For UPDATES on this Cardinal Conference and for REGISTRATION, go to

Panel Discussion: Oncology – The Emperor of BioPharma Development

Posted in BioTechnology - Venture Creation, BioTechnology - Venture Creation, Venture Capital, Conference Coverage with Social Media, Drug Development Process, drug repurposing, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Informatics, Pharmaceutical R&D Investment, Pharmacodynamics and Pharmacokinetics, Pharmacogenomics, Pharmacovigilance, Value-based Drug Pricing on April 30, 2019| 2 Comments »

8:40 AM – 9:10 AM	Registration and Networking
9:10 AM – 9:20 AM	Welcome address: Karun Rishi, President, USAIC Opening comments: Dr Andrew Plump, President R&D and Director, Takeda Pharmaceuticals
9:20 AM – 9:40 AM	Fireside Chat Mark Abdoo, Acting Deputy Commissioner, U.S. Food and Drug Administration Dr Eswara Reddy, Drug Controller General of India, Central Drug Control Organization Moderator: Sanat Chattopadhyay, President, Merck Manufacturing Division; Merck & Co.
9:40 AM – 10:00 AM	Presentation on CAR (chimeric antigen receptor) T-cell Therapies Dr. Carl June, Director of Translational Research, Abramson Cancer Center University of Pennsylvania Moderator: Dr. Raju Kucherlapati, Professor of Genetics, Harvard Medical School
10:00 AM – 10:50 AM	Panel Discussion: Oncology – The Emperor of BioPharma Development Panelists: Dr. Arjun Surya, Co-Founder & CSO, Curadev Pharma Dr. Christopher Arendt, Head- Immunology Unit and Oncology DDU, Takeda Dr. David Meeker, President & CEO, KSQ Therapeutics Dr. Marcela Maus, Director of Cellular Immunotherapy, MGH Cancer Center Dr. Sanjiv Patel, President & Chief Executive Officer, Relay Therapeutics Moderator: Dr. Christiana Bardon, Managing Director, MPM Capital
10:50 AM – 11:20 AM	Networking Break
11:20 AM – 12:10 PM	Panel Discussion: Future of Clinical Trials and Drug Development Panelists: Dr. Alise Reicin, President, Global Clinical Development, Celgene Dr. Bruce Chabner, Director of Clinical Research, Mass General Hospital Cancer Center Dr. Mace Rothenberg, Chief Medical Officer, Pfizer Dr. Michael Rosenblatt, Chief Medical Officer, Flagship Pioneering Dr. Rob Scott, Chief Medical Officer, Abbvie Moderator: Dr. William Chin, Professor of Medicine, Emeritus, Harvard Medical School
12:10 PM – 1:00 PM	Panel Discussion: Manufacturing in the Future Panelists: Hari Bhartia, Founder and Co-Chairman, Jubilant Bhartia Group Mark Abdoo, Acting Deputy Commissioner, U.S. Food and Drug Administration Dr. Paul McKenzie, Executive Vice President, Pharma Operations & Technology, Biogen Sanat Chattopadhyay, President, Merck Manufacturing Division; Merck & Co. Vinay Ranade, Chief Executive Officer, Reliance Life Sciences Moderator: Professor N. Venkat Venkatraman, Boston University Questrom School of Business
1:00 PM – 1:50 PM	Lunch
1:50 PM – 1:55 PM	Video message from Suresh Prabhu, Hon’ble Minister of Commerce & Industry, Gov. of India
1:55 PM – 2:45 PM	Panel Discussion: One in a million – Emerging trends in Rare Diseases Panelists: Dr. Daniel Curran, Head of the Rare Diseases Therapeutic Area Unit, Takeda David Lucchino, Co-Founder and CEO, Frequency Therapeutics Dr. Dhaval Patel, Executive Vice President and Chief Scientific Officer, UCB Dr. James Wilson, Director- Gene Therapy Program, University of Pennsylvania Dr. Timothy Yu, Assistant Professor in Pediatrics, Harvard Medical School Moderator: Dr. Samarth Kulkarni, Chief Executive Officer, CRISPR Therapeutics
2:45 PM – 3:20 PM	Networking & Tea Break
3:20 PM – 3:50 PM	Fireside Chat: Value and Access – The ongoing debate Christopher Viehbacher, Managing Partner, Gurnet Point Capital Dr. John Maraganore, Chief Executive Officer, Alnylam Pharmaceuticals Dr. Stelios Papadopoulos, Chairman, Biogen Moderator: Dr Andrew Plump, President R&D, Takeda Pharmaceuticals
3:50 PM – 4:10 PM	India update on Clinical Trial Regulations Arun Singhal, Additional Secretary, Ministry of Health & Family Welfare, India Dr Eswara Reddy, Drug Controller General of India, Central Drug Control Organization
4:10 PM – 5:00 PM	Panel Discussion: Research and Development Strategies and Trends Panelists: Dr Andrew Plump, President R&D, Takeda Pharmaceuticals Dr. James Bradner, President, Novartis Institutes for BioMedical Research Dr. Mathai Mammen, Global Head of R&D, Janssen Pharmaceutical Companies of J&J Moderator: Dr. Martin Mackay, Co-Founde, Rallybio
5:00 PM – 5:05 PM	Closing Remarks
5:05 PM – 6:15 PM	Cocktails & Networking Reception

9:10 AM – 9:20 AM

Welcome address: Karun Rishi, President, USAIC

Opening comments: Dr Andrew Plump, President R&D and Director, Takeda Pharmaceuticals

tomorrow announcement @Shire
India 1.3Billion in India, each person is a potential patient in the largest democracy in the World
China – transformation takes place every day
The Patient and the Pricing of Drugs the biggest issue missing the ball dialoguing on Panel today

9:20 AM – 9:40 AM

Fireside Chat

Mark Abdoo, Acting Deputy Commissioner, U.S. Food and Drug Administration (FDA)
Dr Eswara Reddy, Drug Controller General of India (DCGI), Central Drug Control Organization

Moderator: Sanat Chattopadhyay, President, Merck Manufacturing Division; Merck & Co.

9:40 AM – 10:00 AM Presentation on CAR (chimeric antigen receptor) T-cell Therapies
Dr. Carl June, Director of Translational Research, Abramson Cancer Center University of Pennsylvania Moderator: Dr. Raju Kucherlapati, Professor of Genetics, Harvard Medical School

Video on child with recurrent twice of leukhimia
T-cell HIV Virus infect

10:00 AM – 10:50 AM

Panelists:

Dr. Arjun Surya, Co-Founder & CSO, Curadev Pharma
Dr. Christopher Arendt, Head- Immunology Unit and Oncology DDU, Takeda

solid vs blood tumors
T-Cells amplification microenvironment and biology
PD-1 in combination therapies thousand Trials
Biomarker allows to check response in conjunction with genomics data brings insights
Tumors World, Biomarkers in Immuno oncology respond to PD-1 no response to other drug
stratify patients

Dr. David Meeker, President & CEO, KSQ Therapeutics

Protein experimental data compound design from simulations of VIRTUAL compounds,
how to incentivise to take on new innovations

Dr. Marcela Maus, Director of Cellular Immunotherapy, MGH Cancer Center

more that one single administration by injection
response rates different even in one patient let alone among patients
detection gene
CAR-T glioblastoma
pancreatic cancer good responses in combination therapies
immunr repertoire biology so complex that biomarkers are limited

Dr. Sanjiv Patel, President & Chief Executive Officer, Relay Therapeutics

Moderator: Dr. Christiana Bardon, Managing Director, MPM Capital

30% patinets with complete cure

10:50 AM – 11:20 AM Networking Break11:20 AM – 12:10 PM

Panel Discussion: Future of Clinical Trials and Drug Development

Panelists:

Dr. Alise Reicin, President, Global Clinical Development, Celgene

endpoints need to be redefined it effect price of drug development
in Oncology – Basket and Umbrellas Trial – two stufies approval for melanoma, biomarker
Is response rate is 30% va 50% and Phase 3 is negative Kertuda when worked at Merck dose ranging last phase when response dropped from 60% to 30% in the case of Study C3
30% of the cost of the study – 30% was translational
CRO model appropriate oversite vs douplication of tasks

Dr. Bruce Chabner, Director of Clinical Research, Mass General Hospital Cancer Center

Old paradigm Phase 1,2,3 – off the board now, New drugs do not need the old paradigm
Phase i1 changed if genomics is involved multiple cohorts at same time
FDA play amazing role
patient selection is key
mutations in rare disease vs mutations in cancer
immunotherapy and endogenic drugs with chemo in RENAL cancer
check-points – lung cancer understood money spent to find responders
HOW to select which cheno therapy — no improvement today vs past
40 drugs approved by accelerated approval one came back on the market
Financial burden of being in a clinical trial
Foundation gives money to Institutions to reimburse patients for flights, meals, acommodation, Pharma are reluctant to participants due to potential accusation of bias id Pharma pays Patients that participate in Clinical Trials

Dr. Mace Rothenberg, Chief Medical Officer, Pfizer

FDA recognizes approval process – systems involved AFTER approval for reimbursement and monitoring after market
regulatory by countires are different
which factors are sacrifiable in the long tern in clinical trial design

Dr. Michael Rosenblatt, Chief Medical Officer, Flagship Pioneering

Safety – benefit risk is what physicians work with every day
Drugs paradign of small molecules does not hold is you have a drug that deliver entire organelle – how you dose for half life how you prive the rate of replication in the body
Surrogate markers
Taking a drug off the market ->> conditional approvals [approval can be taken back or require additional studies] not a favorable view of Pharma in the present to support Conditional approval vs accelerated approval

Dr. Rob Scott, Chief Medical Officer, Abbvie

speed
differentiation from competition
drug development in crisis is CVD not cancer, US and the rest of the world – lowest investment in drugs is CVD
Studies designed by Physicians using SAME design
need to create experts to use ML in the course of clinical trial design
regulators as Partners not as Barriers
Proof of efficacy is a burden on the developers of the drug not on the Regulatory
Increase use of advertising to recruit
70% OF PATIENTS WILLING TO PARTICIPATE lives to far from site of trials
Telecommunication between administrators of study ans clinical Trials participants
Back when I was at Pfizer, designing study – patients burden relieved more willingness to participate
Preferrs to run studies in house vs use CRO they are not effective in monitoring like study run in house

Moderator: Dr. William Chin, Professor of Medicine, Emeritus, Harvard Medical School

Probability of success to clinic has not changed
challenge is design and execution in clinical trials
changes in drug modalities: RNA, DNA,
which combination to use
how to find the many patients needed
Basket and Umbrellas Trial

12:10 PM – 1:00 PM

Panel Discussion: Manufacturing in the Future

Panelists:

Hari Bhartia, Founder and Co-Chairman, Jubilant Bhartia Group

supply change
blockchain
quality by design
CPK
productivity will go up variability will decrease
manufacturng must happen in India
Genetics price selection
Secure system, data quality the data logic and the analytics
infrastructure in manufacturing is not completed yet
Training by augmented reality Turnover high in India
cyber security – digitization and central control
demonstration data offense

Mark Abdoo, Acting Deputy Commissioner, U.S. Food and Drug Administration

next 10 years India and China will improve regulatory activities and match better the US requirements
review foreign hosts
skills and location of hosts:
India: Standards and unannounced inspections and
China: same
Blockchain is experienced as experimentation at FDA across each all parts of the Agency

Dr. Paul McKenzie, Executive Vice President, Pharma Operations & Technology, Biogen

raw material to patients: Pharma very slow than other industries Reliable needs be very high, relationships
Hurrican in PortoRIco affected supply chain
Reality, every one HAVE to be in China
Platforming for each modality for Scaling out vs Scaling up
diversify vs modality x
build capacity and capabilities customization of ultra filtration different in two plants lowers standardizations
Training on Demand, Virtually, documnetation needs to change to electronic
Continueous manufacturing Academic contribution

Vinay Ranade, Chief Executive Officer, Reliance Life Sciences

Pharma was slow in India the manufacturing
infantile diarreha vaccine 70,000 in 4 years needs that drug,
massive intellectual capital in India
How to implement and make best use of data to improve processes
cyber security was not experiences

Sanat Chattopadhyay, President, Merck Manufacturing Division; Merck & Co.

Phase 1 scaling out vs up – it is different in vaccine field
ML, Block chain, supply chain and manufacturing will be adapted in supply chain
Apply analytics and relationships in manufacturing
obsolescence and upgrades
capture data electronically
cyber security can be a hazard hard to mitigate when all systems are down
significant challenges in manufacturing and data security

Moderator: Professor N. Venkat Venkatraman, Boston University Questrom School of Business

How can Pharma become leaner
heterogenuious environment for production
cyber security

1:00 PM – 1:50 PMLunch1:50 PM – 1:55 PM Video message from Suresh Prabhu, Hon’ble Minister of Commerce & Industry, Gov. of India1:55 PM – 2:45 PM

Panel Discussion: One in a million – Emerging trends in Rare Diseases

Panelists:

Dr. Daniel Curran, Head of the Rare Diseases Therapeutic Area Unit, Takeda

worked with Academic community on how to treat rare disease in the future

David Lucchino, Co-Founder and CEO, Frequency Therapeutics

Show clinical benefit and impact multiplemyeloma
patients becoming activists
access
foundation by patients
Patient to get cloud

Dr. Dhaval Patel, Executive Vice President and Chief Scientific Officer, UCB

if a modality will cure a disease justify innovation Model for payment: Mortgage Model
Access INDEX pricing – US will benchmark the price in other parts of the world
Gene therapy is not only got monognenic diseases but for
decrease work involved in development of drugs

Dr. James Wilson, Director – Gene Therapy Program, University of Pennsylvania

tension between physicians and development of the perfect drug.
AV
Protein replacement therapy repeated infusion gene therapy infrastructure develop in China for China, Develop in India for India vs develop in US for India or China
Cost of manufacturing to decrease

Dr. Timothy Yu, Assistant Professor in Pediatrics, Harvard Medical School

Scalability beyond the one case: the mechanism for the drug has generability for other aptients iwth same mutation the method has no limit
Molecular type of mutation Spice Switching strategy, just-in-time manufacturing

Moderator: Dr. Samarth Kulkarni, Chief Executive Officer, CRISPR Therapeutics

Rare diseases, potential for cure
Academia, Hospitals, biotech
commercial model of the disease

2:45 PM – 3:20 PMNetworking & Tea Break3:20 PM – 3:50 PM

Fireside Chat: Value and Access – The ongoing debate

Christopher Viehbacher, Managing Partner, Gurnet Point Capital

since 2003 testify in the House, against Canadian David Brenner was asked about importation from Canada of breast cancer tamoxiphen at a lower price than in the US.
From importation crisis to Obama Care – stable system Medicare Part D – drug coverage for Olderly
After Obama – Price is part of doing business REBATES $100Billion the valur of REBATES
Co-Insurance

Dr. John Maraganore, Chief Executive Officer, Alnylam Pharmaceuticals

right for innovation will be preserved
price increase
give and take
Co-pay – We need lower co-pay
with current administration, sink finding the Well instead of Well funding the sick
CHange is coming, co-pay will change

Dr. Stelios Papadopoulos, Chairman, Biogen

Genzyme days vs 2019
changes how drugs are priced?
Flaws of the system:Gevernment induce prices that will change
$800,000 drug is now $80 [ala Regeneron] – R&D was $2Billion
CO-pay for hospital stay is lower than co-pay on drugs – 10% twice a year

Moderator: Dr Andrew Plump, President R&D, Takeda Pharmaceuticals

3:50 PM – 4:10 PM

India update on Clinical Trial Regulations

Arun Singhal, Additional Secretary, Ministry of Health & Family Welfare, India

Each patient deserve access to healthcare in India
experimenting

Dr Eswara Reddy, Drug Controller General of India, Central Drug Control Organization

Time line for Application approval for drugs, if approved in another country 60 days
Gov’t hospitals can import New drugs which have not been permitted in India

4:10 PM – 5:00 PM

Panel Discussion: Research and Development Strategies and Trends

Panelists:

Dr Andrew Plump, President R&D, Takeda Pharmaceuticals

Neuroscience – Pharma understand biomarkers and now genetics
Vaccines – across species in the animal WORLD

Dr. James Bradner, President, Novartis Institutes for BioMedical Research

Attempt not to tweak the PIPELINE: CVD, NEUROSCIENCE AND CANCER
485 Teams doing R&D convluence of interests to develop cure
Modularity – BioMolecule — multimodality biophysical biochemical protein degradation – rewire disease cells with biomolecules combing propertitie of permiability of small molecules
PHARMACOLOGICAL PREVENTION – biotech is inspiring only Pharma can solve

Dr. Mathai Mammen, Global Head of R&D, Janssen Pharmaceutical Companies of J&J

immunooncology – mutation signature – marker protein signature — that group of diseases respond to
colon cancer and multiple myeloma — understanding of the biology was deep

Moderator: Dr. Martin Mackay, Co-Founder, Rallybio

5:00 PM – 5:05 PM Closing Remarks

5:05 PM – 6:15 PM Cocktails & Networking Reception

http://pharmaceuticalintelligence.com

Posted in Biochemical pathways, Enzymes and isoenzymes, Metabolomics, Neurodegenerative Diseases, Neurological Diseases, Parkinson's disease dyskinesia levodopa, Pharmacodynamics and Pharmacokinetics, Pharmacologic toxicities, tyrosine decarboxylases on January 23, 2019| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Decarboxylase enzymes can convert levodopa into dopamine. In contrast to levodopa, dopamine cannot cross the blood-brain barrier, so patients are also given a decarboxylase inhibitor. “But the levels of levodopa that will reach the brain vary strongly among Parkinson’s disease patients.

The bacterial tyrosine decarboxylase enzyme, which normally converts tyrosine into tyramine, but was found to also convert levodopa into dopamine. “We then determined that the source of this decarboxylase was Enterococcus bacteria.” The researchers also showed that the conversion of levodopa was not inhibited by a high concentration of the amino acid tyrosine, the main substrate of the bacterial tyrosine decarboxylase enzyme.

Carbidopa is over 10,000 times more potent in inhibiting the human decarboxylase,

the higher abundance of bacterial enzyme in the small intestines of rats reduced levels of levodopa in the bloodstream,

positive correlation between disease duration and levels of bacterial tyrosine decarboxylase.

Some Parkinson’s disease patients develop an overgrowth of small intestinal bacteria including Enterococci due to frequent uptake of proton pump inhibitors, which they use to treat gastrointestinal symptoms associated with the disease.

Altogether, these factors result in a vicious circle leading to an increased levodopa/decarboxylase inhibitor dosage requirement in a subset of patients.El Aidy concludes that

the presence of the bacterial tyrosine decarboxylase enzyme can explain why some patients need more frequent dosages of levodopa to treat their motor fluctuations. “This is considered to be a problem for Parkinson’s disease patients, because a higher dose will result in dyskinesia, one of the major side effects of levodopa treatment.“

SOURCE

https://www.rdmag.com/news/2019/01/how-gut-bacteria-affect-treatment-parkinsons-disease?type=cta&et_cid=6585419&et_rid=461755519&linkid=Mobius_Link

Article | OPEN | Published: 18 January 2019

Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease

Sebastiaan P. van Kessel,

Alexandra K. Frye,

Ahmed O. El-Gendy,

Maria Castejon,

Ali Keshavarzian,

Gertjan van Dijk &

Sahar El Aidy

Nature Communications volume 10, Article number: 310 (2019) | Download Citation

Abstract

Human gut microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we characterize gut-associated bacteria in their ability to decarboxylate levodopa to dopamine via tyrosine decarboxylases. Bacterial tyrosine decarboxylases efficiently convert levodopa to dopamine, even in the presence of tyrosine, a competitive substrate, or inhibitors of human decarboxylase. In situ levels of levodopa are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson’s disease. Finally, the higher relative abundance of bacterial tyrosine decarboxylases at the site of levodopa absorption, proximal small intestine, had a significant impact on levels of levodopa in the plasma of rats. Our results highlight the role of microbial metabolism in drug availability, and specifically, that abundance of bacterial tyrosine decarboxylase in the proximal small intestine can explain the increased dosage regimen of levodopa treatment in Parkinson’s disease patients.

Posted in Conference Coverage with Social Media, Drug Delivery Platform Technology, Drug Development Process, Drug Discovery Chemistry, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Informatics, Pharmaceutical R&D Investment, Pharmacodynamics and Pharmacokinetics, Pharmacogenomics, Pharmacologic toxicities on February 21, 2018| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Dr. Aviva Lev-Ari, PhD, RN, Editor-in-Chief, PharmaceuticalIntelligence.com will be in attendance covering this event for the Press using Social Media via 12 Channels

LOGO of LPBI Group

Our Journal has 1,373,977 eReaders on 1/29/2018, for All Time and 7,283 Scientific Comments

Aviva’s – +6,430 BIOTECH Followers on LinkedIn

http://www.linkedin.com/in/avivalevari

Aviva is a Member of +60 LinkedIn Groups in Biotech related fields

https://www.linkedin.com/groups/my-groups

LPBI Group’s FaceBook Page

http://www.facebook.com/LeadersInPharmaceuticalBusinessIntelligence

https://pharmaceuticalintelligence.com/2016/05/12/preliminary-agenda-available-and-exclusive-discount-to-attend-understanding-crispr-mechanisms-to-applications-symposium-in-boston-september-19-2016

LPBI Group’s Twitter Account

http://twitter.com/pharma_BI

LinkedIn (LI) Group Launcher and Manager of Three LI Groups

Cardiovascular Biotech & Pharma UK & US Networking Group

918 members (1/2018)

Leaders in Pharmaceutical Business Intelligence

342 members (1/2018)

Innovation in Israel

188 members (1/2018)

LPBI Group’s Company’s Page on LinkedIn

https://www.linkedin.com/company/9325543?trk=tyah&trkInfo=clickedVertical%3Acompany%2CclickedEntityId%3A9325543%2Cidx%3A1-1-1%2CtarId%3A1439226813927%2Ctas%3ALeaders%20in%20Pharmaceutica

For PROGRAMS, go to

September 26-27

September 27-28

September 26-27

September 27-28

September 26-27

September 27-28

September 26-27

September 27-28

September 25

Leadership we provide on curation of scientific findings in the eScientific publishing for Medical Education contents.

In Section 1, the Leadership we provide on curation of scientific findings in the eScientific publishing for Medical Education contents is demonstrated by a subset of several outstanding curations with high electronic Viewer volume. Each article included presents unique content contribution to Medical Clinical Education.

· These articles are extracted from the list of all Journal articles with >1,000 eReaders, 4/28/2012 to 1/29/2018.

Article Title, # of electronic Viewers, Author(s) Name

Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

16,114

Larry H. Bernstein, MD, FCAP

Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)		11,606	Vivek Lal, MBBS, MD, FCIR, Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care		5,865	Aviva Lev-Ari, PhD, RN
Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes	1,919			Aviva Lev-Ari, PhD, RN

Bystolic’s generic Nebivolol – Positive Effect on circulating Endothelial Progenitor Cells Endogenous Augmentation

1,059

Aviva Lev-Ari, PhD, RN

Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

1,339

Aviva Lev-Ari, PhD, RN

Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?	1,472		Aviva Lev-Ari, PhD, RN
Treatment of Refractory Hypertension via Percutaneous Renal Denervation	1,085		Aviva Lev-Ari, PhD, RN

Select

Aviva Lev-Ari, PhD, RN 2012pharmaceutical

3,064 Articles

· All (5,288)

avivalev-ari@alum.berkeley.edu

Administrator

3064

2.1 Volume of Articles in the Journal and in the 16 Volume-BioMed e-Series

1. Volume of Articles in the Journal since Journal inception on 4/28/2012:

· Total articles by ALL authors in Journal Archive on 1/29/2018 = 5,288

· ALL articles/posts Authored, Curated, Reported by Aviva Lev-Ari, PhD, RN = 3,064

2. Volume of Articles in the 16 Volume-BioMed e-Series

· Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-aviva-lev-ari-phd-rn/

· LPBI Group’s Founder: Biography and Bibliographies – Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/founder/

2.2 Digital Presence measured by eViews: Clicks on article by Author Name

Top Authors for all days ending 2018-01-29 (Summarized)

All Time

Author Name		electronic Views
Aviva Lev-Ari, PhD, RN [2012pharmaceutical]		352,153

LPBI Group

1,201

2.3 Digital KOL Parameters

Key Opinion Leader (KOL) – Aviva Lev-Ari, PhD, RN, as Evidenced by

https://pharmaceuticalintelligence.com/2016/07/21/key-opinion-leader-kol-aviva-lev-ari-phd-rn-as-evidenced-by/

L.H. Bernstein, MD, FCAP

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-larry-h-bernstein-md-fcap/

As BioMed e-Series Editor–in-Chief, I was responsible for the following functions of product design and product launch

· 16 Title creations for e-Books

· Designed 16 Cover Pages for a 16-Volume e-Books e-Series in BioMed

· Designed Series A eTOCs and approved of all 16 electronic Table of Contents (eTOCs), working in tandem with all the Editors of each volume and all the Author contributors of article contents in the Journal.

· Commissioned Articles by Authors/Curators per Author’s expertise on a daily basis

Below, see Volume Titles and Cover Pages:

13 LIVE results for Kindle Store: “Aviva Lev-Ari”

Oct 16, 2017 | Kindle eBook

by Larry H. Bernstein and Aviva Lev-Ari

Subscribers read for free.

$49.00^$ 49 ⁰⁰ to buy Kindle Edition

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

May 13, 2017 | Kindle eBook

by Larry H. Bernstein and Demet Sag

Subscribers read for free.

$100.00^$ 100 ⁰⁰ to buy Kindle Edition

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

Sep 4, 2017 | Kindle eBook

by Larry H. Bernstein and Aviva Lev-Ari

Subscribers read for free.

$115.00^$ 115 ⁰⁰ to buy Kindle Edition

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

Jun 20, 2013 | Kindle eBook

by Margaret Baker PhD and Tilda Barliya PhD

Subscribers read for free.

Get it TODAY, Jan 29

5 out of 5 stars 6

Sold by: Amazon Digital Services LLC

Dec 9, 2017 | Kindle eBook

by Larry H. Bernstein and Aviva Lev-Ari

Subscribers read for free.

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

Nov 28, 2015 | Kindle eBook

by Justin D. Pearlman MD ME PhD MA FACC and Stephen J. Williams PhD

Subscribers read for free.

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

Nov 29, 2015 | Kindle eBook

by Larry H. Bernstein MD FCAP and Aviva Lev-Ari PhD RN

Subscribers read for free.

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

Dec 30, 2017 | Kindle eBook

by Larry H. Bernstein and Irina Robu

Subscribers read for free.

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

Jul 21, 2015 | Kindle eBook

by Larry H. Bernstein MD FCAP and Prabodah Kandala PhD

Subscribers read for free.

Get it TODAY, Jan 29

5 out of 5 stars 1

Sold by: Amazon Digital Services LLC

Aug 10, 2015 | Kindle eBook

by Larry H Bernstein MD FCAP and Prabodh Kumar Kandala PhD

Subscribers read for free.

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

Nov 22, 2015 | Kindle eBook

by Sudipta Saha PhD and Ritu Saxena PhD

Subscribers read for free.

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

Dec 26, 2015 | Kindle eBook

by Larry H. Bernstein MD FACP and Aviva Lev-Ari PhD RN

Subscribers read for free.

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

Dec 26, 2015 | Kindle eBook

by Justin D. Pearlman MD ME PhD MA FACC and Ritu Saxena PhD

Subscribers read for free.

Get it TODAY, Jan 29

Sold by: Amazon Digital Services LLC

As BioMed e-Series Editor–in-Chief, Aviva Lev-Ari, PhD, RN was responsible for

· All the documentation (Instruction manuals) on Style setting, and for

· Training all team members

· Journal Articles Format

· Journal Comment Exchange Format

· e-Books Production Process:

1. Volume creation from Journal’s Article Archive,

2. Format Translation from HTML to .mobi for Kindle devices,

3. Proof reading process,

4. Title release,

5. Book electronic Upload to Amazon.com Cloud.

6. Connection of all articles and e-Books to Social Media, Ping back generation by mentioning other related articles published in the Journal

Lastly, 6, below

Title	Date of Publication	Number of Pages
Perspectives on Nitric Oxide in Disease Mechanisms	6/21/2013	895
Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation	11/30/2015	11039 KB
Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics	11/29/2015	12333 KB
Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases	12/26/2015	11668 KB
Genomics Orientations for Personalized Medicine	11/23/2015	11724 KB
Cancer Biology & Genomics for Disease Diagnosis	8/11/2015	13744 KB
Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery	5/18/2017	5408 pages
Metabolic Genomics and Pharmaceutics	7/21/2015	13927 KB
The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications	9/4/2017	3747 pages
The VOICES of Patients, Hospitals CEOs, Health Care Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures	10/16/2017	826 pages
Medical Scientific Discoveries for the 21st Century & Interviews with Scientific Leaders	12/9/2017	2862 pages
Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics	12/27/2015	11125 KB
Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices	12/30/2017	1005 pages
Pharmacological Agents in Treatment of Cardiovascular Disease	Work-in-Progress, Expected Publishing date in 2018	???
Interventional Cardiology and Cardiac Surgery for Disease Diagnosis and Guidance of Treatment	Work-in-Progress, Expected Publishing date in 2018	???

https://www.nih.gov/news-events/news-releases/new-drug-formulary-will-help-expedite-use-agents-clinical-trials

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Informatics, Pharmaceutical R&D Investment, Pharmacodynamics and Pharmacokinetics, The NCI Formulary on January 12, 2017| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Wednesday, January 11, 2017

istock/Astakhova

The National Cancer Institute (NCI) today launched a new drug formulary (the “NCI Formulary”) that will enable investigators at NCI-designated Cancer Centers to have quicker access to approved and investigational agents for use in preclinical studies and cancer clinical trials. The NCI Formulary could ultimately translate into speeding the availability of more-effective treatment options to patients with cancer.

The NCI Formulary is a public-private partnership between NCI, part of the National Institutes of Health, and pharmaceutical and biotechnology companies. It is also one of NCI’s efforts in support of the Cancer Moonshot, answering Vice President Biden’s call for greater collaboration and faster development of new therapies for patients. The availability of agents through the NCI Formulary will expedite the start of clinical trials by alleviating the lengthy negotiation process — sometimes up to 18 months — that has been required for investigators to access such agents on their own.

“The NCI Formulary will help researchers begin testing promising drug combinations more quickly, potentially helping patients much sooner,” said NCI Acting Director Douglas Lowy, M.D. “Rather than spending time negotiating agreements, investigators will be able to focus on the important research that can ultimately lead to improved cancer care.”

The NCI Formulary launched today with fifteen targeted agents from six pharmaceutical companies:

Bristol-Myers Squibb
Eli Lilly and Company
Genentech
Kyowa Hakko Kirin
Loxo Oncology
Xcovery Holding Company LLC

“The agreements with these companies demonstrate our shared commitment to expedite cancer clinical trials and improve outcomes for patients,” said James Doroshow, M.D., NCI Deputy Director for Clinical and Translational Research. “It represents a new drug development paradigm that will enhance the efficiency with which new treatments are discovered.”

The establishment of the NCI Formulary will enable NCI to act as an intermediary between investigators at NCI-designated Cancer Centers and participating pharmaceutical companies, facilitating and streamlining the arrangements for access to and use of pharmaceutical agents. Following company approval, investigators will be able to obtain agents from the available formulary list and test them in new preclinical or clinical studies, including combination studies of formulary agents from different companies.

The NCI Formulary leverages lessons learned through NCI’s Cancer Therapy Evaluation Program (CTEP) and the NCI-MATCH trial, a study in which targeted agents from different companies are being tested alone or in combination in patients with genetic mutations that are targeted by these drugs. As the use of genomic sequencing data becomes more common in selecting cancer therapies, requests for access to multiple targeted agents for the conduct of clinical trials are becoming more common.

“We are very pleased that several additional pharmaceutical companies have already pledged a willingness to participate and are in various stages of negotiation with NCI,” said Dr. Doroshow, who is also director of NCI’s Division of Cancer Treatment and Diagnosis. “By the end of 2017, we expect to have doubled the number of partnerships and drugs available in the NCI Formulary.”

CTEP staff continue to discuss the NCI Formulary with pharmaceutical companies to make additional proprietary agents available for studies initiated by investigators at NCI-designated Cancer Centers.

The Formulary will complement NIH’s plans for another new public-private partnership in oncology, the Partnership to Accelerate Cancer Therapies (PACT). Through PACT, the NIH, U.S. Food and Drug Administration, biopharmaceutical groups in the private sector, foundations, and cancer advocacy organizations will come together to support new research projects to accelerate progress in cancer research as part of the Cancer Moonshot. PACT research will center on the identification and validation of biomarkers of response and resistance to cancer therapies, with special emphasis on immunotherapies. PACT will also establish a platform for selecting and testing combination therapies. PACT is expected to launch in 2017.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and the NIH’s efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI’s Cancer Information Service at 1-800-4-CANCER.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

SOURCE

https://pharmaceuticalintelligence.com/2016/05/18/pancreatic-cancer-targeted-treatment/

Posted in Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cell death pathways, Drug Delivery Platform Technology, Immune Engineering, Immuno-Oncology & Genomics, Immunology, Oncolytic virus & OncoViro-Therapy, Pharmacodynamics and Pharmacokinetics, Translational Research, virology, tagged HSV, Pancreatic cancer, Poxviruses, virotherapy, virus delivery on July 24, 2016| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

We covered MGH’s Innovation on Tumor targeted therapy in Pancreatic Cancer in

Curator: Larry H. Bernstein, MD, FCAP

ONYX-015 was the first TOV used in a clinical trial for pancreatic cancer. ONYX-015 was administered intratumourally under endoscopic ultrasound-guidance into patients with locally advanced adenocarcinoma of the pancreas or metastatic disease in phase I/II trials[132]. The treatment was well-tolerated in most patients, however no objective responses were seen with ONYX-015 as a single agent and only 2/21 patients experienced mild responses when combined with gemcitabine[132]. A second adenovirus vector carries a deletion in the E1A gene[133]. E1A normally binds to the retinoblastoma protein, forcing cells to prematurely enter the S phase of the cell cycle. Since most pancreatic cancers harbor a mutation in CDKN2A[134], the E1A protein is unnecessary for entry of the TOV into cancer cells. Furthermore a double-deleted (E1A and E1B19) adenovirus demonstrated increase potency and selectivity in pancreatic cancer models[135,136]. This demonstrates that TOVs can be genetically engineered to increase selectivity and efficacy while maintaining their potency. Adenovirus selectivity has also been improved by engineering tumour-specific promoters such as a human CEA promoter[137] or by substituting the adenovirus serotype 5 fiber knob with the fiber knob from serotype 3[138]. The potency of TOVs can also be improved further by engineering them with therapeutic genes that stimulate the immune system and/or improve direct oncolysis. Adenovirus ZD55-IL-24 expressing IL-24 locally in pancreatic tumours in immune competent mice inhibited tumour growth and induced a stronger T cell response compared to its backbone virus, as measured by IL-6 and IFN-γ levels[139].

Two oncolytic HSV-1 vectors are currently in clinical trials for the treatment of pancreatic cancer. HF10 is a non-engineered, naturally occurring oncolytic HSV that demonstrated regression in 1/6 of the patients treated[140,141]. OncoVex GM-CSF is a ∆34.5 and ICP47-deleted mutant expressing GM-CSF, whereby the deletions allow for tumour-selective replication and inhibition of protein-kinase R activation, respectively[142]. Phase I/II trials in various solid tumours demonstrated OncoVex GM-CSF to be well-tolerated at high and repeated doses[143,144]. A phase I clinical trial with OncoVex GM-CSF in patients with unresectable pancreatic cancer is underway.

The most widely studied poxvirus is VV, which is highly immunogenic and produces a strong cytotoxic T cell response[145] and circulating neutralizing antibodies which can be detected decades later[146]. For its crucial role in the eradication of smallpox, much has been learned about its potential role in immunotherapy today. The Lister strain of vaccinia remarkably showed no replication degradation even under the hypoxic conditions of PDAC[147]. A second Lister strain, thymidine kinase-deleted replicating VV armed with IL-10 demonstrated superior and long-lasting antitumour immunity in both a subcutaneous pancreatic cancer model and a Kras-p53 mutant-transgenic pancreatic cancer model after systemic delivery compared to its unarmed backbone virus[148]. Myxoma virus, a rabbit-specific poxvirus combined with gemcitabine resulted in 100% long-term survival in Pan02-engrafted immunocompetent intraperitoneal dissemination models of pancreatic cancer[149]. The only poxvirus to be tested in clinical trials is a non-replicative VV that expresses the pancreatic TAAs CEA and MUC-2[150]. The vaccine also includes a triad of costimulatory molecules, B7.1 (CD80), ICAM-1 (intra-cellular adhesion molecule-1) and LFA-3 (leukocyte function-associated antigen-3) (TRICOM) (PANVAC-VF)[150]. GM-CSF was also used as an adjuvant following each vaccination of PANVAC-VF. Phase I trials demonstrated antigen-specific antitumour responses in 62.5% of patients enrolled and antibody responses against VV was observed in all ten patients, which was associated with an increase in survival (15.1 mo vs 3.9 mo)[48]. A phase III clinical trial for the treatment of metastatic pancreatic cancer after failing treatment with gemcitabine, however, was terminated after failing to reach its primary efficacy endpoint[151].

Parvovirus, measles virus and reovirus have also demonstrated pre-clinical activity in pancreatic cancer models. Parvoviruses particularly demonstrated enhanced IL-2-activated NK responses against PDAC cells[152,153]. An armed measles virus (MV), MV-purine nucleoside phosphorylase (PNP)-anti-prostate stem cell antigen, that expresses the prodrug convertase PNP, which then activates the prodrug fludarabine, was shown to enhance the oncolytic efficacy of the virus in gemcitabine-resistant PDAC cells[154]. Reovirus is another promising TOV for pancreatic cancer therapy, particularly because its selectivity depends on the cellular activity of Ras, which is constitutively active in pancreatic cancer[155]. Reolysin^® (Oncolytics Biotech Inc., Calgary, AB, Canada) a reovirus administered intraportally resulted in decreased metastatic tumour volumes in the liver of immunocompetent animal models[156,157]. A phase II study of Reolysin^® in combination with gemcitabine in patients with advanced PDAC has been completed (clinicaltrials.gov: NCT00998322). A two-armed randomized phase II study of carboplatin and paclitaxel plus Reolysin^® vs carboplatin and paclitaxel alone in recurrent or metastatic pancreatic cancer is currently being conducted by the United States National Cancer Institute (NCI-8601/OSU-10045).

A understanding how antitumour immunity is regulated allows us to recognize barriers against effective immunotherapy delivery and furthermore, allow for the development of rational combination therapies aiming targeting these mechanisms[108,158,159]. This approach allows therapies to work synergistically and also has the potential to benefit a broader patient population[108]. Tumours have evolved to avoid immune recognition and/or destruction at every stage in the antitumour response, therefore targeting more than one immune resistance mechanism will enhance antitumour immunity.

An important immunological barrier in cancer immunotherapy is the tolerance towards self-antigens. Tumours downregulate their antigenicity through various mechanisms in response to selective pressure by the immune system, a process called “immunoediting”[37]. Therefore, in order to raise an effective antitumour response, the immunological tolerance must be broken to allow tumour antigen-specific cytotoxic T cell responses[158]. This can be achieved by increasing the tumour load and/or enhance antigen presentation[108]. TOVs can initiate selective infection and replication in the tumour bed, exposing TAA, disrupting the immunotolerance employed by the tumour while re-engaging adaptive immune effector responses[39]. Combining an agent that can cause disruption to the tumour bed i.e., an oncolytic virus, with a novel antitumour immunomodulating agent such as anti-PD-1/PD-L1 antibodies can maximize immune-stimulating and immune-recruiting inflammatory responses[39]. Specifically, TOV lysis induces the release of tumour antigens into the microenvironment, which are then cross-presented to T cells in the draining lymph nodes by APCs[159] (Figure (Figure1).1). This allows T cell infiltration to the tumour bed. Next, T cell dysfunction must be reversed[108,158]. Immune checkpoint inhibitors alleviate immunosuppression, allowing the elimination of the tumour by the adaptive immune system[70]. TOVs in combination with immune checkpoint inhibitors can therefore potentiate and activate the immune system synergistically, ultimately creating a pro-inflammatory environment. Pre-existing TILs are strong prognostic predictors in cancer[106]. This is extremely relevant for tumours with poor immune-cell infiltration, such as pancreatic cancer, which would depend on TOV-infection mediated lymphocyte infiltration for an enhanced response to immune checkpoint blockade. Zamarin et al[160] demonstrated constrained replication of an intratumoural-injected Newcastle disease virus in a B16 melanoma model. Lymphocytic infiltrates, however, were detected in both TOV-injected and non-TOV-injected tumours, and rendered the tumours sensitive to CTLA-4 blockade. The antitumour activity was dependent on CD8⁺ T cells, NK cells and type I and II IFNs[160]. Ipilimumab with or without talimogene laherparapvec, is in early clinical testing in patients with unresected melanoma (clinicaltrials.org: NCT01740297). Interestingly, an MV engineered to express CTLA-4 or PD-L1 antibodies delayed tumour progression and prolonged median OS in B16 melanoma models[161]. Finally, TOVs have demonstrated a tolerable toxicity profile, whereby flu-like symptoms are the most common adverse events, and in fact, most of the side effects seen so far in the combination regiment are related to the immune checkpoint blockade inhibitor[162]. Dias et al[163] suggested an oncolytic adenovirus expressing CTLA-4 locally might reduce systemic side effects normally induced with anti-CTLA-4 antibodies alone.

The main issue with virotherapy is systemic delivery for targeting metastatic cancer cells. Intravenous administration is more practical, especially for treatment of a tumour in a hard-to-reach location such as the pancreas, and with the majority of patients presenting with advanced or metastatic disease. However, nonimmune human serum and existing anti-TOV antibodies may neutralize the TOV in the bloodstream. Furthermore, non-specific hepatic and splenic sequestration of the TOV and ineffective extravasation into the tumours are important issues[164]. Currently, studies in pre-clinical models aim to overcome these obstacles. These include chemical modification of viral coat proteins by conjugation of biocompatible polymers e.g. polyethylene glycosylation[165,166], using mesenchymal stem cell carrier systems to deliver the TOV to the tumour bed[167–169], and increasing vessel permeabilization[170,171].

In PDAC, however, the biggest hurdle may not be the host immune system, but the TME. The TME has played a significant role in not only acting as a physical barrier to deliver treatments, but it also in the development of resistance to conventional drugs. The TME remains a problem for successful TOV treatment. The TOV must be able to spread in the hypoxic and densely stromal-rich TME in order to attract enough attention to induce antitumour immunity[172]. Breaching the stromal barrier in PDAC is needed for TOVs to access the cancer cells[173]. Paradoxically, a recent study by Ilkow et al[174] demonstrated that the cross-talk between CAFs and cancer cells actually lead to increased permissibility of TOV-based therapeutics. Tumour cells producing TGF-α reprogrammed CAFs, dampening levels of anti-viral transcripts. This allowed the cells to be more sensitive to VV, vesicular stomatitis virus and maraba MG1 TOVs. The reprogrammed CAFs produced fibroblast growth factor (FGF)-2 which suppressed levels of retinoic acid-inducible gene I and increased the susceptibility of the tumour cells to virus[175]. This study also demonstrated that an FGF2-expressing TOV has improved therapeutic efficacy by sensitizing the tumour cells to virotherapy and is particularly relevant to pancreatic cancers, where CAFs are a major component of the tumour stroma[175]. It is important to note that not only the patient’s existing immune system may impede successful TOV therapy, but that the enhanced antitumour response by combinatory approaches (e.g., the inclusion of immune-checkpoint inhibitors) may also impede successful TOV infection, spread and engagement of the immune system. This stresses the importance of determining strategic combinations, dosing and timing schedules in future studies.

The poor prognosis of pancreatic cancer due in part to the limited efficacy of conventional and targeted therapies, appeals for a novel strategy to treat this disease. It has become very clear that the immune system has the greatest potential to selectively destroy tumours, and when it is strategically induced, a durable benefit can be achieved. Past and present studies have defined means for tumour escape from immune surveillance and have developed immunotherapies to counteract these mechanisms. However, with the various escape strategies leading to low immunogenicity and highly immunosuppressive tumour beds, a successful control of tumour growth by immunotherapy does not come without various obstacles and challenges. Future steps include the development of immune-monitoring strategies for the identification of biomarkers, to establishment guidelines to assess clinical end points of immunotherapy and finally to evaluate combination therapeutic strategies to maximize clinical benefit[176]. The ability of TOVs to stimulate inflammation, deliver genes and immunomodulatory agents as well as reduce tumour burden by direct cell lysis, allows them to be important therapeutic vectors for a highly immunosuppressed tumour such as PDAC. Immune checkpoint blockade agents can then reverse T cell anergy and further boost OV-induced responses. As this combinatory approach may exist as a double-edged sword, it is crucial to determine appropriate timing, dosing and sequence schedules of each agent.

SOURCE & REFERENCES

World J Gastroenterol. 2016 Jan 14; 22(2): 748–763.

Published online 2016 Jan 14. doi: 10.3748/wjg.v22.i2.748

PMCID: PMC4716074

Andrea Marie Ibrahim and Yao-He Wang

Author information ► Article notes ► Copyright and License information ►

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716074/

http://www.genengnews.com/gen-articles/pharmacogenetics-for-the-rest-of-us/5751/

Posted in Personalized and Precision Medicine & Genomic Research, Pharmaceutical Drug Discovery, Pharmacodynamics and Pharmacokinetics, Pharmacogenomics, tagged Personalized medicine, Pharmacogenetics on May 5, 2016| Leave a Comment »

Larry H. Bernstein, MD, FCAP, Curator

LPBI

The New Landscape of Pharmacogenetics

Standardized Assays Are Driving Preemptive Genotyping and Personalized Drug Therapies

Eric T. Fung, M.D., Ph.D.

For decades, genotyping has promised to serve as a practical means of relating genetic make-up and pharmacological efficiency—first at the level of patient groups and more recently at the level of individuals. Genotyping, however, still has a fairly limited role in determining which drug therapies, and which doses, should be used in specific circumstances.

If genotyping is to find widespread adoption, it will have to overcome several barriers, most notably variation in assays and delay in reporting, difficulty in translating genotype into specific actions, and a perceived lack of economic and/or clinical value. Technological advances coupled with changes in the availability of genetic information will dramatically change the landscape of pharmacogenetics.

The efficacy of any given drug therapy is dependent on a number of factors, most commonly described through the pharmacokinetic parameters of absorption, distribution, metabolism, and elimination (ADME). Together, these factors determine whether a patient will need increased or decreased dosages, or whether a given therapy will work at all in that patient. Additionally, these factors can determine drug-drug interactions for patients on polypharmacy.
Genotype Variants

Although a detailed description of specific genotype variants is beyond the scope of this article, a brief survey of the diversity of genotypes is helpful to provide a sense of the complexity that is inherent in genotyping, which has, in some ways, slowed the adoption of pharmacogenetics. As an example, human leukocyte antigen (HLA) genes are among the most highly polymorphic genes; more than 3,600 HLA class II alleles have been described.

More than 50 human cytochromes P450 (CYPs) have been identified, and most have at least several single nucleotide polymorphisms (SNPs), with CYP2D6 having over 100 identified SNPs. Specific combinations of polymorphisms are translated into star alleles, which are used to predict the impact on therapeutic response.

As might be expected, any individual enzyme can metabolize multiple drugs, and most drugs can be metabolized by multiple enzymes. Drugs can also inhibit metabolizing enzymes, while metabolizing enzymes can activate drugs by converting prodrugs into active metabolites. Generally, changes in functional activity of the enzyme are translated clinically by categorizing patients as poor, intermediate, extensive, or ultrarapid metabolizers.

The FDA has now included pharmacogenomics information in the labeling of 166 approved drugs, some of which include specific action to be taken based on biomarker information. Table 1summarizes the biomarkers and indications for the pharmacogenomics labels. The FDA labels rangefrom dosage and pharmacokinetics information to precautions and, in nine of the labels, boxed warnings to highlight potentially serious adverse reactions.

Most pharmacogenetics assays are currently offered as laboratory-developed tests; therefore, there is a wide range in the specific variants that are reported for any given target. As noted above, CYP2D6 has over 100 identified SNPs, and laboratories report various numbers of star alleles. Historically, this is because most genotyping assays involve methods based on the multiplex polymerase chain reaction (PCR). Accordingly, in these assays, the cost or effort to perform the genotyping is approximately proportional to the size of the panel.

Additionally, because some of the functional variants are copy number changes, multiple assays may be required (for example, quantitative PCR for copy number, plus PCR for genotyping). More recent advances in microarray technology make it possible to perform more complete genotyping and copy number analysis of known star alleles simultaneously across multiple genes, thus reducing the cost and increasing the efficiency of pharmacogenomics. For example, the Affymetrix DMET Axiom Assay can analyze over 4,000 genotypes across 900 genes along with copy number in a single assay.

From a regulatory perspective, it is likely that the disparate technologies laboratories use to generate their pharmacogenetics results will coalesce into a few, defined FDA-cleared devices. Because arrays can reproducibly provide comprehensive genotyping and copy number information at low cost, analytical and clinical validity can be readily demonstrated in a regulatory submission.

The translation of specific genotype combinations into actionable clinical utility is hampered by difficulties in interpretation. Part of this relates to the somewhat ambiguous notation of the impact of a given star allele; the designation “ultrametabolizer,” for example, does not obviously translate to a specific dose for a given individual.

Additionally, parameters such as ethnicity, age, body mass index, and gender can influence the pharmacokinetics in any specific individual. The establishment of guidelines can assist the practitioner in utilizing pharmacogenetics information to make therapeutic selections. At the forefront of establishing guidelines is the Clinical Pharmacogenetics Implementation Consortium (CPIC), which provides guidelines centered around specific genes as well as for specific drugs.

Click Image To Enlarge +

Physicians, who need to make therapeutic decisions quickly and cannot wait for genotype results, are increasingly looking at preemptive genotyping as a potential solution to improve treatment options. [iStock/D3Damon]

In most cases, physicians need to make treatment decisions immediately and cannot wait for genotype results. The obvious solution to this is preemptive genotyping, which is being deployed at five academic medical institutions (Mayo Clinic, Mount Sinai, St. Jude Children’s Research Hospital, University of Florida and Shands Hospital, and Vanderbilt University Medical Center) as part of the Translational Pharmacogenetics Program.

For preemptive genotyping to be widely deployed, the structure of electronic health records (EHRs) will need to evolve so that they enable the retrieval, storage, and reporting of complex genotyping data. Moreover, they will need to be able to provide the translation of star alleles with metabolizing status for specific drugs, dosing guidelines or suggestions for alternative drugs, and links to guidelines and other supporting information.

The most sophisticated embodiments of EHRs will also take into account other information that can influence dosing contained within the EHR, such as the patient’s ethnicity, weight, sex, and other medications. Most EHRs lack such capabilities, but two trends will substantially alter this landscape.

First, there is an increasing recognition of the role medical informatics plays in healthcare and an increased emphasis on this role at medical institutions, both academic and community-based. Second, the entry of high-tech giants such as Google and Apple into the medical informatics and large-scale genotyping/genetic analysis arena will accelerate the development of these tools.

Third-party payers have generally been reluctant to pay for most pharmacogenetics tests. The paucity of prospective randomized clinical studies showing either clinical or economic utility remains a fundamental hurdle for widespread adoption of pharmacogenetics. A likely path for the generation of clinical data will be through large, publicly funded genotyping initiatives in combination with investigator-initiated studies that rely primarily on mining EHRs for dosing, adverse reaction, and outcome information.

One such initiative is tied to the Million Veterans Program. It is mining data to explore the pharmacogenetics of metformin response in diabetics with renal disease.

Another push may come from consumers who choose to proactively obtain their pharmacogenetics information. Such activity will heavily depend on the appropriate EHR and bioinformatics infrastructure at primary care centers as well as harmonization of analytical test methods. These requirements suggest that consumer-driven work will lag the efforts at academic medical centers.

Future Perspectives

Future Perspectives

The pace at which pharmacogenetics is incorporated into healthcare will increase due to factors such as the decreasing cost of genotyping, the installation of a medical informatics infrastructure, and increased consumer demand for personal genotyping information. Moreover, these factors will reinforce each other and help preemptive genotyping become the norm rather than the exception.

As this trend gathers momentum, it will begin contributing to a virtuous cycle in which the increased availability of genotyping data associated with outcome information will permit the development of additional and more precise treatment algorithms. Technological advances in genotyping, most notably high-density genotyping at low cost with high reproducibility, and medical informatics will be key to making this a reality.

Eric T. Fung, M.D., Ph.D. (Eric_Fung@affymetrix.com), is vice president of R&D clinical applications at Affymetrix.

http://www.kurzweilai.net/nanoparticle-cluster-bombs-destroy-cancer-cells

Posted in Cancer - General, Cancer and Current Therapeutics, Curation, Nanotechnology for Drug Delivery, Pharmaceutical Drug Discovery, Pharmacodynamics and Pharmacokinetics, Pharmacologic toxicities, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, tagged nanomedicine, particle size, pH stimuli responsive, tumor extracellular, tumor penetration on April 10, 2016| Leave a Comment »

Avoiding chemotherapy toxicities

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Nanoparticle ‘cluster bombs’ destroy cancer cells

New delivery method directly penetrates tumor cells, avoiding toxic side effects of cisplatin chemotherapy drug

http://www.kurzweilai.net/images/Anticancer-cluster-bombs520.png

The nanoparticles start out relatively large (100 nm) (large blue circle, upper left) to enable smooth transport into the tumor through leaky blood vessels. Then, in acidic conditions found close to tumors, the particles discharge “bomblets” (right, small blue circles) just 5 nm in size. Once inside tumor cells, a second chemical step activates the platinum-based drug cisplatin (bottom) to attack the cancer directly. (credit: Emory Health Sciences)

Scientists have devised a triple-stage stealth “cluster bomb” system for delivering the anti-cancer chemotherapy drug cisplatin, using nanoparticles designed to break up when they reach a tumor:

The nanoparticles start out relatively large — 100 nanometers wide — so that they can move through the bloodstream and smoothly transport into the tumor through leaky blood vessels.
As they detect acidic conditions close to tumors, the nanoparticles discharge “bomblets” just 5 nanometers in size to penetrate tumor cells.
Once inside tumor cells, the bomblets release the platinum-based cisplatin, which kills by crosslinking and damaging DNA.

Doctors have used cisplatin to fight several types of cancer for decades, but toxic side effects — to the kidneys, nerves and inner ear — have limited its effectiveness. But in research with three different mouse tumor models*, the researchers have now shown that their nanoparticles can enhance cisplatin drug accumulation in tumor tissues for several types of cancer.

Details of the research — by teams led by professor Jun Wang, PhD, at the University of Science and Technology of China and by professor Shuming Nie, PhD, in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory — were published this week in the journal PNAS.

* When mice bearing human pancreatic tumors were given the same doses of free cisplatin or cisplatin clothed in pH-sensitive nanoparticles, the level of platinum in tumor tissues was seven times higher with the nanoparticles. This suggests the possibility that nanoparticle delivery of a limited dose of cisplatin could restrain the toxic side effects during cancer treatment.

The researchers also showed that the nanoparticles were effective against a cisplatin-resistant lung cancer model and an invasive metastatic breast cancer model in mice. In the lung cancer model, a dose of free cisplatin yielded just 10 percent growth inhibition, while the same dose clothed in nanoparticles yielded 95 percent growth inhibition, the researchers report. In the metastatic breast cancer model, treating mice with cisplatin clothed in nanoparticles prolonged animal survival by weeks; 50 percent of the mice were surviving at 54 days with nanoparticles compared with 37 days for the same dose of free cisplatin.

Abstract of Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.

Hong-Jun Li, Jin-Zhi Du, Xiao-Jiao Du, Cong-Fei Xu, Chun-Yang Sun, Hong-Xia Wang, Zhi-Ting Cao, Xian-Zhu Yang, Yan-Hua Zhu, Shuming Nie, and Jun Wang.
Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy.
PNAS 2016 ; published ahead of print March 28, 2016; doi:10.1073/pnas.1522080113

The facts suggest that big pharma represents only a few companies in most fields of disease. They spend an enormous amount of money in lobbying congress and doctors to get them to do their bidding.They wouldn’t spend the money if they didn’t need to do so.The profit motive is central with patient well being only being practiced if it pays off.Cancer is a superb example, with new drugs being offered usually at astronomical prices in this country. Like wise the FDA is controlled by them and it is in their best interests to make the cost of developing new drugs outrageously expensive.Only big pharma can afford to get new drugs approved.

After the phase 3 trials are completed usually the documentation to ask for approval to market a drug is at least 100,000 pages long. The legal talent needed to compile such documents ( and this is only one of many documents produced in the process) is extremely expensive. The time taken for approval stretches into many years and then the drugs are often not approved.(only a small percentage are approved).

Antibiotics were one example of a group of drugs that really did cure many diseases. Big pharma found it didn’t pay to develop new antibiotics because the treatment was short and so successful that patients used the drugs only for a short time.

Over time, as Alexander Fleming forsaw, the bacteria would develop resistance, especially if they were extensively used indiscriminantly. Now many dangerous bacteria are resistant to many or all antibiotics and there is no treatment available. Since bacteria can pass this resistance to specific antibiotics to almost any species of bacteria, its only a matter of time before we will be back in the pre-antibiotic era.

SINCE IT DOES NOT PAY FOR BIG PHARMA TO DEVELOP NEW ANTIBIOTICS THEY ARE NOW NOT DOING SO AT ALL.

…..

“In the metastatic breast cancer model, treating mice with cisplatin clothed in nanoparticles prolonged animal survival by weeks; 50 percent of the mice were surviving at 54 days with nanoparticles compared with 37 days for the same dose of free cisplatin.”

I’m not so convinced after all. But this is perfectly in line with big pharma goals. Only an idiot would kill its main source of income.

…….

It is almost impossible to set up a conspiracy against big pharma’s abusive practices.Every avenue their high priced lawyers can think of to stop budding conspiracies has been blocked by law where possible. One possible road might be to do research and development in other countries outside US legal juristiction, however most drugs without FDA approval can and are stopped at the border and confiscated even if as in Canada the same drug produced in the US is being manufactured in Canada.Almost certainly Cisplatin is under patent in the US and the patent holder has the right to refuse the use of the drug for any reason they want, including being used in this cluster bomb drug. The manufacturer is almost certainly making huge profits from selling Cisplatin and I doubt they want to see a cheap drug cure many cancers. I guess the only way to go is to try and turn to a country like India.A number of cancer drugs were being sold by US patent holders at wholesale prices that were to high for most Indians. The government of India refused to allow these companies to patent their medicines in India and forced them to license the drugs and much cheaper prices.Most US patents are not operative in India, they can produce US style insulin pumps at a fraction of our cost as they can in China and Vietnam or Mexico. It would be difficult to send these pumps to buyers in the US from India but by shipping them from another country, say Canada or Mexico most would make it past customs. As for Cancer treatment, India and china have some very fine trained biochemist and doctors, who could easily apply many of the immunological treatments against cancer. All arms of the immune system have been used to produce miracle treatments that have cured some patients that were on their death beds.The treatments can be tested carefully in these countries, and improved by any methods including some I have suggested.By advertising in the US to cancer patients that they can inexpensively have these working treatments cheaply as a medical tourist, it is only a matter of time before they will cure the disease wholesale and break the medical industrial complex down. As far as generics that are not being produced here, by setting up a non profit corporation that produces any and all drugs that come off patent as a goal, at the cheapest price less a reasonable markup for cost of manufacture etc. one by one they will end the abuse of not producing or overpricing generics.

………

Significance

Successively overcoming a series of biological barriers that cancer nanotherapeutics would encounter upon intravenous administration is required for achieving positive treatment outcomes. A hurdle to this goal is the inherently unfavorable tumor penetration of nanoparticles due to their relatively large sizes. We developed a stimuli-responsive clustered nanoparticle (iCluster) and justified that its adaptive alterations of physicochemical properties (e.g. size, zeta potential, and drug release rate) in accordance with the endogenous stimuli of the tumor microenvironment made possible the ultimate overcoming of these barriers, especially the bottleneck of tumor penetration. Results in varying intractable tumor models demonstrated significantly improved antitumor efficacy of iCluster than its control groups, demonstrating that overcoming these delivery barriers can be achieved by innovative nanoparticle design.

http://www.pnas.org/content/early/2016/03/23/1522080113.full

Uses light-triggered bioelectric current

Tufts University biologists have demonstrated (using a frog model*) for the first time that it is possible to prevent tumors from forming (and to normalize tumors after they have formed) by using optogenetics (light) to control bioelectrical signalling among cells.

Light/bioelectric control of tumors

Virtually all healthy cells maintain a more negative voltage in the cell interior compared with the cell exterior. But the opening and closing of ion channels in the cell membrane can cause the voltage to become more positive (depolarizing the cell) or more negative (polarizing the cell). That makes it possible to detect tumors by their abnormal bioelectrical signature before they are otherwise apparent.

The study was published online in an open-access paper in Oncotarget on March 16.

The use of light to control ion channels has been a ground-breaking tool in research on the nervous system and brain, but optogenetics had not yet been applied to cancer.

The researchers first injected cells in Xenopus laevis (frog) embryos with RNA that encoded a mutant RAS oncogene known to cause cancer-like growths.

The researchers then used blue light to activate positively charged ion channels,which induced an electric current that caused the cells to go from a cancer-like depolarized state to a normal, more negative polarized state. The did the same with a green light-activated proton pump, Archaerhodopsin (Arch). Activation of both agents significantly lowered the incidence of tumor formation and also increased the frequency with which tumors regressed into normal tissue.

“These electrical properties are not merely byproducts of oncogenic processes. They actively regulate the deviations of cells from their normal anatomical roles towards tumor growth and metastatic spread,” said senior and corresponding author Michael Levin, Ph.D., who holds the Vannevar Bush chair in biology and directs the Center for Regenerative and Developmental Biology at Tufts School of Arts and Sciences.

“Discovering new ways to specifically control this bioelectrical signaling could be an important path towards new biomedical approaches to cancer. This provides proof of principle for a novel class of therapies which use light to override the action of oncogenic mutations,” said Levin. “Using light to specifically target tumors would avoid subjecting the whole body to toxic chemotherapy or similar reagents.”

This work was supported by the G. Harold and Leila Y. Mathers Charitable Foundation.

* Frogs are a good model for basic science research into cancer because tumors in frogs and mammals share many of the same characteristics. These include rapid cell division, tissue disorganization, increased vascular growth, invasiveness and cells that have an abnormally positive internal electric voltage.

Abstract of Use of genetically encoded, light-gated ion translocators to control tumorigenesis

It has long been known that the resting potential of tumor cells is depolarized relative to their normal counterparts. More recent work has provided evidence that resting potential is not just a readout of cell state: it regulates cell behavior as well. Thus, the ability to control resting potential in vivo would provide a powerful new tool for the study and treatment of tumors, a tool capable of revealing living-state physiological information impossible to obtain using molecular tools applied to isolated cell components. Here we describe the first use of optogenetics to manipulate ion-flux mediated regulation of membrane potential specifically to prevent and cause regression of oncogene-induced tumors. Injection of mutant-KRAS mRNA induces tumor-like structures with many documented similarities to tumors, in Xenopus tadpoles. We show that expression and activation of either ChR2^D156A, a blue-light activated cation channel, or Arch, a green-light activated proton pump, both of which hyperpolarize cells, significantly lowers the incidence of KRAS tumor formation. Excitingly, we also demonstrate that activation of co-expressed light-activated ion translocators after tumor formation significantly increases the frequency with which the tumors regress in a process called normalization. These data demonstrate an optogenetic approach to dissect the biophysics of cancer. Moreover, they provide proof-of-principle for a novel class of interventions, directed at regulating cell state by targeting physiological regulators that can over-ride the presence of mutations.

Brook T. Chernet, Dany S. Adams, Maria Lobikin, Michael Levin. Use of genetically encoded, light-gated ion translocators to control tumorigenesis. Oncotarget, March 16, 2016; DOI: 10.18632/oncotarget.8036 (open access)

A biosensor that’s 1 million times more sensitive

Aims at detecting cancers earlier, improving treatment and outcomes

http://www.kurzweilai.net/a-biosensor-thats-1-million-times-more-sensitive

http://www.kurzweilai.net/images/miniaturized-GC-HMM-sensor-device.jpg

A schematic representation of the miniaturized gold-aluminum oxide hyperbolic metamaterial (HMM) sensor device with a fluid flow channel, showing a scanning electron microscope (SEM) image [gray inset] of the 2D subwavelength gold diffraction grating on top of the hyperbolic metamaterials layers (scale bar, 2 µm) (credit: Kandammathe Valiyaveedu Sreekanth et al./Nature Materials

An optical sensor that’s 1 million times more sensitive than the current best available has been developed by Case Western Reserve University researchers. Based on nanostructured metamaterials, it can identify a single lightweight molecule in a highly dilute solution.The research goal is to provide oncologists a way to detect a single molecule of an enzyme produced by circulating cancer cells. That could allow doctors to diagnose and monitor patients with certain cancers far earlier than possible today.

“The prognosis of many cancers depends on the stage of the cancer at diagnosis,” said Giuseppe “Pino” Strangi, professor of physics at Case Western Reserve and research leader. “Very early, most circulating tumor cells express proteins of a very low molecular weight, less than 500 Daltons,” Strangi explained. “These proteins are usually too small and in too low a concentration to detect with current test methods, yielding false negative results.

“With this platform, we’ve detected proteins of 244 Daltons, which should enable doctors to detect cancers earlier — we don’t know how much earlier yet,” he said. “This biosensing platform may help to unlock the next era of initial cancer detection.”

The researchers believe the sensing technology will also be useful in diagnosing and monitoring other diseases.

A biological sieve

The nanosensor, which fits in the palm of a hand, acts like a biological sieve, capable of isolating a small protein molecule weighing less than 800 quadrillionths of a nanogram from an extremely dilute solution.

To make the device so sensitive, Strangi’s team faced two long-standing barriers: Light waves cannot detect objects smaller than their own physical dimensions (about 500 nanometers, depending on wavelength). And molecules in dilute solutions float in Brownian (random) motion and are unlikely to land on the sensor’s surface.

The solution was to use a microfluidic channel to restrict the molecules’ ability to float around and a plasmon-based metamaterial made of 16 nanostructured layers of reflective and conductive gold and transparent aluminum oxide, a dielectric, each 10s of atoms thick. Light directed onto and through the layers is concentrated into a very small volume much smaller than the wavelength of light.*

“It’s extremely sensitive,” Strangi said. “When a small molecule lands on the surface, it results in a large local modification, causing the light to shift.” Depending on the size of the molecule, the reflecting light shifts different amounts. The researchers hope to learn to identify specific biomarker and other molecules for different cancers by their light shifts.

To add specificity to the sensor, the team added a layer of trap molecules — molecules that bind specifically with the molecules they hunt. In tests, the researchers used two trap molecules to catch two different biomolecules: bovine serum albumin, with a molecular weight of 66,430 Daltons, and biotin, with a molecular weight of 244 Daltons. Each produced a signature light shift.

Other researchers have reported using plasmon-based biosensors to detect biotin in solutions at concentrations ranging from more than 100 micromoles per liter to 10 micromoles per liter. This device proved 1 million times more sensitive, finding and identifying biotin at a concentration of 10 picomoles per liter.

Testing and clinical use in process

Strangi’s lab is working with other oncologists worldwide to test the device and begin moving the sensor toward clinical use.

In Cleveland, Strangi and Nima Sharifi, MD, co-leader of the Genitourinary Cancer Program for the Case Comprehensive Cancer Center, have begun testing the sensor with proteins related to prostate cancers.

“For some cancers, such as colorectal and pancreatic cancer, early detection is essential,” said Sharifi, who is also the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic. “High sensitivity detection of cancer-specific proteins in blood should enable detection of tumors when they are at an earlier disease stage.

“This new sensing technology may help us not only detect cancers, but what subset of cancer, what’s driving its growth and spread, and what it’s sensitive to,” he said. “The sensor, for example, may help us determine markers of aggressive prostate cancers, which require treatments, or indolent forms that don’t.”

The research is published online in the journal Nature Materials.

* The top gold layer is perforated with holes, creating a grating that diffuses light shone on the surface into two dimensions. The incoming light, which is several hundreds of nanometers in wavelength, appears to be confined and concentrated in a few nanometers at the interface between the gold and the dielectric layer. As the light strikes the sensing area, it excites free electrons causing them to oscillate and generate a highly confined propagating surface wave, called a surface plasmon polariton. This propagating surface wave will in turn excite a bulk wave propagating across the sensing platform. The presence of the waves cause deep sharp dips in the spectrum of reflecting light. The combination and the interplay of surface plasmon and bulk plasmon waves are what make the sensor so sensitive. Strangi said. By exciting these waves through the eight bilayers of the metamaterial, they create remarkably sharp resonant modes. Extremely sharp and sensitive resonances can be used to detect smaller objects.

Abstract of Extreme sensitivity biosensing platform based on hyperbolic metamaterials

Optical sensor technology offers significant opportunities in the field of medical research and clinical diagnostics, particularly for the detection of small numbers of molecules in highly diluted solutions. Several methods have been developed for this purpose, including label-free plasmonic biosensors based on metamaterials. However, the detection of lower-molecular-weight (<500 Da) biomolecules in highly diluted solutions is still a challenging issue owing to their lower polarizability. In this context, we have developed a miniaturized plasmonic biosensor platform based on a hyperbolic metamaterial that can support highly confined bulk plasmon guided modes over a broad wavelength range from visible to near infrared. By exciting these modes using a grating-coupling technique, we achieved different extreme sensitivity modes with a maximum of 30,000 nm per refractive index unit (RIU) and a record figure of merit (FOM) of 590. We report the ability of the metamaterial platform to detect ultralow-molecular-weight (244 Da) biomolecules at picomolar concentrations using a standard affinity model streptavidin–biotin.

Posted in Cerebrovascular and Neurodegenerative Diseases, Clinical Diagnostics, Curation, Dialectic, Discovery process, Disease Biology, Experimental validation, Explanatory, Historical relevance, Neurological Diseases, Neuroscience, Pharmaceutical Drug Discovery, Pharmacodynamics and Pharmacokinetics, Pharmacotherapy of Cardiovascular Disease, Systemic Inflammatory Response Related Disorders, Translational Science, Vision on February 21, 2016| Leave a Comment »

High blood pressure can damage the retina’s blood vessels and limit the retina’s function. It can also put pressure on the optic nerve.

Sourced through Scoop.it from: www.healthline.com

See on Scoop.it – Cardiovascular Disease: PHARMACO-THERAPY

Posted in Drug Delivery Platform Technology, Pharmaceutical Analytics, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical R&D Informatics, Pharmaceutical R&D Investment, Pharmacodynamics and Pharmacokinetics, Pharmacogenomics on January 8, 2016| Leave a Comment »

BioMed e-Series

Reporter: Aviva Lev-Ari, PhD, RN

Applying Pharmacology to New Drug Discovery, April 22, 2016 in San Diego, CA by CHI

The system-independent quantification of molecular drug properties for prediction of therapeutic utility

April 22, 2016

Over the past 6 six years, the primary cause of new drug candidate failures (50%) has been failure of therapeutic efficacy. Put another way, drug discovery programs do everything right, get the defined candidate molecule, only to have it fail in therapeutic trials. Among the most prevalent reasons proposed for this shortcoming is the lack of translation of in vitro and recombinant drug activity to therapeutic in vivo whole systems. Drug activity in complete systems can be characterized with the application of pharmacological principles which translate drug behaviors in various organs with molecular scales of affinity and efficacy.

Pharmacological techniques are unique in that they can convert descriptive data (what we see, potency, activity in a given system) to predictive data (molecular scales of activity that can be used to predict activity in all systems including the therapeutic one, i.e. affinity, efficacy). The predicted outcome of this process is a far lower failure rate as molecules are progressed toward clinical testing.

Instructor

Terry Kenakin presently is a Professor of Pharmacology in the Department of Pharmacology, University of North Carolina School of Medicine. The course is taught from the perspective of industrial drug discovery; Dr. Kenakin has worked in drug industry for 32 years (7 at Burroughs-Wellcome, RTP, NC and 25 at GlaxoSmithKline, RTP. NC). He is Editor-in-Chief of the Journal of Receptors and Signal Transduction and Co-Editor-in-Chief of Current Opinion in Pharmacology and is on numerous journal Editorial Boards. In addition, he has authored over 200 peer reviewed papers and reviews and has written 10 books on Pharmacology.

Course Material

Summary sheets, exercises with answers, relevant papers are included as well as a pdf of all slides. The course is based on the book A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery. 4th Edition, Elsevier/Academic Press, 2014.

This course will describe pharmacological principles and procedures to quantify affinity, efficacy, biased signaling and allostery to better screen for new drugs and characterize drug candidates in lead optimization assays.

1. Assay Formats/Experimental Design

Binding
Functional Assays
Null Method Assays

2. Agonism

Agonist Affinity/Efficacy
Black/Leff Operational model

3. Biased Signaling (Agonism)

Mechanism of Biased Signaling
Quantifying Biased Agonism
Therapeutic application(s)

4. Orthosteric Antagonism (I)

Competitive
Non-Competitive/Irreversible

5. Orthosteric Antagonism (II)

Partial Agonism
Inverse Agonism

6. Allosteric Modulation (I)

Functional Allosteric Model
Negative Allosteric Modulators (NAMs)

7. Allosteric Modulation (II)

Positive Allosteric Modulators (PAMs)
Allosteric Agonism

8. Drug-Receptor Kinetics

Measuring Target Coverage
Allosteric Proof-of-Concept
Application of Real-Time Kinetics

9. Drug Screening

Design of Screening Assays
Screening for Allosteric Modulators

Cambridge Healthtech Institute’s Eleventh Annual Drug Discovery Chemistry is a dynamic conference for medicinal chemists working in pharma and biotech. Focused on discovery and optimization challenges of small molecule drug candidates, this event provides many exciting opportunities for scientists to create a unique program by going back and forth between concurrent meeting tracks to hear presentations most suited to one’s personal interests. New for 2016 is the addition of three symposia on Friday covering the blood-brain barrier, biophysical approaches for drug discovery, and antivirals.

Plenary Keynotes

A New Model for Academic Translational Research

Peter G. Schultz, Ph.D., The Scripps Research Institute

Cell-Penetrating Miniproteins

Gregory L. Verdine, Ph.D., Harvard University

April 19-20	April 20-21	April 22
Inflammation Inhibitors	Kinase Inhibitor Chemistry	Brain Penetrant Inhibitors
Protein-Protein Interactions	Macrocyclics & Constrained Peptides	Biophysical Approaches
Epigenetic Inhibitor Discovery	Fragment-Based Drug Discovery	Antivirals

Short Courses

Make the most of your time in San Diego by adding on one or more short courses*. Topics include trends in physical properties, GPCRs, peptide therapeutics, immunology, phenotypic screening, crystallography, ligand-receptor molecular interactions, inhibitor design, macrocycles, FBDD, and covalent inhibitors.

* separate registration required for short courses

SOURCE

From: Deborah Shear <pete@healthtech.com>

Date: Friday, January 8, 2016 at 11:42 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Training Seminar: Applying Pharmacology to New Drug Discovery