growth more potently than either agent alone. Next steps include clinical
testing of progesterone in combination with standard-of-care estrogen receptor
antagonists in breast cancer patients.
TARGET/MARKER/PATHWAY: Progesterone receptor;
estrogen receptor α
LICENSING STATUS: Unpatented; available for partnering
PUBLICATION DETAILS: Mohammed, H. et al. Nature;
published online July 8, 2015
doi:10.1038/nature14583
CONTACT: Wayne Tilley, University of Adelaide, Adelaide,
Australia
e-mail: wayne.tilley@adelaide.edu.au
CANCER
DISTILLERY
THE DISTILLERY brings you this week’s most essential scientific findings in therapeutics, distilled by BioCentury Innovations editors from a
weekly review of more than 400 papers in 41 of the highest-impact journals in the fields of biotechnology, the life sciences and chemistry. The
Distillery goes beyond the abstracts to explain the commercial relevance of featured research, including licensing status and companies working
in the field, where applicable. This week in therapeutics includes important research findings on targets and compounds, grouped first by disease
class and then alphabetically by indication.
THERAPEUTICS
INDICATION: Breast cancer
In vitro and mouse studies suggest inhibiting DAPK1 could help treat p53-mutant,
triple-negative breast cancer (TNBC). In p53-mutant TNBC cell lines, DAPK1
shRNA or a DAPK1 inhibitor decreased growth compared with no treatment or
vehicle, respectively, whereas in TNBC breast cancer cell lines expressing wild-type
p53, neither treatment affected growth. In mice with p53-mutant TNBC xenografts,
tumor-specific DAPK1 knockout or a DAPK1 inhibitor decreased tumor growth
compared with normal DAPK1 expression or vehicle, respectively. Next steps
include testing DAPK1 inhibitors in additional animal models of TNBC.
TARGET/MARKER/PATHWAY: Death-associated protein
kinase 1 (DAPK1; DAPK)
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Zhao, J. et al. J. Clin. Invest.;
published online June 15, 2015
doi:10.1172/JCI70805
CONTACT: Powel H. Brown, The University of Texas MD
Anderson Cancer Center, Houston, Texas
e-mail: phbrown@mdanderson.org
INDICATION: Cancer
In vitro studies suggest combining TERF2 inhibition and mitotic arrest could help
treat cancer. In a human fibroblast cell line expressing viral proteins that induce
mitotic arrest, shRNA-mediated suppression of TERF2 increased telomeric DNA
breaks and cell death compared with control shRNA. In a human fibrosarcoma cell
line treated with the mitotic arrest-inducing compounds paclitaxel and vinblastine,
shRNA knockdown of TERF2 increased cell death. Next steps include investigating
the effects of paclitaxel on telomere biology in breast cancer patients.
Bristol-Myers Squibb Co. markets Taxol paclitaxel, a microtubule stabilizing agent,
to treat breast and ovarian cancer.
The generic chemotherapy vinblastine is marketed to treat various cancers.
TARGET/MARKER/PATHWAY: Telomeric repeat binding
factor 2 (TERF2)
LICENSING STATUS: Unpatented; available for partnering
PUBLICATION DETAILS: Hayashi, M. et al. Nature;
published online June 24, 2015
doi:10.1038/nature14513
CONTACT: Jan Karlseder, The Salk Institute for Biological
Studies, La Jolla, Calif.
e-mail: karlseder@salk.edu
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THERAPEUTICS
INDICATION: Cancer
In vitro and mouse studies suggest inhibiting FSCN1 activity could help prevent
or treat metastatic cancers. In an in vitro actin-bundling assay, high throughput
screening identified a compound that inhibited FSCN1-mediated actin bundling
required for filopodia formation and tumor cell migration with IC50
values of about
5-8 μM. In human and mouse metastatic breast cancer cell lines, the FSCN1 inhibitor
decreased migration and invasion compared with no treatment. In two mouse
models of metastatic breast cancer, the inhibitor decreased the number of lung
metastases and lung colonization by metastatic cells compared with vehicle. Next
steps could include testing the FSCN1 inhibitor in additional models of metastatic
cancer.
TARGET/MARKER/PATHWAY: Fascin 1 actin-bundling
protein (FSCN1)
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Huang, F.-K. et al. Nat. Commun.;
published online June 17, 2015
doi:10.1038/ncomms8465
CONTACT: Xin-Yun Huang, Weill Cornell Medical College,
New York, N.Y.
e-mail: xyhuang@med.cornell.edu
CANCER
INDICATION: Cancer
In vitro and mouse studies suggest conjugates of EPHA2-targeting peptidomimetics
and paclitaxel could help treat EPHA2-positive cancers. EPHA2 expression in
tumors is associated with increased metastatic behavior. Screening of a panel of
peptides with N-terminal synthetic tyrosine mimetics identified a peptidomimetic
that bound EPHA2 in vitro with a Kd
of 4 μM and had greater stability in rat plasma
than EPHA2-binding peptides with N-terminal tyrosines. In a mouse xenograft
model of pancreatic cancer, paclitaxel conjugated to the peptidomimetic decreased
tumor growth compared with unconjugated paclitaxel. In a mouse xenograft model
of metastatic melanoma, the paclitaxel-peptidomimetic conjugate decreased
tumor growth compared with Abraxane or no treatment. Next steps could include
testing the long-term in vivo safety profile of the conjugate.
Celgene Corp. markets Abraxane nab-paclitaxel, an albumin-stabilized nanoparticle
formulation of paclitaxel, to treat non-small cell lung cancer (NSCLC), gastric,
breast and pancreatic cancers.
TARGET/MARKER/PATHWAY: EPH receptor A2 (EPHA2)
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Wu, B. et al. Chem. Biol.;
published online July 9, 2015
doi:10.1016/j.chembiol.2015.06.011
CONTACT: Maurizio Pellecchia, Sanford Burnham Prebys
Medical Discovery Institute, La Jolla, Calif.
e-mail: mpellecchia@burnham.org
INDICATION: Colorectal cancer
Mouse and patient sample studies suggest inhibiting MCP-1 could help treat
colorectal cancer. In tissue samples from colorectal cancer patients, MCP-1 levels
were higher in tumor cells than in normal colon cells. In a mouse model of intestinal
cancer, an anti-MCP-1 antibody decreased the number of intestinal tumors and
pro-tumorigenic myeloid-derived suppressor cells compared with control. Next
steps could include further testing of MCP-1 inhibitors or anti-MCP-1 antibodies in
colorectal cancer models.
TARGET/MARKER/PATHWAY: Monocyte
chemoattractant protein-1 (MCP-1; CCL2)
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Chun, E. et al. Cell Rep.; published
online July 2, 2015
doi:10.1016/j.celrep.2015.06.024
CONTACT: Wendy S. Garrett, Harvard T. H. Chan School
of Public Health, Boston, Mass.
e-mail: wgarrett@hsph.harvard.edu
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THERAPEUTICS
INDICATION: Liver cancer
In vitro studies identified a Nexavar sorafenib analog that could help treat liver
cancer. In a human hepatocellular carcinoma (HCC) cell line, a diarylurea indazole
analog of Nexavar decreased proliferation and increased apoptosis at lower
concentrations than Nexavar, but decreased proliferation of a normal human liver
cancer cell line at higher concentrations than the parent. In a human umbilical vein
endothelial cell line, the analog inhibited angiogenesis and decreased migration
compared with Nexavar. Next steps could include testing the analog in animal
models of liver cancer.
Amgen Inc. and Bayer AG market Nexavar to treat renal, thyroid and liver cancers.
TARGET/MARKER/PATHWAY: Multiple kinases
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Lu, Y.-Y. et al. J. Pharm.
Pharmacol.; published online June 16, 2015
doi:10.1111/jphp.12440
CONTACT: Xiu-Li Guo, Shandong University, Jinan, China
e-mail: guoxl@sdu.edu.cn
CONTACT: Wen-Bao Li, Ocean University of China,
Qingdao, China
e-mail: wbli@ouc.edu.cn
CANCER
INDICATION: Wounds
Mouse studies suggest CYR61 could promote wound healing. Normal wound healing
depends on CYR61-mediated recognition of apoptotic markers on neutrophils
by integrin α5
(CD49e) on macrophages, followed by macrophage-mediated
neutrophil clearance. In wounded mice, expression of a non-CD49e-binding CYR61
mutant increased wound levels of neutrophils and decreased healing compared
with wild-type CYR61 expression. In wounded mice expressing the mutant CYR61
or diabetic mice with impaired wound healing expressing wild-type CYR61, topical
application of wild-type CYR61 to the wound decreased neutrophil accumulation
and accelerated wound healing compared with vehicle. Next steps could include
testing CYR61 in additional wound models.
TARGET/MARKER/PATHWAY: Cysteine-rich angiogenic
inducer 61 (CYR61; CCN1)
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Jun, J.-I. et al. Nat. Commun.;
published online June 16, 2015
doi:10.1038/ncomms8386
CONTACT: Lester F. Lau, University of Illinois at Chicago,
Chicago, Ill.
e-mail: lflau@uic.edu
DERMATOLOGY
INDICATION: Obesity
Cell culture and mouse studies suggest inhibiting DJ-1 could help treat obesity. In
mice, a high-fat diet increased muscle levels of DJ-1 mRNA compared with a normal
diet. In cultured mouse myoblasts, siRNA targeting DJ-1 increased levels of reactive
oxygen species (ROS), mitochondrial uncoupling and expression of glycolysis genes
and decreased respiration compared with a scrambled siRNA. In a mouse model of
obesity, DJ-1 knockout decreased body weight, adipocyte size and blood glucose
levels compared with normal DJ-1 expression. Next steps could include screening
for small molecule DJ-1 inhibitors.
TARGET/MARKER/PATHWAY: DJ-1 (PARK7)
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Shi, S. et al. Nat. Commun.;
published online June 16, 2015
doi:10.1038/ncomms8415
CONTACT: Minna Woo, University of Toronto, Toronto,
Ontario
e-mail: mwoo@uhnresearch.ca
ENDOCRINE / METABOLIC
17. PRODUCT R&D
TARGETS & MECHANISMS
TOOLS & TECHNIQUES
17 August 6, 2015 TOC
DISTILLERY
THERAPEUTICS
INDICATION: Chikungunya virus
Cell culture and mouse studies suggest broadly neutralizing antibodies (bNAbs)
against the E2 protein component of CHIKVgp2 could help prevent or treat
Chikungunya viral infection. Screening of 30 transformed B cell lines derived from
a patient who had recovered from Chikungunya viral infection identified six bNAbs
against the E2 protein that each neutralized three different Chikungunya viral
strains with EC50
values of less than 10 nM. In a mouse model of lethal Chikungunya
infection, pretreatment or treatment with one of the bNAbs prevented death
in 100% of mice, whereas all mice pretreated or treated with a control antibody
against West Nile virus died. Also in the mouse model, pretreatment with a second
bNAb from the patient or treatment with a third bNAb prevented death in all mice.
Next steps could include testing the bNAbs in non-human primate models of
Chikungunya viral infection.
TARGET/MARKER/PATHWAY: Chikungunya virus
structural polyprotein (CHIKVgp2)
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Smith, S. et al. Cell Host Microbe;
published online July 8, 2015
doi:10.1016/j.chom.2015.06.009
CONTACT: James E. Crowe, Jr., Vanderbilt University
Medical Center, Vanderbilt University, Nashville, Tenn.
e-mail: james.crowe@vanderbilt.edu
INFECTIOUS DISEASE
INDICATION: Coronavirus
Studies in cell lines and mice identified two mAbs that could help prevent or treat
Middle East respiratory syndrome coronaviral (MERS-CoV) infection. Screening of
antibodies from the spleens of chimeric mice immunized with DNA encoding the
MERS-CoV coronavirus S protein identified two mAbs, REGN3051 and REGN3048,
that bound the protein with Kd
values of 43 and 48 pM, respectively. In a mammalian
epithelial cell line, the mAbs inhibited growth of MERS-CoV with IC50
values
of 0.46 and 0.18 nM, respectively. In a humanized mouse model of MERS-CoV
infection, pretreatment with either mAb decreased interstitial lung inflammation
and decreased MERS-CoV RNA levels in the lungs and treatment with either mAb
decreased viral burden in the lungs compared with a control human IgG1 antibody.
Next steps include testing the mAbs in additional models of MERS-CoV infection.
TARGET/MARKER/PATHWAY: Coronavirus S protein
LICENSING STATUS: Patent and licensing status
undisclosed
PUBLICATION DETAILS: Pascal, K. et al. Proc. Natl. Acad.
Sci. USA; published online June 29, 2015
doi:10.1073/pnas.1510830112
CONTACT: Christos A. Kyratsous, Regeneron
Pharmaceuticals Inc., Tarrytown, N.Y.
e-mail: christos.kyratsous@regeneron.com
CONTACT: George D. Yancopoulos, same affiliation as
above
e-mail: george@regeneron.com
INDICATION: HIV / AIDS
Studies in patient samples suggest didehydro-cortistatin A (dCA), an inhibitor
of tat-mediated transcription, could help prevent HIV rebound after cessation of
antiretroviral therapy (ART). In HIV patient-derived CD4+
T cells harboring latent
HIV, co-treatment with dCA and ART followed by ART cessation decreased viral
rebound by 93.5% and 93.1%, respectively, compared with ART treatment alone,
and decreased subsequent viral reactivation by the protein kinase C (PKC) activator
prostratin by 99.9%. Next steps include testing dCA in humanized mouse models
of HIV infection and non-human primate models of SIV infection. (See Cover Story)
TARGET/MARKER/PATHWAY: HIV Tat protein (HIV Tat)
LICENSING STATUS: Patented; available for partnering
PUBLICATION DETAILS: Mousseau, G. et al. mBio;
published online July 7, 2015
doi:10.1128/mBio.00465-15
CONTACT: Susana T. Valente, The Scripps Research
Institute, Jupiter, Fla.
e-mail: svalente@scripps.edu
18. PRODUCT R&D
TARGETS & MECHANISMS
TOOLS & TECHNIQUES
18 August 6, 2015 TOC
DISTILLERY
THERAPEUTICS
INDICATION: Pulmonary fibrosis
Mouse studies suggest activating DC-SIGN could help treat pulmonary fibrosis
and other fibrotic diseases. In a mouse model of acute lung inflammation, a small
molecule activator of DC-SIGN decreased neutrophil accumulation in the lungs
and numbers of macrophages and other immune cells in bronchoalveolar lavage
compared with vehicle. In a mouse model of pulmonary fibrosis, the activator
decreased immune cell accumulation and collagen deposition in the lungs by
increasing levels of the anti-inflammatory cytokine interleukin-10 (IL-10) compared
with vehicle. Next steps include optimizing small molecules and antibodies that
activate DC-SIGN for use in human studies.
TARGET/MARKER/PATHWAY: Dendritic cell-specific
ICAM-3 grabbing nonintegrin (DC-SIGN; CD209)
LICENSING STATUS: Patent applications filed; available
for licensing
PUBLICATION DETAILS: Cox, N. et al. Proc. Natl. Acad. Sci.
USA; published online June 23, 2015
doi:10.1073/pnas.1500956112
CONTACT: Richard H. Gomer, Texas A&M University,
College Station, Texas
e-mail: rgomer@tamu.edu
PULMONARY
INDICATION: Renal damage
Mouse and human sample studies suggest inhibiting IL-34 could help prevent
kidney damage following ischemia/reperfusion injury. In kidney samples from
kidney transplant patients, renal levels of IL-34 were higher in rejected kidneys
than in engrafted kidneys. In a mouse model of ischemia/reperfusion-induced
kidney injury, IL-34 levels were higher in the kidney after reperfusion than before
reperfusion. Also in the model, IL-34 knockout decreased tubular atrophy and
intrarenal macrophage infiltration compared with normal IL-34 expression. Next
steps include targeting IL-34 pharmacologically in models of ischemia/reperfusion-
induced renal injury.
TARGET/MARKER/PATHWAY: Interleukin-34 (IL-34)
LICENSING STATUS: Patent application filed; licensing
status undisclosed
PUBLICATION DETAILS: Baek, J.-H. et al. J. Clin. Invest.;
published online June 29, 2015
doi:10.1172/JCI81166
CONTACT: Vicki R. Kelley, Harvard Institute of Medicine,
Boston, Mass.
e-mail: vkelley@rics.bwh.harvard.edu
RENAL
INDICATION: Tissue replacement
Mouse studies suggest whole-body irradiation plus transplantation of canalicular-
stage fetal lung cells could help regenerate lung tissue after injury. In a mouse model
of chemically induced lung injury, IV transplant of mouse fetal lung cells from the
canalicular stage (days 15-16) increased multilineage engraftment compared with
transplant of mouse fetal lung cells from earlier stages of development. In the
models receiving the canalicular-stage cells, total body irradiation prior to transplant
decreased host lung cell proliferation and increased engraftment of transplants
compared with no irradiation. Next steps include testing the combination of
irradiation and canalicular-stage fetal lung cell transplant in mouse models of cystic
fibrosis (CF).
TARGET/MARKER/PATHWAY: Not applicable
LICENSING STATUS: Patent application filed; licensing
status undisclosed
PUBLICATION DETAILS: Rosen, C. et al. Nat. Med.;
published online July 13, 2015
doi:10.1038/nm.3889
CONTACT: Yair Reisner, Weizmann Institute of Science,
Rehovot, Israel
e-mail: Yair.Reisner@weizmann.ac.il
TRANSPLANT
19. PRODUCT R&D
TARGETS & MECHANISMS
TOOLS & TECHNIQUES
19 August 6, 2015 TOC
DISTILLERY
TECHNIQUES
TECHNOLOGY: Cellular assays
A drug-eluting microarray could help screen patient-derived CSCs for responses
to cancer therapeutics. The microarray plate contains hundreds of silane-grafted
polymer islands, each of which can be loaded with a different concentration or
combination of chemotherapies, with another polymer spotted onto each island to
promote adhesion of sample cells. Seeding the plate with cell samples resulted in
adherence of about 200 cells per island, a sufficient number for analysis of CSCs. On
a drug-eluting microarray loaded with different concentrations and combinations of
two chemotherapies — the generic topoisomerase I (TOP1) inhibitor camptothecin
and an Mdm2 p53 binding protein homolog (MDM2; HDM2) inhibitor — CSCs
isolated from two colon cancer patients gave unique response profiles. Next steps
could include validating the technology in a larger cohort of cancer patients.
DESCRIPTION: Drug-eluting microarrays for personalized
screening of cancer stem cell (CSC) response to cancer
therapies
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Carstens, M. et al. Proc. Natl.
Acad. Sci. USA; published online June 29, 2015
doi:10.1073/pnas.1505374112
CONTACT: Emina H. Huang, Cleveland Clinic, Cleveland,
Ohio
e-mail: huange2@ccf.org
CONTACT: Benjamin G. Keselowsky, University of Florida,
Gainesville, Fla.
e-mail: bkeselowsky@bme.ufl.edu
ASSAYS AND SCREENS
TECHNOLOGY: Proteomics
A cellular signature of clinically relevant signaling proteins could serve as a
prognostic marker in patients with AML. Treatment of a mixture of healthy and
leukemic cells from AML patients with a panel of 16 cytokines and kinase inhibitors,
followed by mass cytometric analysis of the expression and activation states of 14
AML-related signaling proteins, identified signaling signatures that corresponded to
the subpopulations of tumor-initiating primitive cells and mature leukemic cells. In
two independent cohorts totaling 242 adult AML patients, the tumor-initiating cell
signature correlated with poor survival. Next steps include applying the method to
additional cancers and to the characterization of drug-resistant cell populations.
DESCRIPTION: Signaling signature in leukemic cells as a
prognostic marker in acute myelogenous leukemia (AML)
LICENSING STATUS: Unpatented; unlicensed
PUBLICATION DETAILS: Levine, J. et al. Cell; published
online June 18, 2015
doi:10.1016/j.cell.2015.05.047
CONTACT: Garry P. Nolan, Stanford University, Stanford,
Calif.
e-mail: gnolan@stanford.edu
CONTACT: Dana Pe’er, Columbia University, New York,
N.Y.
e-mail: dpeer@biology.columbia.edu
BIOMARKERS
20. PRODUCT R&D
TARGETS & MECHANISMS
TOOLS & TECHNIQUES
20 August 6, 2015 TOC
DISTILLERY
TECHNIQUES
TECHNOLOGY: Animal models
Two mouse models with telomere dysfunction could help identify therapies to treat
IPF, which is associated with telomere damage. The mouse models were developed
by generating telomere dysfunction in one of two ways: inducible knockout of
telomeric repeat binding factor 1 (TERF1; PIN2) in alveolar cells; and systemic
knockout of telomerase reverse transcriptase (TERT) plus subtherapeutic doses
of bleomycin. The first method produced lung cell damage, pulmonary fibrosis,
poor survival and other features that recapitulated human IPF. The second method
produced pulmonary inflammation and fibrosis, impaired respiratory function and
markers of chronic pneumonia that also recapitulated human IPF. Next steps could
include using the models to screen for therapies to treat IPF.
DESCRIPTION: Two telomere dysfunction-driven mouse
models of idiopathic pulmonary fibrosis (IPF)
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Povedano, J. et al. Cell Rep.;
published online July 2, 2015
doi:10.1016/j.celrep.2015.06.028
CONTACT: Maria A. Blasco, Spanish National Cancer
Research Centre (CNIO), Madrid, Spain
e-mail: mblasco@cnio.es
DISEASE MODELS
TECHNOLOGY: Nanoparticles
Polymer-based mucus-penetrating nanoparticles could be used to deliver gene
therapy to the lungs. The PBAE-MPPs, composed of a combination of poly(β-amino
esters) (PBAE) and PEGylated PBAE, form a compact structure with plasmid DNA,
have a near-neutral surface charge to allow diffusion across the positively charged
pulmonary mucus barrier, and remain metabolically stable for in vivo delivery.
In normal mice, intratracheally administered PBAE-MPPs loaded with a green
fluorescent protein (GFP) transgene had better diffusion through the mucus barrier
and higher transgene expression in the total lung cell population than other GFP-
loaded nanoparticle formulations, and PBAE-MPP-mediated transgene expression
lasted for at least two months. Next steps include testing PBAE-MPPs as gene
therapy delivery vehicles in disease models.
DESCRIPTION: Lung-targeted gene therapy using
poly(β-amino esters)-based mucus-penetrating DNA
nanoparticles (PBAE-MPPs)
LICENSING STATUS: Patent application filed; licensing
status unavailable
PUBLICATION DETAILS: Mastorakos, P. et al. Proc. Natl.
Acad. Sci. USA; published online June 29, 2015
doi:10.1073/pnas.1502281112
CONTACT: Justin Hanes, The Johns Hopkins University
School of Medicine, Baltimore, Md.
e-mail: hanes@jhmi.edu
CONTACT: Jung Soo Suk, same affiliation as above
e-mail: jsuk@jhmi.edu
DRUG DELIVERY
TECHNOLOGY: Gene therapy
Chemically modified sgRNAs could enhance the efficiency of CRISPR-Cas9-
mediated gene editing. The modified sgRNAs had methylated phosphorothioate
or thiophosphonoacetate functional groups that made them more resistant to
nucleases and less immunostimulatory than conventional sgRNAs. In CRISPR-Cas9-
mediated editing of a human bone marrow cell line, modified sgRNAs targeting the
loci encoding interleukin-2 (IL-2) receptor γ chain (CD132; IL2RG), hemoglobin β
(HBB) or CC chemokine receptor 5 (CCR5; CD195) increased the frequency of on-
target genomic alterations compared with unmodified sgRNAs. In primary human T
cells and hematopoietic stem cells treated with either Cas9 mRNA or Cas9 protein,
the modified sgRNAs targeting the same three loci induced more on-target edits
than unmodified sgRNAs. Next steps include optimizing the modified sgRNAs for
gene-editing strategies to correct mutations in sickle cell disease, thalassemia, and
immunodeficiency.
DESCRIPTION: Modified single-guide RNAs (sgRNAs) to
enhance efficiency of CRISPR-CRISPR-associated protein
9 (Cas9)-mediated gene editing
LICENSING STATUS: Patent application filed; licensing
status undisclosed
PUBLICATION DETAILS: Hendel, A. et al. Nat. Biotechnol.;
published online June 29, 2015
doi:10.1038/nbt.3290
CONTACT: Laurakay Bruhn, Agilent Research
Laboratories, Santa Clara, Calif.
e-mail: laurakay_bruhn@agilent.com
CONTACT: Matthew H. Porteus, Stanford University,
Stanford, Calif.
e-mail: mporteus@stanford.edu
DRUG PLATFORMS