Leaders in Pharmaceutical Business Intelligence (LPBI) Group

#5

Genetic Basis of Complex Human Diseases: Dan Koboldt’s Advice to Next-Generation Sequencing Neophytes

Article #5: Word Cloud by DM

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Article Title (Live Link)	All Time Views	Categories of Research
#6 Personal Tale of JL’s Whole Genome Sequencing	~143	Bio Instrumentation in Experimental Life Sciences Research, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Patient Experience: Personal Memories of Invasive Medical Intervantion, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Technology Transfer: Biotech and Pharmaceutical

#6

Personal Tale of JL’s Whole Genome Sequencing

Article #6: Word Cloud by DM

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Article Title (Live Link)	All Time Views	Categories of Research
#7 Nobel Laureate Jack Szostak Previews his Plenary Keynote for Drug Discovery Chemistry	~222	Advanced Drug Manufacturing Technology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, BioSimilars, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Genome Biology, Genomic Testing: Methodology for Diagnosis, Interviews with Scientific Leaders, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Proteomics, Scientist: Career considerations, Systemic Inflammatory Response Related Disorders

#7

Nobel Laureate Jack Szostak Previews his Plenary Keynote for Drug Discovery Chemistry

Article #7: Word Cloud by DM

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SESSIONS Date & Presenter	Aviva	Dr. Ofer	Dr. Williams	Dr. Irina	Dr. Irina
#1: 6/23/2020 AVIVA	A
#2: 6/30/2020 Dr. Williams & Dr. Irina	A++		A+	XXX
#3: 7/7/2020 Dr. Ofer	A+	XXX
#4: 7/14/2020 Dr. Ofer	A++ 1.Red color text change to GREEN, add source to Table 2.Atherosclerosis section: Your Paper Can be posted in the Journal if you choose 5 articles on the topic in the Journal and create a curation – Save as Draft – I need to review before you Publish	XXX
#5: 7/21/2020 LPBI Monthly Scientific and Business Sessions: 11AM – 4PM Assignment by Dr. Ofer due 7/28/2020	XXX	XXX
#6: 7/28/2020 Dr. Williams & Dr. Irina	XXX		A+	XXX
#7: 8/4/2020 Dr. Ofer	XXX	XXX
#8: 8/11/2020 Presentation by Dr. Irina Summary: Ofer and Aviva	XXX			XXX
BEYOND 8/11/2020 With AVIVA	XXX

 

 

LPBI Internship Assignment IV

7/15/2020

https://pharmaceuticalintelligence.com/2012/11/06/non-small-cell-lung-cancer-drugs-where-does-the-future-lie/

Sample processing of: Non-small Cell Lung Cancer drugs – where does the Future lie?

“Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and usually grows and spreads more slowly than small cell lung cancer.” “There are three common forms of NSCLC”. “Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.” “Lung cancer is by far the leading cause of cancer death among both men and women.”

“The American Cancer Society’s most recent estimates for lung cancer in the United States for 2012 reveal that about 226,160 new cases of lung cancer will be diagnosed (116,470 in men and 109,690 in women), and there will be an estimated 160,340 deaths from lung cancer (87,750 in men and 72,590 among women), accounting for about 28% of all cancer deaths.” “Different types of treatments are available for non-small cell lung cancer. Treatment depends on the stage of the cancer.” “The market for NSCLC drugs is expected to expand from $4.2 billion in 2010 to $5.4 billion in 2020 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.” “Drug sales for metastatic/advanced squamous cell non-small-cell lung cancer, which comprises only a small fraction of the market, will decrease from nearly 17 percent in 2010 to approximately 13 percent in 2020.”

This paragraph consists of segmented pieces of text from the body of the chosen article. Information on non-small cell lung cancer is presented in a way as to introduce the reader to the topic, and highlighting important information, while filtering out information that may not be considered key. The most aggressive form of NSCLC is highlighted. Since we know that NSCLC is the most common lung cancer, and have been introduced to the most aggressive type, we can now bring to light the fact that lung cancer is the leading cause of death. This allows the reader to understand how devastating this cancer type can be, using statistics. We then use two separate quotes to contextualize the market value of NSCLC drugs. Using a sequential approach, all terms are properly contextualized before being discussed in other contexts. This approach allows us to focus on key information without leading the reader in an incorrect direction of understanding. The purpose of this approach is to preserve the intent of the author, while making the presented data more concise.

“In 2009, antimetabolites dominated the NSCLC market, with Eli Lilly’s Alimta (Pemetrexed) accounting for nearly three-quarters of sales within this drug class.” “It was speculated that the antimetabolites market share would reduce significantly making it the second-largest drug class in NSCLC, while the epidermal growth factor receptor (EGFR) inhibitor class will garner the top market share by 2019.” “Tarceva belongs to the EGFR inhibitor class, and has been prescribed principally along with Eli Lilly’s Alimta, to NSCLC patients. Both these drugs have dominated the NSCLC market till 2010, however, their market hold is expected to weaken from 2015-2020.” “May, 2012 sales of Tarceva in the US have been reported to be around $564.2 million.” “In a recent article published by Vergnenègre et al in the Clinicoeconomic Outcomes Research journal (2012), cross-market cost-effectiveness of Erlotinib was analyzed.” “According to the authors analysis, there was a gain in the costs per-life year as $50,882, $60,025, and $35,669 in France, Germany, and Italy, respectively. Hence, on the basis of the study it was concluded that Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC.”

This paragraph discusses different classes of NSCLC drugs and how their relationship to the market has changed over time. We first start with information on how anti-metabolites dominated the market, followed by another quote with projections on their decrease in market value. This quote provides a smooth transition to discussion of EGFR drugs. The next quote tells us that Tarceva and Alimta are two drugs prescribed to NSCLC patients alongside each other, and that they currently dominate the market but a decline is to be expected. Now with another quote we discuss a May 2012 sales report, relevant to the question of market trends raised in the previous quote. The next quote features a recent article that describes the cost-effectiveness of Tarceva, and the article concludes that it is an effective drug. Using a sequential approach, all terms are properly contextualized before being discussed in other contexts. By presenting the quotes like this, context is concise and we do not leave out key information since we are only focusing on one topic.

Styles

The previously described text blocks feature preserved styles which allow us to view information separately, based on text color. Meanwhile, bold and italicized text indicates that we should pay special attention to this information. Certain wording also allows for preservation of context. For example,

“There are three common forms of NSCLC”. “Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.” “Lung cancer is by far the leading cause of cancer death among both men and women.”

The positioning of the second quote allows the reader to understand that it is not implied that large cell carcinomas are the leading cause of cancer death. Rather, lung cancer generally is.

Repeat Examples

1. from $4.2 billion in 2010 to $5.4 billion in 2020 (NSCLC Drug Market Analysis section)

Formalized

“Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and usually grows and spreads more slowly than small cell lung cancer.” “There are three common forms of NSCLC”. “Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.” “Lung cancer is by far the leading cause of cancer death among both men and women.”

“The American Cancer Society’s most recent estimates for lung cancer in the United States for 2012 reveal that about 226,160 new cases of lung cancer will be diagnosed (116,470 in men and 109,690 in women), and there will be an estimated 160,340 deaths from lung cancer (87,750 in men and 72,590 among women), accounting for about 28% of all cancer deaths.” “Different types of treatments are available for non-small cell lung cancer. Treatment depends on the stage of the cancer.” “The market for NSCLC drugs is expected to expand from $4.2 billion in 2010 to $5.4 billion in 2020 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.” “Drug sales for metastatic/advanced squamous cell non-small-cell lung cancer, which comprises only a small fraction of the market, will decrease from nearly 17 percent in 2010 to approximately 13 percent in 2020.”

https://pharmaceuticalintelligence.com/wp-content/uploads/2012/11/nsclc-drugs.jpg

Methotrexate injection: methotrexate, Antimetabolite, FDA approved, 25 mg/ml; soln for IV. 1g; pwd for IV. 5 mg, 7.5 mg, 10 mg, 15 mg; scored tabs 

Taxotere: docetaxel, Antimicrotubule agent, FDA approved, 40 mg/mL; soln for IV infusion after dilution.

Navelbine: vinorelbine, Antimicrotubule, FDA approved, 10 mg/mL; soln for IV infusion after dilution

Photofrin: porfimer, Photosensitizing agent, FDA approved, 75 mg; pwd for IV inj after reconstitution

Tarceva: erlotinib, Tyrosine Kinase Inhibitors, FDA approved. 25 mg, 100 mg, 150 mg; caps

“NSCLC Drug Market Analysis”

“In 2009, antimetabolites dominated the NSCLC market, with Eli Lilly’s Alimta (Pemetrexed) accounting for nearly three-quarters of sales within this drug class.” “It was speculated that the antimetabolites market share would reduce significantly making it the second-largest drug class in NSCLC, while the epidermal growth factor receptor (EGFR) inhibitor class will garner the top market share by 2019.” “Tarceva belongs to the EGFR inhibitor class, and has been prescribed principally along with Eli Lilly’s Alimta, to NSCLC patients. Both these drugs have dominated the NSCLC market till 2010, however, their market hold is expected to weaken from 2015-2020.” “May, 2012 sales of Tarceva in the US have been reported to be around $564.2 million.” “In a recent article published by Vergnenègre et al in the Clinicoeconomic Outcomes Research journal (2012), cross-market cost-effectiveness of Erlotinib was analyzed.” “According to the authors analysis, there was a gain in the costs per-life year as $50,882, $60,025, and $35,669 in France, Germany, and Italy, respectively. Hence, on the basis of the study it was concluded that Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC.”

LPBI Internship Assignment III

7/14/2020

Topics

Information Retrieval Thesaurus

https://en.wikipedia.org/wiki/Thesaurus_(information_retrieval)#:~:text=In%20the%20context%20of%20information,the%20indexing%20of%20content%20objects.&text=The%20thesaurus%20aids%20the%20assignment,associated%20with%20the%20content%20object.

Scientific Text Processing

https://www.frontiersin.org/articles/10.3389/frma.2019.00002/full

Text as Strings: In the Context of NLP

https://towardsdatascience.com/introduction-to-natural-language-processing-for-text-df845750fb63

Glossary of Terms

National Cancer Institute Glossary of Cancer Terms

https://www.cancer.gov/publications/dictionaries/cancer-terms

Google Machine Learning Glossary

https://developers.google.com/machine-learning/glossary

KDnuggets NLP Glossary

https://www.kdnuggets.com/2017/02/natural-language-processing-key-terms-explained.html

http://staff.um.edu.mt/mros1/csa3202/pdf/spell.pdf

https://medium.com/@theflyingmantis/auto-correction-text-classification-9af0783abc6

How:

• Misspelling results in non-word formation (ex. graffe vs giraffe)
• Misspelling results in formation of real word
  • Typographical: there vs three
  • Homophone: there vs their

Why:

• Quick typing corrupts data
• Writing using phonetic basis: Wister vs Worcester
• Writer does not understand difference between homophones

Tradeoffs in Text Processing

• Entity recognition
  • Difficult to identify text entities from unstructured text which are not philosophically rigid (ex. Ford can refer to the car brand or a person with the last name “Ford”)
• Sentiment analysis
  • Machines are not good at understanding and processing the writer’s emotions, more so the non-abstract, concrete meaning of text
• Document classification
  • Classification of documents requires an elaborate algorithm interfaced with an information system. Achieving balance is not easy.

Word Clouds

http://www.jasondavies.com/wordcloud

Text Sample I

Source: Non-small Cell Lung Cancer drugs – where does the Future lie?

“Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and usually grows and spreads more slowly than small cell lung cancer.” “There are three common forms of NSCLC”. “Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.” “Lung cancer is by far the leading cause of cancer death among both men and women.”

“The American Cancer Society’s most recent estimates for lung cancer in the United States for 2012 reveal that about 226,160 new cases of lung cancer will be diagnosed (116,470 in men and 109,690 in women), and there will be an estimated 160,340 deaths from lung cancer (87,750 in men and 72,590 among women), accounting for about 28% of all cancer deaths.” “Different types of treatments are available for non-small cell lung cancer. Treatment depends on the stage of the cancer.” “The market for NSCLC drugs is expected to expand from $4.2 billion in 2010 to $5.4 billion in 2020 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.” “Drug sales for metastatic/advanced squamous cell non-small-cell lung cancer, which comprises only a small fraction of the market, will decrease from nearly 17 percent in 2010 to approximately 13 percent in 2020.”

Text Sample II

Source – Engin 351 Final Paper – Daniel Menzin

Plaques form due to a complex feedback loop mediated by the immune system. This toxic cascade begins with an abnormally high concentration of blood cholesterol. Chronically elevated blood cholesterol leads to progressive lipid deposition onto the walls of our arteries. Over time, enough fat accumulates on the vessel wall to attract immune cells. The presence of solidified cholesterol irritates the vessel wall, initiating an inflammatory reaction which causes signaling molecules to change the permeability of our blood vessels. Routine inflammatory processes then take place. White blood cells called monocytes travel through the blood stream to the plaque site and then differentiate (transform) into macrophages. Macrophages are cells which degrade material by “gobbling it up.” When a macrophage starts phagocytosing cholesterol, it turns into a foam cell – a cell that contains cholesterol. The macrophage progressively fills until it bursts (lyses), leaving dead cell debris behind. More white blood cells are then attracted to the area and the pattern repeats itself. Meanwhile, more cholesterol may build up if blood cholesterol is still high. During this inflammatory cascade, white blood cells release proinflammatory chemokines and cytokines which damage the vessel wall, causing changes in structure demonstrated by the below graphic.

Text Sample III

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

Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.

LPBI Internship Assignment II

7/14/2020

 

• Smoking related indicated by bold text
• Non-Smoking related indicated by italics

Name	Mutation/Role
Pathway Specific Targeting in Anticancer Therapies https://pharmaceuticalintelligence.com/2015/04/09/pathway-specific-targeting-in-anticancer-therapies-7-7/	ACLY
Targeting the Wnt Pathway https://pharmaceuticalintelligence.com/2015/04/10/targeting-the-wnt-pathway-7-11/	APC, beta-catenin (rare mutations), Dvl, Wnt1, Wnt2, TCF4, LEF1, HOXB9, WIF1, Fzd
Inhibition of Nucleocytoplasmic Shuttling https://pharmaceuticalintelligence.com/2015/10/30/inhibition-of-nucleocytoplasmic-shuttling/	XPO1
Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer https://pharmaceuticalintelligence.com/2014/09/05/multiple-lung-cancer-genomic-projects-suggest-new-targets-research-directions-for-non-small-cell-lung-cancer/	Genetic Information
Lung Cancer Update https://pharmaceuticalintelligence.com/2015/11/22/lung-cancer-update/	EGFR T790M, MET, STK11, TP53, KRAS
Comprehensive Genomic Characterization of Squamous Cell Lung Cancers https://pharmaceuticalintelligence.com/2012/09/10/comprehensive-genomic-characterization-of-squamous-cell-lung-cancers/	TP53, HLA-A class I major histocompatibility gene, NFE2L2, KEAP1, squamous differentiation genes, phosphatidylinositol-3-OH kinase pathway genes, CDKN2A, RB1
Lung Cancer Therapy https://pharmaceuticalintelligence.com/2015/11/06/lung-cancer-therapy/	EphA2, KRAS G12D, TP53, MET, CDH1, TGFβ1, vimentin, SLUG, GLI1, MAPK (possible role), AKT, SMO, AXL, RAF genes, PDL1
Non-small Cell Lung Cancer drugs – where does the Future lie? https://pharmaceuticalintelligence.com/2012/11/06/non-small-cell-lung-cancer-drugs-where-does-the-future-lie/	EGFR, VEGF-A, KRAS, HGFR, ALK, CD74-ROS
New Mutant KRAS Inhibitors Are Showing Promise in Cancer Clinical Trials: Hope For the Once ‘Undruggable’ Target https://pharmaceuticalintelligence.com/2019/11/11/new-mutant-kras-inhibitors-are-showing-promise-in-cancer-clinical-trials-hope-for-the-once-undruggable-target/	KRAS (G12C mutant)
PDL1 tests for Lung Cancer https://pharmaceuticalintelligence.com/2016/04/22/pld1-tests-for-lung-cancer/	PDL1
Personalized Medicine in NSCLC https://pharmaceuticalintelligence.com/2013/03/03/personalized-medicine-in-nsclc/	EGFR (exons 19, 20, 21)  ALK, KRAS
What about PDL-1 in oncotherapy diagnostics for NSCLC? https://pharmaceuticalintelligence.com/2016/05/02/what-about-pdl-1-in-oncotherapy-diagnostics-for-nsclc/	PDL1
Prognostic biomarker for NSCLC and Cancer Metastasis https://pharmaceuticalintelligence.com/2016/03/24/prognostic-biomarker-for-nsclc-and-cancer-metastasis/	CD24, MARK4, EGFR, KRAS

LPBI Internship Assignment I

6/23/20

Topics covered

• PGE2
• TXA2
• Agonist/Antagonists in Pharmacology
• Sepsis

PGE2

Definition:

Prostaglandin E2 is a signaling molecule derived from phospholipids present in the lipid bilayer of cells. It is found in a variety of different tissues and cell types, and is a key mediator involved in inflammation. PGE2 relaxes smooth muscle, making it a potent vasodilator and bronchodilator. It has also found use for childbirth as it relaxes smooth muscle in the cervix, thus dilating it. PGE2 is believed to be a key mediator in inflammation due to its role in dilating blood vessels. This allows immune cells to diffuse through the vascular wall and reach target tissue sites. Meanwhile, PGE2 is believed to also be implicated in T cell receptor signaling repression, and thus resolution of inflammation. This chemical is an oxytocic – a compound resembling oxytocin in structure – and is upregulated by epinephrine, thrombin, angiotensin II, bradykinin, and vasopressin. It is downregulated by steroids. Prostaglandins are unstable compounds with a short half life, of ~30 seconds. Therefore, they perform their function prior to rapid degradation.

Source: https://www.sciencedirect.com/topics/neuroscience/prostaglandin-e2

Lymphatic Cancer Metastasis Model

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Description:

This article demonstrated the connection between chronic sympathetic nervous system (SNS) activation due to stress and pro-tumor lymphatic remodeling. A study conducted on mice demonstrated that chronic stress induces lymph vasculature remodeling which leads to lymphatic involvement in cancer spread (Le, et al). According to this article, chronic stress-associated SNS activation is associated with inflammatory responses in pathways which involve molecules like COX2 and PGE2. Tumor-associated macrophages may respond to β-adrenoceptor stimulation via SNS activation to produce inflammatory molecules such as PGE2 which then may signal tumor cells to produce VEGFC. VEGFC is a growth factor which stimulates lymphatic remodeling via endothelial cell proliferation. This promotes infiltration of lymphatic networks by cancer cells. SNS activation thereby appears to stimulate VEGFC production by cancer cells through indirect means (i.e. neural-inflammatory axis activation). But once VEGFC levels rise, lymph activation becomes much more likely.

Organoid Development

Curator: Larry H Bernstein, MD, FCAP

Organoid Development

Targeting the Wnt Pathway [7.11]

Writer and Curator: Larry H Bernstein, MD, FCAP 

Targeting the Wnt Pathway [7.11]

Pathway Specific Targeting in Anticancer Therapies [7.7]

Writer and Curator: Larry H. Bernstein, MD, FCAP 

Pathway Specific Targeting in Anticancer Therapies [7.7]

Acute Lung Injury

Writer and Curator: Larry H. Bernstein, MD, FCAP 

Acute Lung Injury

TXA2

Definition:

Thromboxane A2 is a lipid in the eicosanoids family. Eicosanoids are metabolites of arachidonic acid generated by PLA2, COX-1/COX-2 (proinflammatories), and TXAS. TXA2 is a prothrombotic produced by a variety of different cell types including white blood cells, endothelial cells, as well as platelets. It stimulates the activation of platelets as well as platelet aggregation. In addition, TXA2 is also known to be a vasoconstrictor that is activated during times of tissue injury and inflammation. Prostacyclin (PGI2) counterbalances the thrombotic and vasoconstrictive properties of TXA2, and this balance becomes dysregulated in pathological settings. TXA2 is an important signaling molecule as it may play a role in the pathogenesis of myocardial infarction, stroke, atherosclerosis, and bronchial asthma. Increased TXA2 signaling also has implications in pulmonary hypertension, kidney injury, hepatic injury, allergies, angiogenesis, and metastasis of cancer cells.

Source: https://www.ncbi.nlm.nih.gov/books/NBK539817/

Diabetic Nephropathy

Larry H. Bernstein, MD, FCAP, Curator

Diabetic Nephropathy

This article introduced a novel drug called EV-077, a thromboxane receptor antagonist and thromboxane synthase inhibitor investigated for vascular complications resulting from DM Type II. Several important concepts were discussed in this article that help illustrate the mechanism of action of EV-077. Patients with DM Type II have an increased propensity to generate TXA2, which contributes to heightened platelet reactivity. Increased platelet aggregation in vessels contributes to inflammatory damage which results in stenosed vessels. In the case of diabetic nephropathy, this means stenosed nephrons. Nephrons are the tiny vessels through which urine travels in the kidneys during the process of filtration, secretion, excretion, and resorption. Nephrosclerosis will cause a decreased glomerular filtration rate (GFR), and thus an inadequate excretion of harmful toxins from the human body. EV-077 functions to down-regulate thromboxane receptor activity via it’s antagonistic effects. It also inhibits thromboxane synthase, an enzyme involved in the synthesis of thromboxane compounds such as TXA2. Therefore, EV-077 was thought to be capable of reducing reactive platelet processes and thus preventing inflammation via these pathways. Less inflammation equates to less fibrosis and thus less nephrosclerosis.

Action of Hormones on the Circulation

Writer and Curator: Larry H. Bernstein, MD, FCAP 

Action of Hormones on the Circulation

Nitric Oxide Function in Coagulation – Part II

Curator and Author: Larry H. Bernstein, MD, FCAP

Nitric Oxide Function in Coagulation – Part II

Platelets in Translational Research – Part 1

Reviewer and Curator: Larry H Bernstein, MD, FCAP 

Platelets in Translational Research – Part 1

Nitric Oxide, Platelets, Endothelium and Hemostasis (Coagulation Part II)

Curator: Larry H. Bernstein, MD, FCAP 

Nitric Oxide, Platelets, Endothelium and Hemostasis (Coagulation Part II)

Agonist/Antagonists in Pharmacology

Definition:

Agonists are biochemicals which mimic the activity of receptor ligands by binding to and activating receptors, producing a biological response. Normally, this is a response within the cell. Agonists are used to up-regulate activity of certain receptors without needing to naturally boost extracellular concentrations of the ligand. Antagonists on the other hand, function to physically block receptors from activation by agonists. Antagonists therefore are involved in the downregulation of receptor activity, serving to essentially shut receptors down. This is useful when there is an abnormal amount of activity present in certain signaling pathways. Both agonistic and antagonistic drugs are susceptible to pharmacodynamic tolerance, which is a phenomenon in which the receptor becomes less sensitive to activation by the compound. For agonists, this means a decreased cellular response occurring as a result of agonistic binding. For antagonists, this means an increase in receptor signaling.

Source: https://www.sciencedirect.com/science/article/abs/pii/S1472029906003845#:~:text=An%20agonist%20binds%20to%20the,receptor%20to%20a%20natural%20agonist.&text=Insurmountable%20antagonists%20bind%20strongly%20to,not%20reversed%20by%20additional%20agonist.

Are CXCR4 Antagonists Making a Comeback in Cancer Chemotherapy?

Reporter: Stephen J. Williams, Ph.D.

Are CXCR4 Antagonists Making a Comeback in Cancer Chemotherapy?

This article written in 2015 describes the role of the CXCR4/CXCL12 receptor-ligand pair in the growth and metastasis of solid tumors. The therapeutic potential for CXCR4 inhibitors was also discussed at this time. This article explains key interactions and physiological processes. The CXCR4 receptor is a chemokine receptor that is frequently overexpressed in cancer cells. In the context of the tumor micro-environment, this receptor-ligand pair induces autocrine and paracrine signaling which promotes pro-tumor inflammation, angiogenesis, and thus increased tumor aggressiveness. Overactive CXCR4 signaling is also implicated in immunosuppression of the tumor micro-environment, by masking the tumor with non-cancerous immuno-suppressive cells which interfere with immune surveillance. Lastly, the release of chemokines in tissues distant from the tumor appears to guide and attract cancer cells from a primary tumor site. Therefore, autocrine and paracrine signaling from the CXCR4 receptor both guides and induces metastasis.

Advancing Immunotherapies: Emerging Agonist and Antagonist Targets

Reporting: Aviva Lev-Ari, PhD, RN

Advancing Immunotherapies: Emerging Agonist and Antagonist Targets

SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19

Reporter: Aviva Lev-Ari, PhD, RN – Bold face and colors are my addition

SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19

Insulin Receptor – Agonists and Antagonists Agents

Curator: Larry H Bernstein, MD, FCAP

Insulin Receptor – Agonists and Antagonists Agents

Liver Toxicity halts Clinical Trial of IAP Antagonist for Advanced Solid Tumors

Writer/Curator Stephen J. Williams, Ph.D.

Liver Toxicity halts Clinical Trial of IAP Antagonist for Advanced Solid Tumors

Sepsis

Definition:

Sepsis is a condition in which the body’s response to infection results in damage to its own organs. Those who are immunocompromised and have overactive immune systems are prone to sepsis. Sepsis is mostly an inflammatory condition in which systemic inflammation due to the release of chemokines and cytokines causes damage to multiple organ systems. Without treatment, sepsis will quickly lead to multiple organ failure and death. The main initial presenting symptom in most patients with sepsis is a fever with pneumonia. As sepsis progresses, additional symptoms arise indicating severe inflammation and eventually multiple organ failure. Sepsis is due to heightened white blood cell activation causing severe systemic inflammation.

Source: https://www.sciencedirect.com/science/article/pii/S0002944010613570

Sepsis Detection using an Algorithm More Efficient than Standard Methods

Reporter : Irina Robu, PhD

Sepsis Detection using an Algorithm More Efficient than Standard Methods

This article describes sepsis as a condition and current treatments for sepsis. The first symptom of sepsis is usually fever with pneumonia. The primary initial goal of treatment is respiratory stabilization and additional aggressive fluid resuscitation. The article goes on to describe a novel machine-learning algorithm trained using patient data from two different institutions. The purpose of this algorithm is to catch sepsis before it becomes serious, in hospital patients. Data from two different hospitals was used to obtain data from demographically miscellaneous patient populations. This way the algorithm could be properly trained. The patients in this study were admitted to the hospital without sepsis and at least one of six vital signs were recorded. During their hospital stay, some patients contracted sepsis while others did not. Sepsis affects at least 1.7 million adults primarily outside of hospital settings and 270,000 patients will die from this illness.

Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions

Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC

and

Article Curator: Aviva Lev-Ari, PhD, RN

Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions

Sepsis, Multi-organ Dysfunction Syndrome, and Septic Shock: A Conundrum of Signaling Pathways Cascading Out of Control

Curator and Author: Larry H Bernstein, MD, FCAP

Sepsis, Multi-organ Dysfunction Syndrome, and Septic Shock: A Conundrum of Signaling Pathways Cascading Out of Control

Clinical Trial for the Use of Nitric Oxide to Treat Severe COVID-19 Infection

Reporter and Curator: Aviva Lev-Ari, PhD, RN

Clinical Trial for the Use of Nitric Oxide to Treat Severe COVID-19 Infection

Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

Author: Larry H Bernstein, MD, FCAP

Advanced Topics in Sepsis and the Cardiovascular System at its End Stage