Silence Therapeutics' presentation to ASCO 2012 - American Society of Clinical Oncology - given 01st - 05th June 2012. It reveals the latest results of Silence's RNAi therapeutic Atu027.
For more information, please go to www.silence-therapeutics.com or www.twitter.com/rnaihub
The Role of Nrf2 in the Attenuation of Cardiovascular DiseaseLifeVantage
This document discusses the role of the transcription factor Nrf2 in attenuating cardiovascular disease through regulating antioxidant defenses. It begins by explaining how oxidative stress contributes to cardiovascular diseases and how early trials of antioxidant supplements were disappointing. It then describes how Nrf2 is the master regulator of cellular antioxidant defenses, regulating over 200 genes. Nrf2 is normally bound by Keap1 in the cytoplasm and targeted for degradation, but oxidative stress or phytochemicals can activate Nrf2 by modifying Keap1 or through kinase signaling. Activated Nrf2 upregulates antioxidant enzymes and other genes to maintain redox homeostasis and protect against disease. Exercise and certain phytochemicals are highlighted as potential ways to activate Nrf2 and attenu
1. The document describes a study on using vitamin E TPGS-emulsified PLGA nanoparticles as carriers for delivering paclitaxel to treat cardiovascular restenosis.
2. The nanoparticles were characterized and found to have higher drug encapsulation efficiency and cytotoxicity compared to PVA-emulsified nanoparticles in cellular studies.
3. The TPGS-emulsified PLGA nanoparticles showed potential for effective and sustainable delivery of antiproliferative drugs for developing nanoparticle-coated cardiovascular stents to prevent restenosis.
The document examines the effects of the TACE inhibitor BMS-561392 on APP processing both in vitro and in vivo. In cell cultures expressing APP, BMS-561392 reduced secretion of sAPPα without increasing Aβ production. Conversely, a BACE inhibitor decreased sAPPβ and Aβ without affecting sAPPα. In vivo infusion of BMS-561392 into mouse brains decreased sAPPα levels but did not significantly change steady-state Aβ levels. The findings suggest that under normal conditions, BACE and TACE do not compete for APP as a substrate, though they share localization in the trans-Golgi network. Inhibition of TACE may therefore reduce TNFα levels in
Acute and chronic hyperammonemia modulate antioxidantrkkoiri
1) The study examines the effects of acute and chronic hyperammonemia on antioxidant enzyme levels and oxidative damage in the cerebral cortex and cerebellum of rats.
2) Acute hyperammonemia decreased antioxidant enzyme levels in both brain regions but increased lipid peroxidation only in the cerebellum.
3) Chronic hyperammonemia increased antioxidant enzyme levels in the cerebral cortex but decreased levels in the cerebellum, suggesting the cerebellum is more susceptible to oxidative stress during chronic hyperammonemia.
Presentation given at the 11th Annual Biotech in Europe Investor Forum 13-14 September 2011 in Zurich by Thomas Christély. Chief Operating Officer of Silence Therapeutics. Silence Therapeutics is involved in the development and delivery of RNAi therapeutics for the treatment of serious diseases, such as lung cancer.
This presentation outlines the history and recent developments of Silence Therapeutics, a biopharmaceutical company developing novel therapeutics based on RNA interference. Silence Therapeutics is a world leader in the discovery, development and delivery of novel RNA interference (RNAi) therapeutics for the treatment of serious diseases.
With an experienced team leading pharmaceutical development, almost half of all on-going siRNA clinical trials are based on Silence technology. Find out more in the presentation or go to the website www.silence-therapeutics.com
“Comparability of biotherapeutic products following manufacturing process improvement. Quality aspects and comparability issues”
Focuses on improvements in manufacturing processes of biotherapeutics
The Role of Nrf2 in the Attenuation of Cardiovascular DiseaseLifeVantage
This document discusses the role of the transcription factor Nrf2 in attenuating cardiovascular disease through regulating antioxidant defenses. It begins by explaining how oxidative stress contributes to cardiovascular diseases and how early trials of antioxidant supplements were disappointing. It then describes how Nrf2 is the master regulator of cellular antioxidant defenses, regulating over 200 genes. Nrf2 is normally bound by Keap1 in the cytoplasm and targeted for degradation, but oxidative stress or phytochemicals can activate Nrf2 by modifying Keap1 or through kinase signaling. Activated Nrf2 upregulates antioxidant enzymes and other genes to maintain redox homeostasis and protect against disease. Exercise and certain phytochemicals are highlighted as potential ways to activate Nrf2 and attenu
1. The document describes a study on using vitamin E TPGS-emulsified PLGA nanoparticles as carriers for delivering paclitaxel to treat cardiovascular restenosis.
2. The nanoparticles were characterized and found to have higher drug encapsulation efficiency and cytotoxicity compared to PVA-emulsified nanoparticles in cellular studies.
3. The TPGS-emulsified PLGA nanoparticles showed potential for effective and sustainable delivery of antiproliferative drugs for developing nanoparticle-coated cardiovascular stents to prevent restenosis.
The document examines the effects of the TACE inhibitor BMS-561392 on APP processing both in vitro and in vivo. In cell cultures expressing APP, BMS-561392 reduced secretion of sAPPα without increasing Aβ production. Conversely, a BACE inhibitor decreased sAPPβ and Aβ without affecting sAPPα. In vivo infusion of BMS-561392 into mouse brains decreased sAPPα levels but did not significantly change steady-state Aβ levels. The findings suggest that under normal conditions, BACE and TACE do not compete for APP as a substrate, though they share localization in the trans-Golgi network. Inhibition of TACE may therefore reduce TNFα levels in
Acute and chronic hyperammonemia modulate antioxidantrkkoiri
1) The study examines the effects of acute and chronic hyperammonemia on antioxidant enzyme levels and oxidative damage in the cerebral cortex and cerebellum of rats.
2) Acute hyperammonemia decreased antioxidant enzyme levels in both brain regions but increased lipid peroxidation only in the cerebellum.
3) Chronic hyperammonemia increased antioxidant enzyme levels in the cerebral cortex but decreased levels in the cerebellum, suggesting the cerebellum is more susceptible to oxidative stress during chronic hyperammonemia.
Presentation given at the 11th Annual Biotech in Europe Investor Forum 13-14 September 2011 in Zurich by Thomas Christély. Chief Operating Officer of Silence Therapeutics. Silence Therapeutics is involved in the development and delivery of RNAi therapeutics for the treatment of serious diseases, such as lung cancer.
This presentation outlines the history and recent developments of Silence Therapeutics, a biopharmaceutical company developing novel therapeutics based on RNA interference. Silence Therapeutics is a world leader in the discovery, development and delivery of novel RNA interference (RNAi) therapeutics for the treatment of serious diseases.
With an experienced team leading pharmaceutical development, almost half of all on-going siRNA clinical trials are based on Silence technology. Find out more in the presentation or go to the website www.silence-therapeutics.com
“Comparability of biotherapeutic products following manufacturing process improvement. Quality aspects and comparability issues”
Focuses on improvements in manufacturing processes of biotherapeutics
Edward T. Hall was a social anthropologist who studied nonverbal communication. His research found that less than 35% of social meanings in a conversation are conveyed through words, while at least 65% are transmitted nonverbally. Facial expressions and the eyes are particularly important for silent communication and can express feelings like fear, anger, sadness, surprise, and happiness. The face is an important indicator of one's mind and inner state. Being aware of nonverbal cues can help avoid misunderstandings during interpersonal interactions.
The Power of Silence in Interpersonal CommunicationMark Montiel
The document discusses different aspects of silence including as a means of communication, miscommunication, and its positive and negative values across cultures. It explores how silence can carry meaning in communication and discourse. It also examines the power of pausing and how different pause times can convey different meanings. Finally, the document looks at the value of silence in Japanese culture and how it relates to concepts of inner and outer truth.
This document summarizes Elisabeth Noelle-Neumann's Spiral of Silence theory, which proposes that individuals are less likely to voice unpopular opinions due to a fear of isolation. It describes the "quasi-statistical organ" that allows people to sense public opinion. Research methods like surveys on optimism and the hypothetical "train/plane test" are discussed. Criticisms of Noelle-Neumann's assumptions and reliance on hypothetical scenarios over observations are also presented.
The Spiral of Silence Theory argues that individuals are less likely to express opinions that they believe are unpopular for fear of isolation. People perceive the majority opinion through mass media. This theory is relevant to studying public opinion, interpersonal communication, and the influence of mass media. However, questions remain about whether the theory applies universally or is culture-specific, and whether fear of isolation is the primary factor in willingness to express opinions.
Conversation analysis (CA) is a method that studies how people organize and accomplish social interaction through talk-in-interaction. It examines recordings of real-life conversations to understand rules and practices from an interactional perspective. CA focuses on features like turn-taking, sequence organization through question-answer pairs, and repair when problems arise. Recordings are transcribed with notation to retain prosodic and sequential elements, allowing researchers to analyze how conversations are structured through turns and sequences of communicative actions.
The document discusses key aspects of conversation including turn-taking, adjacency pairs, speech acts and illocutionary acts. It provides examples of common adjacency pairs such as question-answer, request-granting, apology-acceptance. It also categorizes different types of speech acts such as assertives, directives, commissives, expressives and declarations. The document concludes with an example conversation analyzing it in terms of adjacency pairs and speech acts.
This document discusses neurotrophins and their potential and limitations for neuroprotection and neurorestoration. Specifically, it mentions NGF, BDNF, and neurturin. The main limitations are their poor bioavailability in target organs after systemic delivery and undesirable side effects from non-targeted central delivery. Potential solutions discussed include localized central delivery, surgical implants, targeted delivery, and gene therapy approaches. It also provides examples of specific neurotrophin delivery clinical trials like CERE-110 for NGF delivery and CERE-120 for neurturin delivery.
Circumventing Traditional Bottlenecks In Glioblastoma...Melanie Smith
This study investigated whether the nonstructural protein 2B of human rhinovirus 16 (HRV16) induces an endoplasmic reticulum (ER) stress response. A HRV16 2B fusion protein with GFP was expressed in baby hamster kidney (BHK) cells. Results showed HRV16 2B induced high expression of the ER chaperone GRP78 in a time-dependent manner and activated the PERK-eIF2α signaling pathway, leading to increased expression of p-PERK, p-eIF2α, and CHOP. HRV16 2B decreased expression of p-IRE1 and ATF6 p50. This demonstrated for the first time that the PER
brief overview on oligonucleotide, oligonucleoside and its application in medicine. given the basic knowledge as well about the DNA and its composition.
Antisense therapy uses synthetic nucleic acid strands that bind to messenger RNA (mRNA) to inactivate genes and their protein production. It has potential applications for treating various diseases like cancer, diabetes, and genetic disorders. Antisense oligonucleotides work by binding to mRNA, preventing translation into protein via RNase H activity or steric hindrance. While promising, antisense drugs require further clinical trials to prove efficacy compared to other treatments.
The document provides an overview of the renin-angiotensin-aldosterone system (RAAS). It discusses the classical components of RAAS including renin, angiotensinogen, angiotensin peptides, angiotensin receptors, and angiotensin converting enzyme. It also covers newer concepts such as local tissue RAAS, intracellular RAAS, receptor heterodimerization, and the roles of angiotensin converting enzyme 2 and angiotensin (1-7). The document highlights functions of RAAS in various organs and pathophysiological processes.
Several Types of PROTACs Based On Nucleic AcidsDoriaFang
So far, more than 10 nucleic acid drugs have been approved for marketing worldwide, and many nucleic acid drugs are in the stage of clinical trials. Nucleic acid drugs are expected to become the third type of drugs after small molecule drugs and antibody drugs.
A randomised, placebo controlled trial of low level laser therapy for activat...FUAD HAZIME
This randomized controlled trial investigated whether low-level laser therapy (LLLT) has an anti-inflammatory effect on activated Achilles tendinitis. Seven patients with bilateral Achilles tendinitis received either active LLLT or placebo LLLT on their two tendons. Prostaglandin E2 (PGE2) concentrations, measured via microdialysis, were significantly reduced after active LLLT compared to placebo and pre-treatment levels, indicating LLLT's anti-inflammatory effect. Pressure pain threshold also increased more after active LLLT than placebo LLLT. The study demonstrates that LLLT can reduce inflammation and pain in activated Achilles tendinitis.
Introduction to Oligonucleotides and vaccinesMoremrunal
1) The document introduces oligonucleotides and vaccines, discussing their pharmacokinetics and pharmacodynamics. It covers topics like absorption, distribution, metabolism, and excretion of antisense oligonucleotides and vaccine antigens.
2) A case study demonstrates that treatment with an antisense oligonucleotide targeting SCN8A increased survival in mouse models of epileptic encephalopathies by inhibiting gene expression.
3) While the pharmacokinetics and pharmacodynamics of oligonucleotides and vaccines are not fully understood, studies indicate parenteral administration results in wide tissue distribution, with metabolism being a major elimination pathway.
This document discusses an in silico study that screened six compounds (IQ3, echothiophate, 15d-PGJ2, mefenamic acid, phentolamine, and nateglinide) against four protein targets related to Alzheimer's disease (AChE, beta-secretase 1, C-Jun N-terminal kinase-3, and peroxisome proliferator-activated receptor γ) using molecular docking. Pharmacokinetic properties were also analyzed using software. The results suggested that IQ3, nateglinide, phentolamine, and mefenamic acid strongly bound to the selected AD targets based on docking scores. No ligands violated Lipinski's rules and all
Antisense RNA technology involves introducing short oligonucleotides that are complementary to a target gene's mRNA, interrupting normal gene expression. This can partially or fully suppress protein production from the gene. Antisense RNA works by binding to the target mRNA, preventing translation into protein via mechanisms like RNaseH degradation. It has applications in cancer treatment, fruit ripening control in agriculture, and drug development by the pharmaceutical industry. Challenges include rapid degradation of antisense oligonucleotides inside cells, but chemical modifications now help overcome this. Antisense therapy is emerging as a potential tool for gene therapy and treatment of various diseases.
The Role Of G Protein Coupled ReceptorssAngela Hays
- G protein-coupled receptors (GPCRs) are seven transmembrane receptors located on cell surfaces that play an important role in intracellular signaling pathways and crucial physiological processes.
- When a ligand binds to a GPCR, it activates a heterotrimeric G protein within the cell. This leads to the production of second messengers like DAG and IP3, which mediate different cellular functions such as muscle contraction.
- The IP3 receptor releases intracellular calcium stores when bound by IP3, increasing cytosolic calcium levels and activating calcium-dependent signaling pathways.
Nanotechnology essentially restructures molecules to make materials lighter, stronger, more penetrating or absorbant, among many innovative qualities. In cancer research, it offers a unique opportunity to study and interact with normal and cancer cells in real time, at the molecular and cellular scales, and during the various stages of the cancer process. For cancer researchers, a special interest lies in ligand-targeted therapeutic nanoparticles (TNP), which are expected to selectively deliver drugs and especially cytotoxic agents specifically to tumor cells and enhance intracellular drug accumulation. Targeting can be achieved by various mechanisms. For example, nanoparticles with numerous targeting ligands can provide multi-valent binding to the surface of tumor cells with high receptor density (as opposed to low receptor density on normal cells) or nanoparticle agents can enhance permeability and retention (EPR) effect to exit blood vessels in the tumor, to target surface receptors on tumor cells, and to enter tumor cells by endocytosis before releasing their drug payloads.
In this presentation we shall look at nanotechnology in drug development with a focus on anticancers and the advantages of nanoparticles as therapeutic platform technology. Approved nanotech based drugs and their clinical trials will be discussed. Two specific clinical trial case studies will be focused on along at some length with a mention of some ongoing clinical trials of nanotherapeutics. We shall also take a look at the future direction of nanotechnology based therapeutics.
"Bioluminescent Imaging of Histidyl-Transfer RNA Synthetase-Induced Myositis ...Nicholas Young
My talk from the American College of Rheumatology Meeting in Boston, MA, November 14-19, 2014: • "Bioluminescent Imaging of Histidyl-Transfer RNA Synthetase-Induced Myositis Reveals Early-Phase Involvement of NF-kB-Mediated Inflammation".
The document discusses CD117, a membrane tyrosine kinase receptor located on chromosome 4. It has an extracellular domain containing 5 Ig-like domains involved in binding to stem cell factor. The transmembrane region connects to a juxtamembrane domain and tyrosine kinase domain. CD117 plays an important role in stem cell proliferation and differentiation.
Antibody–Oligonucleotide Conjugates (AOCs) in Clinical Trials.pdfDoriaFang
Summary of Antibody–Oligonucleotide Conjugates(AOCs) in Clinical Trials, including products from Avidity Biosciences, Dyne Therapeutics, Tallac Therapeutics and Denali Therapeutics.
This document discusses immunotherapy strategies for metastatic renal cell carcinoma (RCC), including cytokines like interleukin-2 (IL-2) and interferon-α (IFN-α). It finds that high-dose IL-2 produces durable responses in a small percentage of selected patients, while IFN-α provides a modest survival benefit. Combining cytokines with targeted therapies may improve outcomes compared to cytokine monotherapy. Biomarkers like carbonic anhydrase IX expression and histologic subtype may help predict which patients are most likely to benefit from IL-2 therapy. Ongoing research aims to better select patients for IL-2 and explore combination therapies and novel immunotherapies to optimize treatment of metastatic RCC.
Edward T. Hall was a social anthropologist who studied nonverbal communication. His research found that less than 35% of social meanings in a conversation are conveyed through words, while at least 65% are transmitted nonverbally. Facial expressions and the eyes are particularly important for silent communication and can express feelings like fear, anger, sadness, surprise, and happiness. The face is an important indicator of one's mind and inner state. Being aware of nonverbal cues can help avoid misunderstandings during interpersonal interactions.
The Power of Silence in Interpersonal CommunicationMark Montiel
The document discusses different aspects of silence including as a means of communication, miscommunication, and its positive and negative values across cultures. It explores how silence can carry meaning in communication and discourse. It also examines the power of pausing and how different pause times can convey different meanings. Finally, the document looks at the value of silence in Japanese culture and how it relates to concepts of inner and outer truth.
This document summarizes Elisabeth Noelle-Neumann's Spiral of Silence theory, which proposes that individuals are less likely to voice unpopular opinions due to a fear of isolation. It describes the "quasi-statistical organ" that allows people to sense public opinion. Research methods like surveys on optimism and the hypothetical "train/plane test" are discussed. Criticisms of Noelle-Neumann's assumptions and reliance on hypothetical scenarios over observations are also presented.
The Spiral of Silence Theory argues that individuals are less likely to express opinions that they believe are unpopular for fear of isolation. People perceive the majority opinion through mass media. This theory is relevant to studying public opinion, interpersonal communication, and the influence of mass media. However, questions remain about whether the theory applies universally or is culture-specific, and whether fear of isolation is the primary factor in willingness to express opinions.
Conversation analysis (CA) is a method that studies how people organize and accomplish social interaction through talk-in-interaction. It examines recordings of real-life conversations to understand rules and practices from an interactional perspective. CA focuses on features like turn-taking, sequence organization through question-answer pairs, and repair when problems arise. Recordings are transcribed with notation to retain prosodic and sequential elements, allowing researchers to analyze how conversations are structured through turns and sequences of communicative actions.
The document discusses key aspects of conversation including turn-taking, adjacency pairs, speech acts and illocutionary acts. It provides examples of common adjacency pairs such as question-answer, request-granting, apology-acceptance. It also categorizes different types of speech acts such as assertives, directives, commissives, expressives and declarations. The document concludes with an example conversation analyzing it in terms of adjacency pairs and speech acts.
This document discusses neurotrophins and their potential and limitations for neuroprotection and neurorestoration. Specifically, it mentions NGF, BDNF, and neurturin. The main limitations are their poor bioavailability in target organs after systemic delivery and undesirable side effects from non-targeted central delivery. Potential solutions discussed include localized central delivery, surgical implants, targeted delivery, and gene therapy approaches. It also provides examples of specific neurotrophin delivery clinical trials like CERE-110 for NGF delivery and CERE-120 for neurturin delivery.
Circumventing Traditional Bottlenecks In Glioblastoma...Melanie Smith
This study investigated whether the nonstructural protein 2B of human rhinovirus 16 (HRV16) induces an endoplasmic reticulum (ER) stress response. A HRV16 2B fusion protein with GFP was expressed in baby hamster kidney (BHK) cells. Results showed HRV16 2B induced high expression of the ER chaperone GRP78 in a time-dependent manner and activated the PERK-eIF2α signaling pathway, leading to increased expression of p-PERK, p-eIF2α, and CHOP. HRV16 2B decreased expression of p-IRE1 and ATF6 p50. This demonstrated for the first time that the PER
brief overview on oligonucleotide, oligonucleoside and its application in medicine. given the basic knowledge as well about the DNA and its composition.
Antisense therapy uses synthetic nucleic acid strands that bind to messenger RNA (mRNA) to inactivate genes and their protein production. It has potential applications for treating various diseases like cancer, diabetes, and genetic disorders. Antisense oligonucleotides work by binding to mRNA, preventing translation into protein via RNase H activity or steric hindrance. While promising, antisense drugs require further clinical trials to prove efficacy compared to other treatments.
The document provides an overview of the renin-angiotensin-aldosterone system (RAAS). It discusses the classical components of RAAS including renin, angiotensinogen, angiotensin peptides, angiotensin receptors, and angiotensin converting enzyme. It also covers newer concepts such as local tissue RAAS, intracellular RAAS, receptor heterodimerization, and the roles of angiotensin converting enzyme 2 and angiotensin (1-7). The document highlights functions of RAAS in various organs and pathophysiological processes.
Several Types of PROTACs Based On Nucleic AcidsDoriaFang
So far, more than 10 nucleic acid drugs have been approved for marketing worldwide, and many nucleic acid drugs are in the stage of clinical trials. Nucleic acid drugs are expected to become the third type of drugs after small molecule drugs and antibody drugs.
A randomised, placebo controlled trial of low level laser therapy for activat...FUAD HAZIME
This randomized controlled trial investigated whether low-level laser therapy (LLLT) has an anti-inflammatory effect on activated Achilles tendinitis. Seven patients with bilateral Achilles tendinitis received either active LLLT or placebo LLLT on their two tendons. Prostaglandin E2 (PGE2) concentrations, measured via microdialysis, were significantly reduced after active LLLT compared to placebo and pre-treatment levels, indicating LLLT's anti-inflammatory effect. Pressure pain threshold also increased more after active LLLT than placebo LLLT. The study demonstrates that LLLT can reduce inflammation and pain in activated Achilles tendinitis.
Introduction to Oligonucleotides and vaccinesMoremrunal
1) The document introduces oligonucleotides and vaccines, discussing their pharmacokinetics and pharmacodynamics. It covers topics like absorption, distribution, metabolism, and excretion of antisense oligonucleotides and vaccine antigens.
2) A case study demonstrates that treatment with an antisense oligonucleotide targeting SCN8A increased survival in mouse models of epileptic encephalopathies by inhibiting gene expression.
3) While the pharmacokinetics and pharmacodynamics of oligonucleotides and vaccines are not fully understood, studies indicate parenteral administration results in wide tissue distribution, with metabolism being a major elimination pathway.
This document discusses an in silico study that screened six compounds (IQ3, echothiophate, 15d-PGJ2, mefenamic acid, phentolamine, and nateglinide) against four protein targets related to Alzheimer's disease (AChE, beta-secretase 1, C-Jun N-terminal kinase-3, and peroxisome proliferator-activated receptor γ) using molecular docking. Pharmacokinetic properties were also analyzed using software. The results suggested that IQ3, nateglinide, phentolamine, and mefenamic acid strongly bound to the selected AD targets based on docking scores. No ligands violated Lipinski's rules and all
Antisense RNA technology involves introducing short oligonucleotides that are complementary to a target gene's mRNA, interrupting normal gene expression. This can partially or fully suppress protein production from the gene. Antisense RNA works by binding to the target mRNA, preventing translation into protein via mechanisms like RNaseH degradation. It has applications in cancer treatment, fruit ripening control in agriculture, and drug development by the pharmaceutical industry. Challenges include rapid degradation of antisense oligonucleotides inside cells, but chemical modifications now help overcome this. Antisense therapy is emerging as a potential tool for gene therapy and treatment of various diseases.
The Role Of G Protein Coupled ReceptorssAngela Hays
- G protein-coupled receptors (GPCRs) are seven transmembrane receptors located on cell surfaces that play an important role in intracellular signaling pathways and crucial physiological processes.
- When a ligand binds to a GPCR, it activates a heterotrimeric G protein within the cell. This leads to the production of second messengers like DAG and IP3, which mediate different cellular functions such as muscle contraction.
- The IP3 receptor releases intracellular calcium stores when bound by IP3, increasing cytosolic calcium levels and activating calcium-dependent signaling pathways.
Nanotechnology essentially restructures molecules to make materials lighter, stronger, more penetrating or absorbant, among many innovative qualities. In cancer research, it offers a unique opportunity to study and interact with normal and cancer cells in real time, at the molecular and cellular scales, and during the various stages of the cancer process. For cancer researchers, a special interest lies in ligand-targeted therapeutic nanoparticles (TNP), which are expected to selectively deliver drugs and especially cytotoxic agents specifically to tumor cells and enhance intracellular drug accumulation. Targeting can be achieved by various mechanisms. For example, nanoparticles with numerous targeting ligands can provide multi-valent binding to the surface of tumor cells with high receptor density (as opposed to low receptor density on normal cells) or nanoparticle agents can enhance permeability and retention (EPR) effect to exit blood vessels in the tumor, to target surface receptors on tumor cells, and to enter tumor cells by endocytosis before releasing their drug payloads.
In this presentation we shall look at nanotechnology in drug development with a focus on anticancers and the advantages of nanoparticles as therapeutic platform technology. Approved nanotech based drugs and their clinical trials will be discussed. Two specific clinical trial case studies will be focused on along at some length with a mention of some ongoing clinical trials of nanotherapeutics. We shall also take a look at the future direction of nanotechnology based therapeutics.
"Bioluminescent Imaging of Histidyl-Transfer RNA Synthetase-Induced Myositis ...Nicholas Young
My talk from the American College of Rheumatology Meeting in Boston, MA, November 14-19, 2014: • "Bioluminescent Imaging of Histidyl-Transfer RNA Synthetase-Induced Myositis Reveals Early-Phase Involvement of NF-kB-Mediated Inflammation".
The document discusses CD117, a membrane tyrosine kinase receptor located on chromosome 4. It has an extracellular domain containing 5 Ig-like domains involved in binding to stem cell factor. The transmembrane region connects to a juxtamembrane domain and tyrosine kinase domain. CD117 plays an important role in stem cell proliferation and differentiation.
Antibody–Oligonucleotide Conjugates (AOCs) in Clinical Trials.pdfDoriaFang
Summary of Antibody–Oligonucleotide Conjugates(AOCs) in Clinical Trials, including products from Avidity Biosciences, Dyne Therapeutics, Tallac Therapeutics and Denali Therapeutics.
This document discusses immunotherapy strategies for metastatic renal cell carcinoma (RCC), including cytokines like interleukin-2 (IL-2) and interferon-α (IFN-α). It finds that high-dose IL-2 produces durable responses in a small percentage of selected patients, while IFN-α provides a modest survival benefit. Combining cytokines with targeted therapies may improve outcomes compared to cytokine monotherapy. Biomarkers like carbonic anhydrase IX expression and histologic subtype may help predict which patients are most likely to benefit from IL-2 therapy. Ongoing research aims to better select patients for IL-2 and explore combination therapies and novel immunotherapies to optimize treatment of metastatic RCC.
T.W. presents with signs and symptoms consistent with rheumatoid arthritis (RA), including morning stiffness lasting hours, fatigue, joint pain, and swelling in the hands and feet. Examination finds symmetrical swelling and tenderness in the small joints of the hands and feet. Laboratory tests show elevated ESR and CRP, positive RF and anti-CCP, and mild anemia. Radiographs show soft tissue swelling, joint space narrowing, and bone erosions in the hands. These findings meet criteria for a diagnosis of RA and help assess disease activity and response to treatment over time.
1) The combination of the HDAC inhibitor entinostat and anti-PD-1 antibody significantly inhibited tumor growth in a murine renal cell carcinoma model more than either treatment alone.
2) Analysis of the tumor microenvironment showed the combination increased CD8+ T cells and decreased regulatory T cells, resulting in an increased CD8+/Treg ratio.
3) The combination also increased two subsets of myeloid-derived suppressor cells in the tumor and altered tumor-associated macrophages and CD8+ T cells, indicating changes to the immune cell populations in the microenvironment.
Bioanalytical support plays a vital role during the lead optimization stages. The major goal of the bioanalysis is to assess the over-all ADME characteristics of the NCEs and biologics. Bioanalytical tools can play a significant role and impact the progress in drug discovery and development. Dramatic increases in investments in new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and ADC, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME and PK properties.https://www.medicilon.com/blog/featured-stories/dmpk-bioanalysis/
Proteasome inhibitors in treatment of multiple myelomaAlok Gupta
This document summarizes the development of the proteasome inhibitor bortezomib, including its mechanism of action, clinical trials, safety profile, and peripheral neuropathy issues. Key findings include:
- Bortezomib is a reversible inhibitor of the proteasome's chymotrypsin-like activity and was found to induce apoptosis in cancer cells.
- Phase I and II clinical trials demonstrated efficacy in hematological malignancies like multiple myeloma with a tolerable safety profile.
- Peripheral neuropathy is a common side effect that can often improve after stopping treatment.
- Further research aimed to improve response rates, overcome resistance, expand use to solid tumors, and address neuropathy issues.
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Ivanti’s Patch Tuesday breakdown goes beyond patching your applications and brings you the intelligence and guidance needed to prioritize where to focus your attention first. Catch early analysis on our Ivanti blog, then join industry expert Chris Goettl for the Patch Tuesday Webinar Event. There we’ll do a deep dive into each of the bulletins and give guidance on the risks associated with the newly-identified vulnerabilities.
How to Interpret Trends in the Kalyan Rajdhani Mix Chart.pdfChart Kalyan
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Skybuffer AI: Advanced Conversational and Generative AI Solution on SAP Busin...Tatiana Kojar
Skybuffer AI, built on the robust SAP Business Technology Platform (SAP BTP), is the latest and most advanced version of our AI development, reaffirming our commitment to delivering top-tier AI solutions. Skybuffer AI harnesses all the innovative capabilities of the SAP BTP in the AI domain, from Conversational AI to cutting-edge Generative AI and Retrieval-Augmented Generation (RAG). It also helps SAP customers safeguard their investments into SAP Conversational AI and ensure a seamless, one-click transition to SAP Business AI.
With Skybuffer AI, various AI models can be integrated into a single communication channel such as Microsoft Teams. This integration empowers business users with insights drawn from SAP backend systems, enterprise documents, and the expansive knowledge of Generative AI. And the best part of it is that it is all managed through our intuitive no-code Action Server interface, requiring no extensive coding knowledge and making the advanced AI accessible to more users.
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See how organizational priorities and strategic approaches to data security and privacy are evolving around the globe.
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Ocean Lotus cyber threat actors represent a sophisticated, persistent, and politically motivated group that poses a significant risk to organizations and individuals in the Southeast Asian region. Their continuous evolution and adaptability underscore the need for robust cybersecurity measures and international cooperation to identify and mitigate the threats posed by such advanced persistent threat groups.
Skybuffer SAM4U tool for SAP license adoptionTatiana Kojar
Manage and optimize your license adoption and consumption with SAM4U, an SAP free customer software asset management tool.
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A Comprehensive Guide to DeFi Development Services in 2024Intelisync
DeFi represents a paradigm shift in the financial industry. Instead of relying on traditional, centralized institutions like banks, DeFi leverages blockchain technology to create a decentralized network of financial services. This means that financial transactions can occur directly between parties, without intermediaries, using smart contracts on platforms like Ethereum.
In 2024, we are witnessing an explosion of new DeFi projects and protocols, each pushing the boundaries of what’s possible in finance.
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Ready to take your DeFi project to the next level? Partner with Intelisync for expert DeFi development services today!
Driving Business Innovation: Latest Generative AI Advancements & Success StorySafe Software
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During the hour, we’ll take you through:
Guest Speaker Segment with Hannah Barrington: Dive into the world of dynamic real estate marketing with Hannah, the Marketing Manager at Workspace Group. Hear firsthand how their team generates engaging descriptions for thousands of office units by integrating diverse data sources—from PDF floorplans to web pages—using FME transformers, like OpenAIVisionConnector and AnthropicVisionConnector. This use case will show you how GenAI can streamline content creation for marketing across the board.
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Custom AI Models: Discover how to leverage FME to build personalized AI models using your data. Whether it’s populating a model with local data for added security or integrating public AI tools, find out how FME facilitates a versatile and secure approach to AI.
We’ll wrap up with a live Q&A session where you can engage with our experts on your specific use cases, and learn more about optimizing your data workflows with AI.
This webinar is ideal for professionals seeking to harness the power of AI within their data management systems while ensuring high levels of customization and security. Whether you're a novice or an expert, gain actionable insights and strategies to elevate your data processes. Join us to see how FME and AI can revolutionize how you work with data!
2. Disclaimer
The statements made in this presentation may contain certain
forward-looking comments. Actual events or results may differ
from the Company’s expectations. In addition to the matters
described in the presentation, future actions by the European
Agency for Evaluation of Medicinal Products, the U.S. Food and
Drug Administration or equivalent regulatory authorities in
other countries and results of pending or future clinical trials, as
well as other risk factors outlined from time to time in the
Company ’ s regulatory filings, may affect actual results
achieved by the Company. The Alternative Investment Market
(AIM) has not reviewed and does not accept responsibility for
the adequacy or accuracy of this presentation.
3. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the vascular endothelium
Product Description
Atu027 is an siRNA in a liposomal formulation,
forming particles (siRNA-lipoplexes) which can
be administered systemically. Atu027 is
composed of four-components including a
chemically synthesized double-stranded
ribonucleotide (23-mer blunt-ended siRNA), a
cationic lipid, a neutral helperlipid and
PEGylated lipid, “lipoplexed” in isotonic
sucrose carrier. Atu027 produced as sterile
lyophilized concentrate for infusion solution RNAi mediated inhibition of PKN3
and becomes reconstituted by dilution with in non-human primates
isotonic Xylitol solution for application in the
clinic.
Further reading: The liposomal complex (siRNA-lipoplex) is exclusively taken up by endothelial cells of fairly all
vascular beds, delivering siRNAs functionally into the cytoplasm of these cells in vivo for
(1) Aleku et al. 2008. Atu027, a
liposomal small interfering RNA
degradation of the cognate PKN3-mRNA by an RNA interference mode of action. This
formulation targeting protein kinase pharmacodynamic effect was seen in monkeys at the dose of 0.3 mg/kg/q4d with a down-
N3, inhibits cancer progression. regulation of PKN3 mRNA in lung homogenates1,2. No effects on pulmonary or cardiovascular
Cancer Res. 68 (23): 9788-9798.
functions as well as central nervous function were observed. The non-clinical pharmacology was
(2) Santel et al.2010. Atu027 prevents evaluated in nude mice, rats and Cynomolgus monkeys after repeated i.v. administration. Safety
pulmonary metastasis in pharmacology studies were performed. The toxicology program comprised acute as well as
experimental and spontaneous mouse
metastasis models. repeated dose toxicology studies in rats and non-human primates and included a
Clin Cancer Res. 16 (22): 5469-5480. pharmacokinetic and distribution assessment. Genotoxicity and immunogenicity were addressed.
4. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the vascular endothelium
Control Rationale &
Mechanism of Action
PKN3 was found to be a novel
downstream target of PI-3 kinase.
Atu027 enables a systemic means
for RNAi mediated suppression of
PKN3 expression in the vascular
endothelium of both tumor and
tissue vasculatures1. This
particular spatial suppression of
Atu027
PKN3 ensues for some anti-tumor
activity but more profoundly
robust inhibition of both
lymphogenicas well as
hematogenous metastasis.
In particular, loss of PKN3 in vascular endothelial cells is likely to bloc intercellular barrier disruption
as well as pro-inflammatory cell activation. This kind of pharmacological modulation of the
endothelium makes blood vessels less susceptible for promoting successful cancer cell dissemination
and outgrowth during metastasis, rather than blocking tumor growth in the classical anti-angiogenic
manner of traditional anti-angiogenic drugs2. Therefore, Atu027 is destined for therapeutic support of
any anti-neoplastic drug (e.g. chemotherapy) in a combination regimen by addressing the stromal
compartment. In addition, it may act as single drug agent in an adjuvant setting for the prevention of
metastasis. Atu027 offers the opportunity of therapeutic intervention for all metastatic cancers.
5. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the vascular endothelium
Clinical status
Atu027 is currently being evaluated in a Phase-I trial in patients (first-in-man) with various
advanced or metastatic solid tumors. The trial is assessing the safety and tolerability in a dose-
escalating manner across ten dose levels, in order to determine a DLT and MTD. To date,
Atu027 has been administered in 34 patients as single and repeated i.v. infusions. The trial is
ongoing in the last (10th) dose-level and will be completed by mid-summer 2012.
Study Phase Study title Design Description
Atu027 Phase-I A prospective, open label, 1° Objective : DLT, MTD; PK
single-centre, dose (plasma siRNA conc.), PD
Dose-escalation finding phase I study with (biomarker), cytokine,
NCT009385 10 dose levels Atu027 (an siRNA complement
74 formulation) in subjects
Monotherapy with advanced solid 2° Clinical Response according
cancer “Atu027-I-01” to RECIST
6. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the vascular endothelium
Safety Event Outcome
The clinical safety, tolerability of the drug Serious 17 SAEs in 13 different patients
and potential biomarkers reflecting Adverse All SAEs judged unrelated to
Atu027 PD are being evaluated. As a Events Atu027 treatment
secondary objective the clinical response (SAEs)
is monitored according to RECIST
criteria. According to the clinical trial • Fatigue grade G1 (6pts),
protocol a dose-escalation over 11 levels • Hair loss G1 (2pts),
was designed and to date dosing of • Sweating G1 (1pt),
patients was completed up to dose level • Abdominal pain G2 (1pt).
10 (DL10). One dose limiting toxicity Adverse
occurred at dose level 10 (increase of Events AEs (G3) not considered DLT:
lipases, grade 3). Altogether, Atu027 was (AEs) - elevated Lipase (1pt, DL2)
very well tolerated and safe up to the 10th - diarrhea (1pt, DL5)
dose level. No premedication was needed
in support of Atu027 treatment. The AE (G3) considered DLT:
prospective/recommended MTD is at - elevated Lipase (1pt, DL10)
0.336 mg/kg. Sporadic observation of high
Cytokines values scattered across different
time points
Atu027-related transient
activation of the alternative
Complement
pathway of the complement
system (C3a, Bb, sC5b-9)
7. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the vascular endothelium
Clinical Parameter Comments
Atu027 was given to patients as a single 4h- No. Patients 34
infusion with subsequent follow-up for Breast (6), Pancreas CA (4),
three weeks. Patients were subsequently CUP (3), Gynecologic
treated twice weekly for additional four Cancers (Cervix&Ovarian,
weeks. In case of SD, patients were treated 3), Colon CA (4), Rectum
until PD. Dose escalation was associated Types of advanced
(2), Melanoma (2), NET
with assessment of toxicity, cancer
(2), Sarcoma (2), Prostate
pharmacokinetics (PK), and OncoMap CA (1), Liver & Cholangio
biomarker analyses in plasma from treated (No. Pts)
cellular cancer (1+1),
patients (pts). Kidney (1), Esophageal (2)
“Stable disease” response for three and six and Oropharyngeal
after months after treatment was observed in 10 Squamous CA (1)
and 3 pts, respectively. Two pts with Various chemo-therapies,
neuroendocrine cancer had disease Previous treatments Hormone therapy ,
stabilization for 9 and 12 months. Partial Immune therapy, Antibody,
before regression of pulmonary metastases was
found in 1 pt. Another patient with breast Stable disease/
11 pts (32%) at E.o.S./5 pts
cancer had regression of liver metastases. Compassionate use
8. Atu027- A liposomal siRNA-based inhibitor of PKN3 expression in
the vascular endothelium
Pharmacokinetic &
Pharmakodynamics
Treatment with Atu027 at DL8
(0.18 mg siRNA/kg) reaches the
plasma siRNA concentration
reflecting the dose sufficient to
trigger RNAi of PKN3 in
Cynomolgus non-human primates.
Robust reduction of soluble VEGF-
R1 (sFLT-1) levels was observed in
plasma samples from 8 out of 9
patients in DL6-9 after repeated
Atu027 treatment. The levels of
VEGF-R2 and VEGF-R1 were not
changed upon Atu027 treatment.
Therefore soluble VEGF-R1 might sFLT-1 ELISA with plasma from patients in DL6-9
serve as a biomarker.