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Archive for the ‘Autoimmune Inflammatory DIseases’ Category


Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The importance of B cells to human health is more than what is already known. Vaccines capable of eradicating disease activate B cells, cancer checkpoint blockade therapies are produced using B cells, and B cell deficiencies have devastating impacts. B cells have been a subject of fascination since at least the 1800s. The notion of a humoral branch to immunity emerged from the work of and contemporaries studying B cells in the early 1900s.

 

Efforts to understand how we could make antibodies from B cells against almost any foreign surface while usually avoiding making them against self, led to Burnet’s clonal selection theory. This was followed by the molecular definition of how a diversity of immunoglobulins can arise by gene rearrangement in developing B cells. Recombination activating gene (RAG)-dependent processes of V-(D)-J rearrangement of immunoglobulin (Ig) gene segments in developing B cells are now known to be able to generate an enormous amount of antibody diversity (theoretically at least 1016 possible variants).

 

With so much already known, B cell biology might be considered ‘‘done’’ with only incremental advances still to be made, but instead, there is great activity in the field today with numerous major challenges that remain. For example, efforts are underway to develop vaccines that induce broadly neutralizing antibody responses, to understand how autoantigen- and allergen-reactive antibodies arise, and to harness B cell-depletion therapies to correct non-autoantibody-mediated diseases, making it evident that there is still an enormous amount we do not know about B cells and much work to be done.

 

Multiple self-tolerance checkpoints exist to remove autoreactive specificities from the B cell repertoire or to limit the ability of such cells to secrete autoantigen-binding antibody. These include receptor editing and deletion in immature B cells, competitive elimination of chronically autoantigen binding B cells in the periphery, and a state of anergy that disfavors PC (plasma cell) differentiation. Autoantibody production can occur due to failures in these checkpoints or in T cell self-tolerance mechanisms. Variants in multiple genes are implicated in increasing the likelihood of checkpoint failure and of autoantibody production occurring.

 

Autoantibodies are pathogenic in a number of human diseases including SLE (Systemic lupus erythematosus), pemphigus vulgaris, Grave’s disease, and myasthenia gravis. B cell depletion therapy using anti-CD20 antibody has been protective in some of these diseases such as pemphigus vulgaris, but not others such as SLE and this appears to reflect the contribution of SLPC (Short lived plasma cells) versus LLPC (Long lived plasma cells) to autoantibody production and the inability of even prolonged anti-CD20 treatment to eliminate the later. These clinical findings have added to the importance of understanding what factors drive SLPC versus LLPC development and what the requirements are to support LLPCs.

 

B cell depletion therapy has also been efficacious in several other autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, and rheumatoid arthritis (RA). While the potential contributions of autoantibodies to the pathology of these diseases are still being explored, autoantigen presentation has been posited as another mechanism for B cell disease-promoting activity.

 

In addition to autoimmunity, B cells play an important role in allergic diseases. IgE antibodies specific for allergen components sensitize mast cells and basophils for rapid degranulation in response to allergen exposures at various sites, such as in the intestine (food allergy), nose (allergic rhinitis), and lung (allergic asthma). IgE production may thus be favored under conditions that induce weak B cell responses and minimal GC (Germinal center) activity, thereby enabling IgE+ B cells and/or PCs to avoid being outcompeted by IgG+ cells. Aside from IgE antibodies, B cells may also contribute to allergic inflammation through their interactions with T cells.

 

B cells have also emerged as an important source of the immunosuppressive cytokine IL-10. Mouse studies revealed that B cell-derived IL-10 can promote recovery from EAE (Experimental autoimmune encephalomyelitis) and can be protective in models of RA and type 1 diabetes. Moreover, IL-10 production from B cells restrains T cell responses during some viral and bacterial infections. These findings indicate that the influence of B cells on the cytokine milieu will be context dependent.

 

The presence of B cells in a variety of solid tumor types, including breast cancer, ovarian cancer, and melanoma, has been associated in some studies with a positive prognosis. The mechanism involved is unclear but could include antigen presentation to CD4 and CD8 T cells, antibody production and subsequent enhancement of presentation, or by promoting tertiary lymphoid tissue formation and local T cell accumulation. It is also noteworthy that B cells frequently make antibody responses to cancer antigens and this has led to efforts to use antibodies from cancer patients as biomarkers of disease and to identify immunotherapy targets.

 

Malignancies of B cells themselves are a common form of hematopoietic cancer. This predilection arises because the gene modifications that B cells undergo during development and in immune responses are not perfect in their fidelity, and antibody responses require extensive B cell proliferation. The study of B cell lymphomas and their associated genetic derangements continues to be illuminating about requirements for normal B cell differentiation and signaling while also leading to the development of targeted therapies.

 

Overall this study attempted to capture some of the advances in the understanding of B cell biology that have occurred since the turn of the century. These include important steps forward in understanding how B cells encounter antigens, the co-stimulatory and cytokine requirements for their proliferation and differentiation, and how properties of the B cell receptor, the antigen, and helper T cells influence B cell responses. Many advances continue to transform the field including the impact of deep sequencing technologies on understanding B cell repertoires, the IgA-inducing microbiome, and the genetic defects in humans that compromise or exaggerate B cell responses or give rise to B cell malignancies.

 

Other advances that are providing insight include:

  • single-cell approaches to define B cell heterogeneity,
  • glycomic approaches to study effector sugars on antibodies,
  • new methods to study human B cell responses including CRISPR-based manipulation, and
  • the use of systems biology to study changes at the whole organism level.

With the recognition that B cells and antibodies are involved in most types of immune response and the realization that inflammatory processes contribute to a wider range of diseases than previously believed, including, for example, metabolic syndrome and neurodegeneration, it is expected that further

  • basic research-driven discovery about B cell biology will lead to more and improved approaches to maintain health and fight disease in the future.

 

References:

 

https://www.cell.com/cell/fulltext/S0092-8674(19)30278-8

 

https://onlinelibrary.wiley.com/doi/full/10.1002/hon.2405

 

https://www.pnas.org/content/115/18/4743

 

https://onlinelibrary.wiley.com/doi/full/10.1111/all.12911

 

https://cshperspectives.cshlp.org/content/10/5/a028795

 

https://www.sciencedirect.com/science/article/abs/pii/S0049017218304955

 

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Will Lab-Grown Insulin-Producing Cells be the Next Insulin Pill?

Reporter: Irina Robu, PhD

Type 1 diabetes is an autoimmune disorder that destroys the insulin-producing beta cells of the pancreas, typically in childhood. Starved of insulin’s ability to regulate glucose levels in the blood, spikes in blood sugar can cause serious organ damage and eventually death. Replacing insulin cells lost in patients with Type 1 diabetes, has been a goal in regenerative medicine, but until now researchers had not been able to figure out how to produce cells in a lab dish that work as they do in healthy adults.

Dr. Matthias Hebrok, director of Diabetes Center at UCSF published a study on Feb 1, 2019 in Nature Cell Biology looked into generating insulin-producing cells that look and act a lot like the pancreatic beta cell. Hebrok and colleagues replicated the physical process by which the cells separate from the rest of the pancreas and form the so-called islets of Langerhans in the lab.

When the researchers replicated that process in lab dishes by artificially separating partially differentiated pancreatic stem cells and reforming them into islet-like clusters, the cells’ development unexpectedly leap forward. Not only did the beta cells begin responding to blood sugar more like mature insulin-producing cells, but similarly appeared to develop in ways that had never been realized in a laboratory setting. The scientist then transplanted these lab-grown islets into healthy mice and found that that in a matter of days, they produce more insulin than the animals’ own islets.

In partnership with bioengineers, geneticists, and other colleagues at UCSF, Hebrok’s team is by now working to move regenerative therapies to reality by using CRISPR gene editing to make these cells transplantable into patients without the necessity for immune-suppressing drugs or by screening drugs that could reinstate proper islet function in patients with Type 1 diabetes by protecting and expanding the few remaining beta cells to restart pancreatic insulin production.

SOURCE
https://www.universityofcalifornia.edu/news/functional-insulin-producing-cells-grown-lab?utm_source=fiat-lux

 

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Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

Curator: Stephen J. Williams, PhD 

Below is a series of posts and articles related to the role of G protein coupled receptors (GPCR) in various chronic diseases.  This is only a cursory collection and by no means represents the complete extensive literature on pathogenesis related to G protein function or alteration thereof.  However it is important to note that, although we think of G protein signaling as rather short lived, quick, their chronic activation may lead to progression of various disease. As to whether disease onset, via GPCR, is a result of sustained signal, loss of desensitization mechanisms, or alterations of transduction systems is an area to be investigated.

From:

Molecular Pathogenesis of Progressive Lung Diseases

Author: Larry H. Bernstein, MD, FCAP

 

Chronic Obstructive Lung Disease (COPD)

Inflammatory and infectious factors are present in diseased airways that interact with G-protein coupled receptors (GPCRs), such as purinergic receptors and bradykinin (BK) receptors, to stimulate phospholipase C [PLC]. This is followed by the activation of inositol 1,4,5-trisphosphate (IP3)-dependent activation of IP3 channel receptors in the ER, which results in channel opening and release of stored Ca2+ into the cytoplasm. When ER Ca2+ stores are depleted a pathway for Ca2+ influx across the plasma membrane is activated. This has been referred to as “capacitative Ca2+ entry”, and “store-operated calcium entry” (3). In the next step PLC mediated Ca2+ i is mobilized as a result of GPCR activation by inflammatory mediators, which triggers cytokine production by Ca2+ i-dependent activation of the transcription factor nuclear factor kB (NF-kB) in airway epithelia.

 

 

 

In Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model

Larry H. Bernstein, MD, FCAP, Curator discusses findings from a research team at University of California at San Diego (UCSD) which the neuropeptide hormone corticotropin-releasing factor (CRF) as having an important role in the etiology of Alzheimer’s Disease (AD). CRF activates the CRF receptor (a G stimulatory receptor).  It was found inhibition of the CRF receptor prevented cognitive impairment in a mouse model of AD.  Furthermore researchers at the Flanders Interuniversity Institute for Biotechnology found the loss of a protein called G protein-coupled receptor 3 (GPR3) may lower the amyloid plaque aggregation, resulting in improved cognitive function.  Additionally inhibition of several G-protein coupled receptors alter amyloid precursor processing, providing a further mechanism of the role of GPCR in AD (see references in The role of G protein-coupled receptors in the pathology of Alzheimer’s disease by Amantha Thathiah and Bart De Strooper Nature Reviews Feb 2011; 12: 73-87 and read post).

 

In Cardiovascular and Thrombotic Disease

 

Adenosine Receptor Agonist Increases Plasma Homocysteine

 

and read related articles in curation on effects of hormones on the cardiovascular system at

Action of Hormones on the Circulation

 

In Cancer

A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial

 

Further curations and references of G proteins and chronic disease can be found at the Open Access journal https://pharmaceuticalintelligence.com using the search terms “GCPR” and “disease” in the Search box in the upper right of the home page.

 

 

 

 

 

 

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Benefits of Fiber in Diet

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

UPDATED on 1/15/2019

This is How Much Daily Fiber to Eat for Better Health – More appears better in meta-analysis — as in more than 30 g/day

by Ashley Lyles, Staff Writer, MedPage Today

In the systematic review, observational data showed a 15% to 30% decline in cardiovascular-related death, all-cause mortality, and incidence of stroke, coronary heart disease, type 2 diabetes, and colorectal cancer among people who consumed the most dietary fiber compared to those consuming the lowest amounts.

Whole grain intake yielded similar findings.

Risk reduction associated with a range of critical outcomes was greatest when daily intake of dietary fibre was between 25 g and 29 g. Dose-response curves suggested that higher intakes of dietary fibre could confer even greater benefit to protect against cardiovascular diseases, type 2 diabetes, and colorectal and breast cancer.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(18)31809-9.pdf

Eating more dietary fiber was linked with lower risk of disease and death, a meta-analysis showed.

According to observational studies, risk was reduced most for a range of critical outcomes from all-cause mortality to stroke when daily fiber consumption was between 25 grams and 29 grams, reported Jim Mann, PhD, of University of Otago in Dunedin, New Zealand, and colleagues in The Lancet.

By upping daily intake to 30 grams or more, people had even greater prevention of certain conditions: colorectal and breast cancer, type 2 diabetes, and cardiovascular diseases, according to dose-response curves the authors created.

Quantitative guidelines relating to dietary fiber have not been available, the researchers said. With the GRADE method, they determined that there was moderate and low-to-moderate certainty of evidence for the benefits of dietary fiber consumption and whole grain consumption, respectively.

Included in the systematic review were 58 clinical trials and 185 prospective studies for a total of 4,635 adult participants with 135 million person-years of information (one trial in children was included, but analyzed separately from adults). Trials and prospective studies assessing weight loss, supplement use, and participants with a chronic disease were excluded.

 

Food is digested by bathing in enzymes that break down its molecules. Those molecular fragments then pass through the gut wall and are absorbed in our intestines. But our bodies make a limited range of enzymes, so that we cannot break down many of the tough compounds in plants. The term “dietary fiber” refers to those indigestible molecules. These dietary fibers are indigestible only to us. The gut is coated with a layer of mucus, on which sits a carpet of hundreds of species of bacteria, part of the human microbiome. Some of these microbes carry the enzymes needed to break down various kinds of dietary fibers.

 

Scientists at the University of Gothenburg in Sweden are running experiments that are yielding some important new clues about fiber’s role in human health. Their research indicates that fiber doesn’t deliver many of its benefits directly to our bodies. Instead, the fiber we eat feeds billions of bacteria in our guts. Keeping them happy means our intestines and immune systems remain in good working order. The scientists have recently reported that the microbes are involved in the benefits obtained from the fruits-and-vegetables diet. Research proved that low fiber diet decreases the gut bacteria population by tenfold.

 

Along with changes to the microbiome there were also rapid changes observed in the experimental mice. Their intestines got smaller, and its mucus layer thinner. As a result, bacteria wound up much closer to the intestinal wall, and that encroachment triggered an immune reaction. After a few days on the low-fiber diet, mouse intestines developed chronic inflammation. After a few weeks, they started putting on fat and developing higher blood sugar levels. Inflammation can help fight infections, but if it becomes chronic, it can harm our bodies. Among other things, chronic inflammation may interfere with how the body uses the calories in food, storing more of it as fat rather than burning it for energy.

 

In a way fiber benefits human health is by giving, indirectly, another source of food. When bacteria finished harvesting the energy in the dietary fiber, they cast off the fragments as waste. That waste — in the form of short-chain fatty acids — is absorbed by intestinal cells, which use it as fuel. But the gut’s microbes do more than just make energy. They also send messages. Intestinal cells rely on chemical signals from the bacteria to work properly. The cells respond to the signals by multiplying and making a healthy supply of mucus. They also release bacteria-killing molecules. By generating these responses, gut bacteria help to maintain a peaceful coexistence with the immune system. They rest on the gut’s mucus layer at a safe distance from the intestinal wall. Any bacteria that wind up too close get wiped out by antimicrobial poisons.

 

A diet of fiber-rich foods, such as fruits and vegetables, reduces the risk of developing diabetes, heart disease and arthritis. Eating more fiber seems to lower people’s mortality rate, whatever be the cause. Researchers hope that they will learn more about how fiber influences the microbiome to use it as a way to treat disorders. Lowering inflammation with fiber may also help in the treatment of immune disorders such as inflammatory bowel disease. Fiber may also help reverse obesity. They found that fiber supplements helped obese people to lose weight. It’s possible that each type of fiber feeds a particular set of bacteria, which send their own important signals to our bodies.

 

References:

 

https://www.nytimes.com/2018/01/01/science/food-fiber-microbiome-inflammation.html

 

 

https://www.ncbi.nlm.nih.gov/pubmed/29276171

 

https://www.ncbi.nlm.nih.gov/pubmed/29276170

 

https://www.ncbi.nlm.nih.gov/pubmed/29486139

 

https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/fiber/art-20043983

 

https://nutritiouslife.com/eat-empowered/high-fiber-diet/

 

http://www.eatingwell.com/article/287742/10-amazing-health-benefits-of-eating-more-fiber/

 

http://www.cookinglight.com/eating-smart/nutrition-101/what-is-a-high-fiber-diet

 

https://www.helpguide.org/articles/healthy-eating/high-fiber-foods.htm

 

https://www.gicare.com/diets/high-fiber-diet/

 

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Expanding area of Tolerance-inducing Autoimmune Disease Therapeutics: Key Players

Reporter: Aviva Lev-Ari, PhD, RN

Patients with autoimmune diseases have immune systems that see natural proteins as foreign and attack them. Anokion’s approach to treating such diseases is to use tolerance mechanisms in the body to reeducate the immune system. The company’s technology also allows it to create proteins masked as native to the body that can dial down immune system responses to beneficial drugs.

Key Players in Tolerance-inducing Autoimmune Disease Therapeutics

  • Swiss biotech Anokion has sealed a multimillion dollar deal with Celgene to develop candidates in the expanding area of tolerance-inducing autoimmune disease therapeutics. The deal gives Celgene an equity interest in Anokion and the exclusive right to acquire the smaller drugmaker at undisclosed but pre-specified “option exercise points.” The privately-held company stands to receive $45 million upfront under the collaboration and could bring in an additional $10 million if they reach certain preclinical development milestones.
  • Parvus Therapeutics, with programs in type 1 diabetes, multiple sclerosis and liver disease in preclinical development, and
  • Selecta Biosciences, whose immune tolerance pipeline includes type 1 diabetes and celiac disease.

The global autoimmune disease market could be worth almost $16 billion by 2022, with a projected compound annual growth rate of almost 4%, according an April report from market intelligence firm Intelliroi.

 

SOURCE

http://www.biopharmadive.com/news/celgene-anokion-option-takeover-autoimmune/433707/

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LIVE 9/21 3:20PM to 6:40PM KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS & KINASE INHIBITORS FOR AUTOIMMUNE AND INFLAMMATORY DISEASES at CHI’s 14th  Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

http://www.discoveryontarget.com/

http://www.discoveryontarget.com/crispr-therapies/

Leaders in Pharmaceutical Business Intelligence (LPBI) Group is a

Media Partner of CHI for CHI’s 14th Annual Discovery on Target taking place September 19 – 22, 2016 in Boston.

In Attendance, streaming LIVE using Social Media

Aviva Lev-Ari, PhD, RN

Editor-in-Chief

http://pharmaceuticalintelligence.com

#BostonDOT16

@BostonDOT

 

KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS

3:20 Chairperson’s Opening Remarks

Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)

3:25 FEATURED PRESENTATION: Inhibition of PI3K and Tubulin

Doriano_Fabbro

Doriano Fabbro, Ph.D., CSO, PIQUR Therapeutics

The PI3K signaling pathway is frequently activated in tumors. PQR309 is a selective dual inhibitor of PI3K and mTOR (currently in Phase I) in cancer patients. The preclinical pharmacology and toxicology of PQR309 is presented, including its activity in lymphoma preclinical models. In addition, we elucidate structural factors defining the PI3K inhibitory activity and tubulin-binding of PQR309 derivatives.

  • PQR309 & GDC0941 arrest cells i G1/S (typical for PI3K/mTOR Inhibitor)
  • What drives Antiproliferative Activity of BKM120: PI3K or MT or both?
  • BKM120 Binds to beta-Tubulin/alpha -Tubulin Interfere
  • T2R-TTL complex
  • Orientation of BKM120 in PI3K
  • PQR309 – is a brain penetrating, PK and BAV by PO, good metabolic stability
  • PQR309 ANti-proliferative in Lymphoma
  • Clinical efficacy – Now in Phase II

4:05 Design and Development of a Novel PI3K-p110β/δ Inhibitor, KA2237 with Combined Tumor Immunotherapeutic, Growth Inhibition and Anti-Metastatic Activity

Stephen_Shuttleworth

Stephen Shuttleworth, Ph.D., FRSC, CChem, CSO, Karus Therapeutics Ltd.

The design and development of KA2237, a novel and selective inhibitor of PI3K-p110β/δ, will be described. This molecule has clinical potential in the treatment of solid and hematological malignancies, through its direct inhibition of tumor growth and metastatic spread, and through immunotherapeutic mechanisms. Phase I studies for KA2237 are scheduled to commence in Q2 2016 at the MD Anderson Cancer Center.

  • Design & Development of Novel, Oral, selective PI3K enzyme family: CLass I,II, III, IV based upon:
  • Class I IA IB
  • KA2237: DUal PI3K – p110beta/delta-selective inhibitor: CTL, Treg, p1 106 T sell response
  • Molecular signature in the tumor
  • WT p110delta, WT 1 10beta+, Mutant p1 10Beta+, PTEN-null, Ibrutinib-resistance, Growth inhibition; suppression of metastesis (p110beta
  • small molecule combination agents: potential aided by selectivity over p110
  • KA2237: clinical Pi3K-p110beta/delta Inhibitor- ATP -comtetitive
  • Doxorubicin -cytotoxic control
  • KA2237 superior activity to Idelasib
  • KA2237 – suppression of micro-metastasis in 4T1 synergenic model
  • Tumor Growth inhibition Pre-Surgery
  • Tumor Re-Growth Inhibition Post-Surgery
  • metastasis post surgery
  • Tumor-free mice post-surgery
  • CHemistry: IHC -pAKT; IHC – FOxp3+
  • KA2237 inhibits HGF-stimulated 4T1 tumor
  • 2004 – Preclinical develpemnt PI3K is reported
  • 2006 First PI#K is enter Clinical Trials
  • Targeting p1110Beta (PIKeCB) mutations in cancer with KA2237
  • DIscovery of the mutations lead drug discovery
  • KA@@#&: Potential in treatment of B-Cell Lymphom AS IN TARGETING IBRUTINIB RESISTENCE
  • GROWTH INHIBITION IN HEMATOLOGICAL CANCERS TUMOE CELL LINE PANEL
  • KA2237 – differentiated from competing Pi3K is Superior efficacy cf. p110delta
  • Combination: Not histone deacetylase but a tubulin deacetylase – Hsp90 ans Hsp70
  • T cell exhausion: Tumor growth inhibition vs Suppression of lung metastasis
  • Tumor BiologyRationale vs Clinical Agents
  • Oncogenic mutants, solid tumor supression magrophage, combination PD-1, CTLA$
  • FDA -approved kinase inhibitors

Summary

  1. phase I clinical study commenced in pathients with B cell Lymphoma
  2. Potential for treatment of solid and hematological malignancies

4:35 InCELL Pulse: A Novel Cellular Target Engagement Assay Platform for Drug Discovery

Treiber_Daniel

Daniel Treiber, Ph.D., Vice President, KINOMEscan, DiscoverX Corporation

InCELL Pulse is a quantitative and rapid method for measuring cellular target engagement potencies for small molecule inhibitors. InCELL Pulse capitalizes on two novel DiscoverX technologies, Enzyme Fragment Complementation (EFC) and Pulse Denaturation, which overcome the limitations of related target engagement methods. Examples across multiple target classes will be described.

  • InCELL Pulse – cellular Target ENgagement Assays
  • cellular thermal stabilization-based approach
  • simple, rapid and generig cellular alternative to CETSa
  • Thermal melting Curves vs Isothermal Inhibitor EC50 curves
  • Pulse Denaturation compound binding, or not binding
  • ABL1 Tyrosine Kinase – dose response curve – allosteric Inhibitor
  • MTH1 Hydrolase: InCELL Pulseassay validated for multiple substrate-competitive inhibitors
  • Validated InCELL Pulse Assays for Diverse Kinases
  • Kinase targets; BRAF, MEC1

Summary

  1. validation across proteins

TTP Labtech4:50 Potential Application of Fluorescence Lifetime Assays to Enable Robust, Rapid Protein Binding Assays

Wylie_Paul

Paul Wylie, Ph.D., Head, Applications, TTP Labtech

Current methods to screen protein binding interactions often have limitations due to the reliance on antibodies, but also interference from fluorescent molecules. Fluorescence lifetime has the potential to overcome these problems through directly labelled proteins and lifetime measurements that are independent of total fluorescence intensity.

  • Protein binding as a target class
  • protein-protein interactions (PPIs)
  1. FRET/HTRF
  2. FP
  3. AlphaScreen

What new in FLT?

  • long lifetime fluorophores, economical reagent platform
  • directly labelled reagents – no antibodies
  • independent of total intensity – reduced interference
  • robustness screen vs nuisance screen – caspase-3
  • productive; reduction false positives: FRET
  • protein-binding assays & FLT formats:
  1. protein – small molecule binding – CECR2
  2. protein – peptide binding: long and sholt lifetime
  3. Site-specific labelling vs Non-selective labelling
  4. Toolbox for PoC
  5. Detection reagents
  6. Further develop technology

5:05 Refreshment Break in the Exhibit Hall with Poster Viewing

 

6:40 End of Day

 

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Milestones in Physiology & Discoveries in Medicine and Genomics: Request for Book Review Writing on Amazon.com


physiology-cover-seriese-vol-3individualsaddlebrown-page2

Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective 

http://www.amazon.com/dp/B019VH97LU 

2015

 

 

Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Chief Scientific Officer

Leaders in Pharmaceutical Business Intelligence

Larry.bernstein@gmail.com

Preface

Introduction 

Chapter 1: Evolution of the Foundation for Diagnostics and Pharmaceuticals Industries

1.1  Outline of Medical Discoveries between 1880 and 1980

1.2 The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

1.3 The Classification of Microbiota

1.4 Selected Contributions to Chemistry from 1880 to 1980

1.5 The Evolution of Clinical Chemistry in the 20th Century

1.6 Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics

 

Chapter 2. The search for the evolution of function of proteins, enzymes and metal catalysts in life processes

2.1 The life and work of Allan Wilson
2.2  The  evolution of myoglobin and hemoglobin
2.3  More complexity in proteins evolution
2.4  Life on earth is traced to oxygen binding
2.5  The colors of life function
2.6  The colors of respiration and electron transport
2.7  Highlights of a green evolution

 

Chapter 3. Evolution of New Relationships in Neuroendocrine States
3.1 Pituitary endocrine axis
3.2 Thyroid function
3.3 Sex hormones
3.4 Adrenal Cortex
3.5 Pancreatic Islets
3.6 Parathyroids
3.7 Gastointestinal hormones
3.8 Endocrine action on midbrain
3.9 Neural activity regulating endocrine response

3.10 Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

 

Chapter 4.  Problems of the Circulation, Altitude, and Immunity

4.1 Innervation of Heart and Heart Rate
4.2 Action of hormones on the circulation
4.3 Allogeneic Transfusion Reactions
4.4 Graft-versus Host reaction
4.5 Unique problems of perinatal period
4.6. High altitude sickness
4.7 Deep water adaptation
4.8 Heart-Lung-and Kidney
4.9 Acute Lung Injury

4.10 Reconstruction of Life Processes requires both Genomics and Metabolomics to explain Phenotypes and Phylogenetics

 

Chapter 5. Problems of Diets and Lifestyle Changes

5.1 Anorexia nervosa
5.2 Voluntary and Involuntary S-insufficiency
5.3 Diarrheas – bacterial and nonbacterial
5.4 Gluten-free diets
5.5 Diet and cholesterol
5.6 Diet and Type 2 diabetes mellitus
5.7 Diet and exercise
5.8 Anxiety and quality of Life
5.9 Nutritional Supplements

 

Chapter 6. Advances in Genomics, Therapeutics and Pharmacogenomics

6.1 Natural Products Chemistry

6.2 The Challenge of Antimicrobial Resistance

6.3 Viruses, Vaccines and immunotherapy

6.4 Genomics and Metabolomics Advances in Cancer

6.5 Proteomics – Protein Interaction

6.6 Pharmacogenomics

6.7 Biomarker Guided Therapy

6.8 The Emergence of a Pharmaceutical Industry in the 20th Century: Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present

6.09 The Union of Biomarkers and Drug Development

6.10 Proteomics and Biomarker Discovery

6.11 Epigenomics and Companion Diagnostics

 

Chapter  7

Integration of Physiology, Genomics and Pharmacotherapy

7.1 Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

7.2 Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

7.3 Diagnostics and Biomarkers: Novel Genomics Industry Trends vs Present Market Conditions and Historical Scientific Leaders Memoirs

7.4 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

7.5 Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

7.6 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

7.7 Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors

7.8 Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

7.9 Preserved vs Reduced Ejection Fraction: Available and Needed Therapies

7.10 Biosimilars: Intellectual Property Creation and Protection by Pioneer and by

7.11 Demonstrate Biosimilarity: New FDA Biosimilar Guidelines

 

Chapter 7.  Biopharma Today

8.1 A Great University engaged in Drug Discovery: University of Pittsburgh

8.2 Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

8.3 Predicting Tumor Response, Progression, and Time to Recurrence

8.4 Targeting Untargetable Proto-Oncogenes

8.5 Innovation: Drug Discovery, Medical Devices and Digital Health

8.6 Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

8.7 Nanotechnology and Ocular Drug Delivery: Part I

8.8 Transdermal drug delivery (TDD) system and nanotechnology: Part II

8.9 The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

8.10 Natural Drug Target Discovery and Translational Medicine in Human Microbiome

8.11 From Genomics of Microorganisms to Translational Medicine

8.12 Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

 

Chapter 9. BioPharma – Future Trends

9.1 Artificial Intelligence Versus the Scientist: Who Will Win?

9.2 The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy

9.3 The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC

9.4 Heroes in Medical Research: The Postdoctoral Fellow

9.5 NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

9.6 1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

9.7 Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

9.8 Heroes in Medical Research: Green Fluorescent Protein and the Rough Road in Science

9.9 Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

9.10 The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

Epilogue

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