This study examined the effects of cerium oxide nanoparticles (CeO2 NPs) on disease progression in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). The mice expressed a mutation in the SOD1 gene associated with familial ALS. Following disease onset, mice were given injections of either saline (control) or CeO2 NPs. Mice treated with CeO2 NPs showed improved motor performance and increased survival time, particularly female mice. The results suggest CeO2 NPs may be a potential treatment for slowing progression of ALS and other neurodegenerative diseases associated with oxidative stress.
Lucy Lin studied the DNA damage response in pluripotent stem cells and differentiated cells from subjects with Ataxia Telangiectasia (A-T). She found that in pluripotent cells, the ATR protein mediates the DNA damage response, while in differentiated cells the ATM protein mediates the response. This represents a switch from ATR-mediated response in pluripotent cells to ATM-mediated response once the cells differentiate. Future studies aim to understand the mechanism behind this switch and examine DNA damage response with ATM and ATR inhibition in pluripotent and differentiated cells.
This document summarizes research analyzing relationships between lysine ubiquitylation and acetylation sites in Arabidopsis thaliana proteins from proteomic datasets. The researchers compared ubiquitylation and acetylation sites identified in previous publications and found that 9 proteins experienced both post-translational modifications. Most of these proteins were located in energy-associated organelles, supporting the hypothesis that ubiquitylation and acetylation interactions could influence metabolic pathways. Future work is needed to identify more acetylation and ubiquitylation sites to better understand potential direct or indirect influences between the two modifications.
Als Paper & Prion Protein Gene Expressionjosephmdphysics
ALS is a degenerative neurological disease that causes motor neuron cell death leading to paralysis and death from respiratory failure. Free radicals, excess glutamate, calcium release, and genetic mutations contribute to motor neuron cell death. The disease progresses through corticomotor neuron death followed by spinal motor neuron denervation atrophy. Epidemiological studies show organophosphate pesticides and heavy metal exposures increase ALS risk by causing oxidative stress and gene imbalances that further damage cells. Electrophysiology shows abnormal cortical excitability occurs in sporadic ALS patients but not all genetic mutation cases, and excitability worsens with disease progression.
This document provides an overview of Huntington's disease (HD), comparing the motor and behavioral symptoms of adult-onset and juvenile HD. It discusses how HD is caused by an excessive repetition of CAG nucleotides on chromosome 4, which produces mutant huntingtin protein and leads to neurodegeneration of the striatum. While both forms share characteristics like chorea and behavioral abnormalities, juvenile HD tends to cause more severe symptoms like autism, learning problems, and spasticity. The document reviews several studies examining HD in animal models and humans.
This document summarizes research analyzing relationships between lysine ubiquitylation and acetylation sites from proteomic datasets in Arabidopsis thaliana proteins. The research compared ubiquitylation and acetylation sites identified in previous publications and found that 9 non-nuclear proteins experienced both post-translational modifications. Most of these proteins were located in energy-associated organelles. While this provides support for potential cross-talk between ubiquitylation and acetylation, more acetylation and ubiquitylation data is still needed to further investigate these relationships and whether acetylation directly or indirectly influences ubiquitylation.
1) Humans and mice lacking the alpha-galactosyltransferase (GALT/KO) gene express high levels of anti-Gal antibodies due to the absence of alpha-gal epitopes.
2) The study found that immunized GALT/KO mice had increased levels of anti-Gal antibodies compared to young GALT/KO mice, and the avidity and affinity of purified anti-Gal antibodies from mice and humans were similar.
3) Immunized GALT/KO mice that received heart transplants from GALT-expressing donors rejected the grafts within 2 hours through massive deposition of IgM and IgG antibodies and complement on endothelial cells, while non-immunized GALT/
This document discusses different types of mutations that can occur in DNA, including point mutations (substitutions, insertions, and deletions), frameshift mutations, chromosomal mutations, and the effects of mutagens. Point mutations involve a change to a single DNA base pair, while frameshift mutations alter the reading frame. Chromosomal mutations change the number or structure of chromosomes. Mutations can be harmful and cause genetic disorders or cancers, but can also occasionally provide beneficial new functions that help organisms adapt.
This study examined the effects of cerium oxide nanoparticles (CeO2 NPs) on disease progression in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). The mice expressed a mutation in the SOD1 gene associated with familial ALS. Following disease onset, mice were given injections of either saline (control) or CeO2 NPs. Mice treated with CeO2 NPs showed improved motor performance and increased survival time, particularly female mice. The results suggest CeO2 NPs may be a potential treatment for slowing progression of ALS and other neurodegenerative diseases associated with oxidative stress.
Lucy Lin studied the DNA damage response in pluripotent stem cells and differentiated cells from subjects with Ataxia Telangiectasia (A-T). She found that in pluripotent cells, the ATR protein mediates the DNA damage response, while in differentiated cells the ATM protein mediates the response. This represents a switch from ATR-mediated response in pluripotent cells to ATM-mediated response once the cells differentiate. Future studies aim to understand the mechanism behind this switch and examine DNA damage response with ATM and ATR inhibition in pluripotent and differentiated cells.
This document summarizes research analyzing relationships between lysine ubiquitylation and acetylation sites in Arabidopsis thaliana proteins from proteomic datasets. The researchers compared ubiquitylation and acetylation sites identified in previous publications and found that 9 proteins experienced both post-translational modifications. Most of these proteins were located in energy-associated organelles, supporting the hypothesis that ubiquitylation and acetylation interactions could influence metabolic pathways. Future work is needed to identify more acetylation and ubiquitylation sites to better understand potential direct or indirect influences between the two modifications.
Als Paper & Prion Protein Gene Expressionjosephmdphysics
ALS is a degenerative neurological disease that causes motor neuron cell death leading to paralysis and death from respiratory failure. Free radicals, excess glutamate, calcium release, and genetic mutations contribute to motor neuron cell death. The disease progresses through corticomotor neuron death followed by spinal motor neuron denervation atrophy. Epidemiological studies show organophosphate pesticides and heavy metal exposures increase ALS risk by causing oxidative stress and gene imbalances that further damage cells. Electrophysiology shows abnormal cortical excitability occurs in sporadic ALS patients but not all genetic mutation cases, and excitability worsens with disease progression.
This document provides an overview of Huntington's disease (HD), comparing the motor and behavioral symptoms of adult-onset and juvenile HD. It discusses how HD is caused by an excessive repetition of CAG nucleotides on chromosome 4, which produces mutant huntingtin protein and leads to neurodegeneration of the striatum. While both forms share characteristics like chorea and behavioral abnormalities, juvenile HD tends to cause more severe symptoms like autism, learning problems, and spasticity. The document reviews several studies examining HD in animal models and humans.
This document summarizes research analyzing relationships between lysine ubiquitylation and acetylation sites from proteomic datasets in Arabidopsis thaliana proteins. The research compared ubiquitylation and acetylation sites identified in previous publications and found that 9 non-nuclear proteins experienced both post-translational modifications. Most of these proteins were located in energy-associated organelles. While this provides support for potential cross-talk between ubiquitylation and acetylation, more acetylation and ubiquitylation data is still needed to further investigate these relationships and whether acetylation directly or indirectly influences ubiquitylation.
1) Humans and mice lacking the alpha-galactosyltransferase (GALT/KO) gene express high levels of anti-Gal antibodies due to the absence of alpha-gal epitopes.
2) The study found that immunized GALT/KO mice had increased levels of anti-Gal antibodies compared to young GALT/KO mice, and the avidity and affinity of purified anti-Gal antibodies from mice and humans were similar.
3) Immunized GALT/KO mice that received heart transplants from GALT-expressing donors rejected the grafts within 2 hours through massive deposition of IgM and IgG antibodies and complement on endothelial cells, while non-immunized GALT/
This document discusses different types of mutations that can occur in DNA, including point mutations (substitutions, insertions, and deletions), frameshift mutations, chromosomal mutations, and the effects of mutagens. Point mutations involve a change to a single DNA base pair, while frameshift mutations alter the reading frame. Chromosomal mutations change the number or structure of chromosomes. Mutations can be harmful and cause genetic disorders or cancers, but can also occasionally provide beneficial new functions that help organisms adapt.
1) A 42-year-old man suffered cardiac arrest due to an acute myocardial infarction (MI) and died after 10 days in the hospital. His lipid profile showed elevated total cholesterol and LDL cholesterol.
2) The genetic basis of MI risk involves both monogenic mutations that confer large effects and polygenic contributions from many common genetic variants. A polygenic risk score can identify individuals at high genetic risk of MI.
3) Statins provide greater reduction in MI risk for individuals at high genetic risk compared to average or low genetic risk individuals. Genetic profiling may help optimize prevention and treatment of MI.
History of Medical Cannabis - Dr. Jahan MarcuSafeAccess
The document summarizes research on the role of the endocannabinoid system and cannabinoid receptors CB1 and CB2 in bone formation and density. Studies show that mice lacking both CB1 and CB2 receptors have increased bone mass despite lower osteoblast proliferation. Targeting these receptors in cell studies alters signaling pathways involved in bone growth like ERK, SMAD, and AKT. This suggests cannabinoids influence bone morphogenic signaling and osteoblast function, providing a potential mechanism for the bone phenotype seen in receptor knockout mice. Future work involves using pathway inhibitors and gene expression analysis to further understand these effects.
This document provides an overview of mutations, which are heritable changes in genetic information that occur due to mistakes during DNA replication. There are two main types of mutations: gene mutations, which affect a single gene, and chromosomal mutations, which involve changes to whole chromosomes. Gene mutations include point mutations like substitutions, insertions, and deletions. Chromosomal mutations involve changes in chromosome number or structure. Mutations can have a variety of effects on genes and organisms, with some being harmful by disrupting gene function and others being beneficial by allowing organisms to adapt to new environments. Factors like environmental stressors and mutagenic chemicals can increase mutation rates.
Louis Stodieck, BioServe Space Technologies, University of Colorado at Boulder: "AMGEN Countermeasures for Bone and Muscle Loss in Space and on Earth." Presented at the 2013 International Space Station Research and Development Conference, http://www.astronautical.org/issrdc/2013.
Mutations are changes in genetic material that can result from errors during DNA replication or damage to DNA. There are two main types of mutations: chromosomal mutations and genetic mutations. Chromosomal mutations include deletions, duplications, inversions, and translocations that involve changes in chromosome structure. Genetic mutations are changes in DNA sequence, such as point mutations involving substitutions, insertions, or deletions of nucleotide bases. Insertion and deletion mutations tend to have the largest effects as they can alter multiple amino acids and proteins, while substitution mutations often have the smallest effects since only a single amino acid may change. Examples of diseases caused by mutations include sickle cell anemia from a substitution and Huntington's disease from an expansion insertion.
This study investigated the effects of a single early life seizure induced by kainic acid (KA-ELS) on hippocampal synaptic plasticity and glutamate receptor function in rats. The key findings were:
1) Enhanced long-term potentiation (LTP) was observed 7 days, but not 2 days, after KA-ELS compared to controls, indicating inappropriate enhancement of synaptic connections in the acute period following seizure.
2) α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptor desensitization was decreased 7 days after KA-ELS, despite no changes in AMPA receptor expression, phosphorylation, or membrane insertion.
This document describes a study that used exome sequencing to identify genetic causes of adult-onset mitochondrial diseases. The study sequenced the exomes of 8 patients with progressive external ophthalmoplegia (PEO) and identified novel variants in the RRM1 and TOP3A genes. Sanger sequencing confirmed the variants and identified a TOP3A variant (p.M100V) in another patient but not in 102 controls. The study concludes that RRM1 and TOP3A may cause mitochondrial disease but further work is needed to verify candidate genes and variants.
This document summarizes the findings of the REDOXS study, a randomized controlled trial that investigated the effects of high-dose glutamine and antioxidant supplementation in critically ill patients with multi-organ failure. The study found that glutamine supplementation was not beneficial and may have been harmful, increasing mortality. Subgroup analyses found the highest risk of harm with glutamine in patients who had renal dysfunction at enrollment. An updated meta-analysis of intravenous glutamine trials did not find an overall increase in mortality, though the REDOXS study results suggest glutamine could be harmful in certain critically ill populations such as those with renal failure.
1. Management of the neck in head and neck cancer involves addressing clinically negative (N0) and positive (N+) lymph nodes.
2. For N0 necks, elective neck dissection may decrease recurrence rates for high-risk primary sites. For N+ necks, selective neck dissection is adequate for early stage single node involvement without extracapsular spread.
3. Post-operative radiotherapy improves local control for N+ necks with adverse features like multiple nodes, extracapsular spread or positive margins. Concurrent chemoradiotherapy is preferred for advanced N2/N3 disease.
This document discusses autosomal disorders of mitochondrial DNA maintenance. It notes that these disorders involve defects in both the nuclear and mitochondrial genomes that can lead to tissue-specific oxidative phosphorylation defects and disease symptoms. Key points include:
1) Mutations in the POLG gene are a major cause of these disorders and can result in a broad spectrum of conditions from mild PEO to Alpers syndrome. Most POLG mutations are autosomal recessive.
2) Mutations in the PEO1 gene are a major cause of autosomal dominant PEO.
3) Mutations in the ANT1 gene are a relatively rare cause of autosomal dominant PEO.
Two case studies are described to illustrate POL
This document discusses autosomal disorders of mitochondrial DNA maintenance. It notes that these disorders involve defects in both the nuclear and mitochondrial genomes that can lead to tissue-specific oxidative phosphorylation defects and disease symptoms. Key points include:
1) Mutations in the POLG gene are a major cause of these disorders and can result in a broad spectrum of conditions from mild PEO to Alpers syndrome. Most POLG mutations are autosomal recessive.
2) Mutations in the PEO1 gene are a major cause of autosomal dominant PEO.
3) Mutations in the ANT1 gene are a relatively rare cause of autosomal dominant PEO.
Two case studies are described to illustrate POL
Unrelated Cord Blood Transplantation In Adults with Hematological Malignancie...cordbloodsymposium
This document summarizes research on unrelated cord blood transplantation (UCBT) for adults with hematological malignancies. It provides updates from the Eurocord registry on over 11,000 UCBT cases. It then reviews outcomes from UCBT for specific diseases like acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). Favorable factors are identified such as disease status, age, and cell dose. Conditioning regimens and complications are also discussed. Surveys of UCBT for ALL and AML provide more detailed analyses of 2-year survival rates based on disease characteristics and transplant factors.
Presented at the 2014 Bio-IT World Expo in Boston, this slideshow provides info on the use of Lyons-Weiler's entropy-based measures of genotypic signal to improve concordance among alternative variant calling algorithms and to evaluate various steps in the GATK best practices pipeline. The second part of the talk presented data showing a demarcation bias in the widely used measure of fold change in selected differentially expressed genes, transcripts or proteins from microarray and RNASeq data.
http://www.bio-itworldexpo.com/Next-Gen-Sequencing-Informatics/
This document summarizes preliminary results from a study of 267 prostate cancer patients treated with high-dose intensity-modulated radiation therapy (IMRT) guided by seed markers and kV X-ray imaging. Toxicity outcomes were excellent, with only 5 patients experiencing rectal complaints and 1 developing urinary incontinence. Biochemical disease-free survival was 97% at a median follow-up of 1.5 years. Potency preservation rates were high, with 77% of initially potent non-hormonally treated patients maintaining some function. The results suggest modern image-guided IMRT may achieve low morbidity for prostate cancer treatment.
The LANCELOT-ACS trial investigated the safety and tolerability of the PAR-1 inhibitor atopaxar in 603 patients with acute coronary syndrome. The trial found that atopaxar achieved potent platelet inhibition through PAR-1 without significantly increasing bleeding risk compared to placebo. There were favorable trends for reduced major cardiac events but dose-dependent increases in liver enzymes and QTc interval prolongation at higher doses. Further studies are still needed to fully establish the safety and efficacy of atopaxar.
2016 Presentation at the University of Hawaii Cancer CenterCasey Greene
Date: February 19, 2016
Time: 10:30 am
Place: University of Hawaii Cancer Center 701 Ilalo Street, Sullivan Conference Room
Details: Dr. Casey Greene
Department of Systems Pharmacology and Translational Therapeutics
Department of Genetics
University of Pennsylvania
Moore Investigator, Gordon and Betty Moore Foundation
1. The document describes research into developing novel and selective agonists for PPARδ to treat cardiovascular disease and obesity.
2. Key findings include developing a highly selective PPARδ agonist called GW501516 and a compound called LY465608 that is moderately selective for PPARδ over other PPAR subtypes.
3. The research involved structure-activity relationship studies where different regions of hit compounds were modified and tested for PPARδ binding and activation, aiming to improve potency and selectivity. This led to insights about important structural features for PPARδ selectivity.
- The addition of selective internal radiation therapy (SIRT) to sorafenib (SOR) did not significantly improve overall survival compared to SOR alone in patients with advanced hepatocellular carcinoma based on two randomized controlled trials.
- Subgroup analyses found potential clinical benefits for younger patients, those with non-alcoholic disease etiology, and those without cirrhosis.
- Regorafenib, a multi-kinase inhibitor, significantly improved progression-free survival, overall survival, and disease control compared to placebo in patients with hepatocellular carcinoma progressing on sorafenib.
- Lenvatinib, an oral multi-kinase inhibitor, demonstrated non-inferior
1) A 42-year-old man suffered cardiac arrest due to an acute myocardial infarction (MI) and died after 10 days in the hospital. His lipid profile showed elevated total cholesterol and LDL cholesterol.
2) The genetic basis of MI risk involves both monogenic mutations that confer large effects and polygenic contributions from many common genetic variants. A polygenic risk score can identify individuals at high genetic risk of MI.
3) Statins provide greater reduction in MI risk for individuals at high genetic risk compared to average or low genetic risk individuals. Genetic profiling may help optimize prevention and treatment of MI.
History of Medical Cannabis - Dr. Jahan MarcuSafeAccess
The document summarizes research on the role of the endocannabinoid system and cannabinoid receptors CB1 and CB2 in bone formation and density. Studies show that mice lacking both CB1 and CB2 receptors have increased bone mass despite lower osteoblast proliferation. Targeting these receptors in cell studies alters signaling pathways involved in bone growth like ERK, SMAD, and AKT. This suggests cannabinoids influence bone morphogenic signaling and osteoblast function, providing a potential mechanism for the bone phenotype seen in receptor knockout mice. Future work involves using pathway inhibitors and gene expression analysis to further understand these effects.
This document provides an overview of mutations, which are heritable changes in genetic information that occur due to mistakes during DNA replication. There are two main types of mutations: gene mutations, which affect a single gene, and chromosomal mutations, which involve changes to whole chromosomes. Gene mutations include point mutations like substitutions, insertions, and deletions. Chromosomal mutations involve changes in chromosome number or structure. Mutations can have a variety of effects on genes and organisms, with some being harmful by disrupting gene function and others being beneficial by allowing organisms to adapt to new environments. Factors like environmental stressors and mutagenic chemicals can increase mutation rates.
Louis Stodieck, BioServe Space Technologies, University of Colorado at Boulder: "AMGEN Countermeasures for Bone and Muscle Loss in Space and on Earth." Presented at the 2013 International Space Station Research and Development Conference, http://www.astronautical.org/issrdc/2013.
Mutations are changes in genetic material that can result from errors during DNA replication or damage to DNA. There are two main types of mutations: chromosomal mutations and genetic mutations. Chromosomal mutations include deletions, duplications, inversions, and translocations that involve changes in chromosome structure. Genetic mutations are changes in DNA sequence, such as point mutations involving substitutions, insertions, or deletions of nucleotide bases. Insertion and deletion mutations tend to have the largest effects as they can alter multiple amino acids and proteins, while substitution mutations often have the smallest effects since only a single amino acid may change. Examples of diseases caused by mutations include sickle cell anemia from a substitution and Huntington's disease from an expansion insertion.
This study investigated the effects of a single early life seizure induced by kainic acid (KA-ELS) on hippocampal synaptic plasticity and glutamate receptor function in rats. The key findings were:
1) Enhanced long-term potentiation (LTP) was observed 7 days, but not 2 days, after KA-ELS compared to controls, indicating inappropriate enhancement of synaptic connections in the acute period following seizure.
2) α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptor desensitization was decreased 7 days after KA-ELS, despite no changes in AMPA receptor expression, phosphorylation, or membrane insertion.
This document describes a study that used exome sequencing to identify genetic causes of adult-onset mitochondrial diseases. The study sequenced the exomes of 8 patients with progressive external ophthalmoplegia (PEO) and identified novel variants in the RRM1 and TOP3A genes. Sanger sequencing confirmed the variants and identified a TOP3A variant (p.M100V) in another patient but not in 102 controls. The study concludes that RRM1 and TOP3A may cause mitochondrial disease but further work is needed to verify candidate genes and variants.
This document summarizes the findings of the REDOXS study, a randomized controlled trial that investigated the effects of high-dose glutamine and antioxidant supplementation in critically ill patients with multi-organ failure. The study found that glutamine supplementation was not beneficial and may have been harmful, increasing mortality. Subgroup analyses found the highest risk of harm with glutamine in patients who had renal dysfunction at enrollment. An updated meta-analysis of intravenous glutamine trials did not find an overall increase in mortality, though the REDOXS study results suggest glutamine could be harmful in certain critically ill populations such as those with renal failure.
1. Management of the neck in head and neck cancer involves addressing clinically negative (N0) and positive (N+) lymph nodes.
2. For N0 necks, elective neck dissection may decrease recurrence rates for high-risk primary sites. For N+ necks, selective neck dissection is adequate for early stage single node involvement without extracapsular spread.
3. Post-operative radiotherapy improves local control for N+ necks with adverse features like multiple nodes, extracapsular spread or positive margins. Concurrent chemoradiotherapy is preferred for advanced N2/N3 disease.
This document discusses autosomal disorders of mitochondrial DNA maintenance. It notes that these disorders involve defects in both the nuclear and mitochondrial genomes that can lead to tissue-specific oxidative phosphorylation defects and disease symptoms. Key points include:
1) Mutations in the POLG gene are a major cause of these disorders and can result in a broad spectrum of conditions from mild PEO to Alpers syndrome. Most POLG mutations are autosomal recessive.
2) Mutations in the PEO1 gene are a major cause of autosomal dominant PEO.
3) Mutations in the ANT1 gene are a relatively rare cause of autosomal dominant PEO.
Two case studies are described to illustrate POL
This document discusses autosomal disorders of mitochondrial DNA maintenance. It notes that these disorders involve defects in both the nuclear and mitochondrial genomes that can lead to tissue-specific oxidative phosphorylation defects and disease symptoms. Key points include:
1) Mutations in the POLG gene are a major cause of these disorders and can result in a broad spectrum of conditions from mild PEO to Alpers syndrome. Most POLG mutations are autosomal recessive.
2) Mutations in the PEO1 gene are a major cause of autosomal dominant PEO.
3) Mutations in the ANT1 gene are a relatively rare cause of autosomal dominant PEO.
Two case studies are described to illustrate POL
Unrelated Cord Blood Transplantation In Adults with Hematological Malignancie...cordbloodsymposium
This document summarizes research on unrelated cord blood transplantation (UCBT) for adults with hematological malignancies. It provides updates from the Eurocord registry on over 11,000 UCBT cases. It then reviews outcomes from UCBT for specific diseases like acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). Favorable factors are identified such as disease status, age, and cell dose. Conditioning regimens and complications are also discussed. Surveys of UCBT for ALL and AML provide more detailed analyses of 2-year survival rates based on disease characteristics and transplant factors.
Presented at the 2014 Bio-IT World Expo in Boston, this slideshow provides info on the use of Lyons-Weiler's entropy-based measures of genotypic signal to improve concordance among alternative variant calling algorithms and to evaluate various steps in the GATK best practices pipeline. The second part of the talk presented data showing a demarcation bias in the widely used measure of fold change in selected differentially expressed genes, transcripts or proteins from microarray and RNASeq data.
http://www.bio-itworldexpo.com/Next-Gen-Sequencing-Informatics/
This document summarizes preliminary results from a study of 267 prostate cancer patients treated with high-dose intensity-modulated radiation therapy (IMRT) guided by seed markers and kV X-ray imaging. Toxicity outcomes were excellent, with only 5 patients experiencing rectal complaints and 1 developing urinary incontinence. Biochemical disease-free survival was 97% at a median follow-up of 1.5 years. Potency preservation rates were high, with 77% of initially potent non-hormonally treated patients maintaining some function. The results suggest modern image-guided IMRT may achieve low morbidity for prostate cancer treatment.
The LANCELOT-ACS trial investigated the safety and tolerability of the PAR-1 inhibitor atopaxar in 603 patients with acute coronary syndrome. The trial found that atopaxar achieved potent platelet inhibition through PAR-1 without significantly increasing bleeding risk compared to placebo. There were favorable trends for reduced major cardiac events but dose-dependent increases in liver enzymes and QTc interval prolongation at higher doses. Further studies are still needed to fully establish the safety and efficacy of atopaxar.
2016 Presentation at the University of Hawaii Cancer CenterCasey Greene
Date: February 19, 2016
Time: 10:30 am
Place: University of Hawaii Cancer Center 701 Ilalo Street, Sullivan Conference Room
Details: Dr. Casey Greene
Department of Systems Pharmacology and Translational Therapeutics
Department of Genetics
University of Pennsylvania
Moore Investigator, Gordon and Betty Moore Foundation
1. The document describes research into developing novel and selective agonists for PPARδ to treat cardiovascular disease and obesity.
2. Key findings include developing a highly selective PPARδ agonist called GW501516 and a compound called LY465608 that is moderately selective for PPARδ over other PPAR subtypes.
3. The research involved structure-activity relationship studies where different regions of hit compounds were modified and tested for PPARδ binding and activation, aiming to improve potency and selectivity. This led to insights about important structural features for PPARδ selectivity.
- The addition of selective internal radiation therapy (SIRT) to sorafenib (SOR) did not significantly improve overall survival compared to SOR alone in patients with advanced hepatocellular carcinoma based on two randomized controlled trials.
- Subgroup analyses found potential clinical benefits for younger patients, those with non-alcoholic disease etiology, and those without cirrhosis.
- Regorafenib, a multi-kinase inhibitor, significantly improved progression-free survival, overall survival, and disease control compared to placebo in patients with hepatocellular carcinoma progressing on sorafenib.
- Lenvatinib, an oral multi-kinase inhibitor, demonstrated non-inferior
2015 04 Tratamiento del NSCLC basado en alteraciones molecularesMartín Lázaro
1) The document discusses biomarker-guided treatment selection for non-small cell lung cancer (NSCLC) and summarizes data from several clinical trials evaluating targeted therapies versus chemotherapy in patients with activating EGFR mutations.
2) The IPASS trial showed that gefitinib resulted in significantly longer progression-free survival compared to carboplatin/paclitaxel in patients with EGFR mutation-positive NSCLC.
3) The EURTAC trial found that erlotinib doubled progression-free survival compared to chemotherapy as first-line treatment for patients with EGFR mutation-positive NSCLC.
1) EGFR mutations are found in 10-30% of NSCLC cases and are associated with response to EGFR TKIs as first-line treatment.
2) Several studies including IPASS, EURTAC and LUX-Lung 3 have shown superior PFS for first-generation EGFR TKIs like gefitinib and erlotinib and the second-generation TKI afatinib compared to platinum-based chemotherapy as first-line treatment for EGFR mutation-positive NSCLC.
3) Meta-analyses of these studies demonstrate improved PFS for EGFR TKIs compared to chemotherapy in EGFR mutation-positive NSCLC, though OS is generally similar between the treatments
Terahertz Spectroscopy for the Solid State Characterisation of Amorphous Systemsjaz22_tag
There is a controversy about the extent to which the primary and secondary dielectric relaxations influence the crystallisation of amorphous organic compounds below the glass transition temperature. Recent studies also point to the importance of fast molecular dynamics on picosecond-to-nanosecond time scales with respect to the glass stability. Here we show terahertz (THz) spectroscopy evidence on the crystallisation of amorphous drugs well below their glass transition temperature and confirm the direct role of Johari-Goldstein (JG) secondary relaxation as a facilitator of the crystallisation. We determine the onset temperature Tβ above which the JG relaxation contributes to the fast molecular dynamics and analytically quantify the level of this contribution. We then show there is a strong correlation between the increase in the fast molecular dynamics and onset of crystallisation in several chosen amorphous drugs. We believe that this technique has immediate applications to quantify the stability of amorphous drug materials.
This document summarizes the debate around providing adjuvant chemotherapy following neoadjuvant chemoradiotherapy for rectal cancer. It outlines the current treatment approaches and evidence for and against adjuvant chemotherapy. Studies have shown conflicting results as to whether adding oxaliplatin to adjuvant chemotherapy improves outcomes. Large trials comparing adjuvant chemotherapy to observation alone did not find significant differences in survival or recurrence, though a meta-analysis found a small improvement in disease-free survival with chemotherapy. The author concludes that for locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy, adjuvant chemotherapy is indicated for high-risk pathologic stage II/III tumors but the benefits are less clear for lower-risk cases.
Similar to Familial ET gene identification using exome sequencing (20)
Locally advanced Rectal cancer debate: adjuvant chemotherapy following neoadj...
Familial ET gene identification using exome sequencing
1. Familial Essential Tremor Gene
Identification Using Exome Sequencing
Anjali Shah
Rutgers University, Class of 2015
Summer Undergraduate Research Fellowship
Ross Lab
2. • Most common movement disorder
• Average age of onset is 35-45 years
• Main symptom is action tremor
• Criteria (Movements Disorder Society):
Symmetrical
Kinetic
Postural
Bilateral
• Motor Symptoms:
Problems with gait and balance
Neuropathy
Rigidity
• Age is a major risk factor for ET
3. • Approximately 50% of ET cases are non-familial
suggesting environmental risk factors play a
significant role (Louis et al. 2010)
• Environmental toxins (Louis et al. 2008):
• β-carboline alkaloids
• Lead
• Pesticides
4. • Familial inheritance is high ( 50-60%)
• Various patterns of inheritance in families:
Autosomal dominant with low penetrance
Multifactorial inheritance
Interplay between more than one gene and environmental factors
Non- Mendelian pattern of inheritance
MA S, DAVIS TL, BLAIR MA et al. Familial essential tremor with apparent autosomal dominant
inheritance: Should we also consider other inheritance modes? Mov Disord 2006;21:1368–74
5. • Linkage studies identified 3 susceptible loci for familial ET:
• ETM1 (chromosome 3q13) (Gulcher et al. 1997)
• 20 million base pairs
• ~100 genes
• Candidate ET gene- DRD3 (dopamine receptor D3 gene)
• ETM2 (chromosome 2p25-p22) (Higgins et al. 1997)
• 41 million base pairs
• ~100 genes
• Candidate ET gene- HS1BP3 (heat shock1-binding protein 3)
• ETM3 (chromosome 6p23) (Shatunov et al. 2006)
• 1.8 million base pairs
• 7 genes
6. GWAS Study (Stefansson et al. 2009):
• 305,624 SNPs were tested for association with ET in
452 cases and 14,394 controls
• Reached the genome-wide significance level with 1
marker in Leucine-rich repeat and Ig domain
containing Nogo receptor interacting protein-1 gene
(LINGO1)
• Some studies replicate the findings and some do not.
7. • First human genome was fully
sequenced in 2003
• It took 13 years and $2.7 billion
NOW:
• Life Technologies introduced a
sequencer that can decode a human
genome in one day for $1000
8. • Nonsense mutation p.Q290X in FUS/TLS (fused
in sarcoma/translocated in liposarcoma)
(Merner. N et al. 2013)
• Screening of 270 ET cases revealed 2 additional
rare variants- p. P431L and p. R216C
• Both variants were found to be highly
conserved and pathogenic by bioinformatics
software.
• 2 other studies
• Parmalee et al. 2012
• Labbé et al. 2013
Did not detect any FUS variants in ET
9. Exome Sequencing of 2 individuals from a family
1200 shared SNPs
Narrowed down to 3
Sequenced using 3730 Sequencer of
variants in Controls and ET series
Non-synonymous variants shared
Segregated in affected members of
the family, not seen in controls, rare
in public data
Objective- Find a rare variant that caused ET in the family.
10. 3
Diagnosis 1 = ET (or postural tremor) Diagnosis 2 = ET (or post. tremor)
11. 3
Diagnosis 1 = ET (or postural tremor) Diagnosis 2 = ET (or post. tremor)
Sent for exome sequencing
12. • Objective- To find novel, non-synonymous variants
that segregated within the affected family members
and that were not seen frequently in public databases
• 20,000 variants in each person
• 1200 shared variants
• 71 Non-synonymous variants shared between the 2
affected family members
• 18 variants were either Sequenced or Genotyped
13. Chr Gene
Base
change
AA
ET ET ET ET ET ?dx ?dx U U U U U U U
Controls
(%)
EVS MAF
(%)
s_31 s_8 8 18 20 24 22 32 33 58 64 19 43 7
12 DDX55 C > A S450R 0
12 P2RX7 G > A R264H 0 0.047
12 KNTC1 G > T V1012L 0 0.037
15 DENND4A T > C S1839G 0
10 AGAP6 G > A R565Q 0.22
13 MIPEP A > G L197P 0
15 AGPHD1 T > A Y145X 0.03
9 KIAA2026 G > C T834R 0
12 POLE C > T V1016M 0 0.116
12 NOC4L G > A R346H 0 0.012
20 C20orf96 C > G S117T 0.01
18 TCEB3C T > G E356A 0
15 CEP152 A > G W867R 0
9 FAM22G C > T P457S 0.07
15 DMXL2 C > A A2372S
4 FRG1 C > T P91S
1 HRNR G > C A2706G
7 PMS2L5 C > T R9X
Carrier
Non-carrier
14. Chr Gene
Base
change
AA
ET ET ET ET ET ?dx ?dx U U U U U U U
Controls
(%)
EVS MAF
(%)
s_31 s_8 8 18 20 24 22 32 33 58 64 19 43 7
12 DDX55 C > A S450R 0
12 P2RX7 G > A R264H 0 0.047
12 KNTC1 G > T V1012L 0 0.037
15 DENND4A T > C S1839G 0
10 AGAP6 G > A R565Q 0.22
13 MIPEP A > G L197P 0
15 AGPHD1 T > A Y145X 0.03
9 KIAA2026 G > C T834R 0
12 POLE C > T V1016M 0 0.116
12 NOC4L G > A R346H 0 0.012
20 C20orf96 C > G S117T 0.01
18 TCEB3C T > G E356A 0
15 CEP152 A > G W867R 0
9 FAM22G C > T P457S 0.07
15 DMXL2 C > A A2372S
4 FRG1 C > T P91S
1 HRNR G > C A2706G
7 PMS2L5 C > T R9X
Carrier
Non-carrier
15. 3
Diagnosis 1 = ET (or postural tremor) Diagnosis 2 = ET (or post. tremor)
Carrier
Non- carrier
16. • C>A base change Serine to Arginine AA
change
• Sequenced in:
ET Cases(N=267)
Controls(N=282)
No positives
17. 3
Diagnosis 1 = ET (or postural tremor) Diagnosis 2 = ET (or post. tremor)
Carrier
Non- carrier
18. • C>G base change Threonine to
Arginine AA change
• Sequenced in:
ET Cases(N=267)
Controls(N=282)
No positives
• C>T base change Threonine to Isoleucine
AA change at the same position
• Sequenced in Controls and ET Cases
• 1 positive ET Case (Familial Case)
Control- CC
Family Het-
CG
ET Het- CT
19. 3
Diagnosis 1 = ET (or postural tremor) Diagnosis 2 = ET (or post. tremor)
Carrier
Non- carrier
20. • G>A base change Valine to Methionine AA change
• Sequenced in:
ET Cases(N=267)
Controls(N=282)
1 positive in ET series (Sporadic case)
Control- GG
ET Het- GA
21. • DDX55
• DEAD box protein 55
• Chromosome 12
• Encodes for DEAD box protein (ASP-ALA-GLU-
ALA)
• Alteration of RNA secondary structure
• Ribosome and spliceosome assembly
• KIAA2026
• Uncharacterized KIAA protein
• Chromosome 9
• POLE
• DNA polymerase epsilon catalytic subunit A enzyme
• Chromosome 12
22. • Genotype more ET samples for these variants
• Sequence the whole genomic region to see if there are
other variants in the promoter or intronic regions that
could be risk variants
• Functional study of the associated variants
1. Role of the mutated variants in cells
2. Create an in-vivo model
23. Entire Ross Lab:
Owen Ross
Alexandra Ortolaza
Sruti Rayaprolu
Ronnie Walton
Catherine Labbé
Kotaro Ogaki
SURF Coordinators:
David Ausejo
Nell Robinson
Benefactors:
David A. and Linda B.
Stein
Editor's Notes
Criteria- has to be visible and persistent
Harmane:
Highly neurotoxic
Exposure can produce intense and generalized action tremor resembling ET (tremor frequency, responsiveness to benzodiazepines, ethanol and barbiturates)
Found in high concentrations in cooked meat
Blood harmane level was elevated in 100 ET patients compared to 100 controls (Louis et al. 2002)
Each 1 g-10/ml increase in blood harmane concentration was associated with an 80% increased odds of ET
Lead:
Blood lead concentrations were higher in ET patients than in controls (Louis et al. 2008)
Each 1 mg/dl increase in blood lead concentration was associated with a 19% increased odds of ET
Size of region and number of genes
PICTURES
Linkage?
300,000 SNPs
How long it took
Different aporiach is next fen exome seq
Exome sequencing of 1 ET family
Sanger sequencing and Genotyping (TaqMan) of variants in Controls and ET patients
32 non synonymous shared variants seen in both the cousins from the family
Other family members screened for these variants to see if they segregated or not
Variants that segregated were followed up in controls
32 non synonymous shared variants seen in both the cousins from the family
Other family members screened for these variants to see if they segregated or not
Variants that segregated were followed up in controls
U carriers- Low penetrance
Serine to arginine
Threonine to arginine
Chromatograms
Valine to methionine
Taqman assay screen picture of the plot
What pole is ?
