Posts Tagged ‘health’

Nutrition: Articles of Note @PharmaceuticalIntelligence.com

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Metabolism, Metabolomics, Nutrition, Systemic Inflammatory Response Related Disorders, tagged Cancer, health, inflammation, Nutrition, Wellbeing on March 28, 2016| Leave a Comment »

Nutrition: Articles of Note @PharmaceuticalIntelligence.com

Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

Nutrition and Wellbeing

Introduction

Larry H. Bernstein, MD, FCAP

The chapters that follow are divided into three parts, but they are also a summary of 25 years of work with nutritional support research and involvement with nutritional support teams in Connecticut and New York, attendance and presentations at the American Association for Clinical Chemistry and the American Society for Parenteral and Enteral Nutrition, and long term collaborations with the surgeons Walter Pleban and Prof. Stanley Dudrick, and Prof. Yves Ingenbleek at the Laboratory of Nutrition, Department of Pharmacy, University Louis Pasteur, Strasbourg, Fr. They are presented in the order: malnutrition in childhood; cancer, inflammation, and nutrition; and vegetarian diet and nutrition role in alternative medicines. These are not unrelated as they embrace the role of nutrition throughout the lifespan, the environmental impact of geo-ecological conditions on nutritional wellbeing and human development, and the impact of metabolism and metabolomics on the outcomes of human disease in relationship to severe inflammatory disorders, chronic disease, and cancer. Finally, the discussion emphasizes the negative impact of a vegan diet on long term health, and it reviews the importance of protein sources during phases of the life cycle.

Malnutrition in Childhood

Protein Energy Malnutrition and Early Child Development

Curator: Larry H. Bernstein, MD, FCAP

The Significant Burden of Childhood Malnutrition and Stunting

Curator: Larry H. Bernstein, MD, FCAP

Is Malnutrition the Cost of Civilization?

Curation: Larry H. Bernstein, MD, FCAP

Malnutrition in India, High Newborn Death Rate and Stunting of Children Age Under Five Years

Curator: Larry H Bernstein, MD, FCAP

Under Nutrition Early in Life may lead to Obesity

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

Protein Malnutrition

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

Cancer, Inflammation and Nutrition

A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

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

Cancer and Nutrition

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

The history and creators of total parenteral nutrition

Curator: Larry H. Bernstein, MD, FCAP

Nutrition Plan

Curator: Larry H. Bernstein, MD, FCAP

Nutrition and Aging

Curator: Larry H Bernstein, MD, FCAP

Vegetarian Diet and Nutrition Role in Alternative Medicines

Plant-based Nutrition, Neutraceuticals and Alternative Medicine: Article Compilation the Journal PharmaceuticalIntelligence.com

Curator: Larry H. Bernstein, MD, FCAP

Metabolomics, Metabonomics and Functional Nutrition: the next step in nutritional metabolism and biotherapeutics

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

2014 Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism Conference: San Francisco, Ca. Conference Dates: San Francisco, CA 3/18-21, 2014

Reporter: Aviva Lev-Ari, PhD, RN

Metabolomics: its Applications in Food and Nutrition Research

Reporter and Curator: Sudipta Saha, Ph.D.

Summary

Larry H. Bernstein, MD, FCAP

The interest in human malnutrition became a major healthcare issue in the 1980’s with the publication of several seminal papers on hospital malnutrition. However, the basis for protein-energy malnutrition that focused on the distinction between kwashiorkor and marasmus was first identified in seminal papers by Ingenbleek and others:

Ingenbleek Y. La malnutrition protein-calorique chez l’enfant en bas age. Repercussions sur la function thyroidienne et les protein vectrices du serum. PhD Thesis. Acco Press. 1997. Univ Louvain.

Ingenbleek Y, Carpentier YA. A prognostic inflammatory and nutrition index scoring critically ill patients. Internat J Vit Nutr Res 1985; 55:91-101.

Ingenbleek Y, Young VR. Transthyretin (prealbumin) in health and disease. Nutritional implications. Ann Rev Nutr 1994; 14:495-533.

Ingenbleek Y, Hardillier E, Jung L. Subclinical protein malnutrition is a determinant of hyperhomocysteinemia. Nutrition 2002; 18:40-46.

It was these early papers that transfixed my attention, and drove me to establish early the transthyretin test by immunodiffusion and later by automated immunoassay at Bridgeport Hospital.

Among the important studies often referred to with respect to hospital malnutrition are:

Hill GL, Blackett RL, Pickford I, Burkinshaw L, Young GA, Warren JV. Malnutrition in surgical patients: An unrecognised problem. Lancet.1977; 310:689–692. [PubMed]
Bistrian BR, Blackburn GL, Vitale J, Cochrane D, Naylor J. Prevalence of malnutrition in general medical patients. JAMA. 1976; 235:1567–1570. [PubMed]
Butterworth CE. The skeleton in the hospital closet. Nutrition Today.1974; 9:4–8.
Buzby GP, Mullen JL, Matthews DC, Hobbs CL, Rosato EF. Prognostic nutritional index in gastrointestinal surgery. Am. J. Surg. 1980; 139:160–167.[PubMed]
Dempsey DT, Mullen JL, Buzby GP. The link between nutritional status and clinical outcomes: can nutritional intervention modify it? Am. J. Clin. Nutr. 1988; 47:352–356. [PubMed]
Detsky AS, Mclaughlin JR, Baker JP, Johnston N, Whittaker S, Mendleson RA, Jeejeebhoy KN. What is subjective global assessment of nutritional status? JPEN J Parenter Enteral Nutr. 1987; 11:8–13. [PubMed]
Scrimshaw NS, DanGiovanni JP. Synergism of nutrition, infection and immunity, an overview. J. Nutr. 1997; 133:S316–S321.
Chandra RK. Nutrition and the immune system: an introduction. Am. J. Clin. Nutr. 1997; 66:460S–463S. [PubMed]
Hill GL. Body composition reserach: Implications for the practice of clinical nutrition. JPEN J. Parenter. Enteral Nutr. 1992; 16:197. [PubMed]
Smith PE, Smith AE. High-quality nutritional interventions reduce costs.Healthc. Financ. Manage. 1997; 5:66–69. [PubMed]
Gallagher-Allred CR, Voss AC, Finn SC, McCamish MA. Malnutrition and clinical outcomes. J. Am. Diet. Assoc. 1996; 96:361–366. [PubMed]
Ferguson M. Uncovering the skeleton in the hoapital closet. What next? Aust. J. Nutr. Diet. 2001; 58:83–84.
Waitzberg DL, Caiaffa WT, Correia MITD. Hospital malnutrition: The Brazilian national survey (IBRANUTRI): a study of 4000 patients. Nutrition.2001; 17:573–580. [PubMed]

The work on hospital (and nursing home) treatment of malnutrition described in this series led to established standards. It first requires identifying a patient at malnutrition risk to be identified via either screening or assessment. This needs to be done on admission, and it has been made mandatory by health care accrediting bodies. In order to achieve this, dietitians need to have the confidence and knowledge to detect malnutrition, which is ideally done using a validated assessment for patient outcomes and financial benefits to be realized.

There is a worldwide relationship between ecological conditions, religious practices, soil conditions, availability of animal food sources, and altitude and river flows has not received the attention that evidence requires. We have seen that the emphasis on the Hindu tradition of not eating beef or having dairy is possibly problematic in the Ganges River basin. There may be other meat sources, but it is questionable that sufficient animal protein is available for the large population. The additional problem of water pollution is an aggravating situation. However, it is this region that is one of the most affected by stunting of children. We have a situation here and in other poor societies where veganism is present, and there is also voluntary veganism in western societies. This is not a practice that leads to any beneficial effect, and it has been shown to lead to a hyperhomocystenemia with the associated risk of arterial vascular disease. For those who voluntarily choose veganism, this is an unexpected result.

Met is implicated in a large spectrum of metabolic and enzyme activities and participates in the conformation of a large number of molecules of survival importance. Due to the fact that plant products are relatively Met-deficient, vegan subjects are more exposed than omnivorous to develop hyperhomocysteinemia – related disorders. Dietary protein restriction may promote supranormal Hcy concentrations which appears as the dark side of adaptive attempts developed by the malnourished and/or stressed body to preserve Met homeostasis. Summing up, we assume that the low TTR concentrations reported in the blood and CSF of AD or MID patients result in impairment of their normal scavenging capacity and in the excessive accumulation of Hcy in body fluids, hence causing direct harmful damage to the brain and cardiac vasculature.

The content of these discussions has also included nutrition and cancer. This is perhaps least well understood. Reasons for such an association may well include chronic exposure to radiation damage, or persistent focal chronic inflammatory conditions. These would result in a cirumferential and repeated cycle of injury and repair combined with an underlying hypoxia. I have already established a fundamental relationship between inflammation, the cytokine storm, the decreased hepatic synthesis of essential plasma proteins, such as, albumin, transferrin, retinol-binding protein, and transthyretin, and the surge of steroid hormones. This results in an imbalance in the protein and free protein equilibrium of essential vitamins, the retinoids, and other circulating ligands transported. This is discussed in the ‘nutrition-inflammatory conundrum”. As stated, whatever the nutritional status and the disease condition, the actual transthyretin (TTR) plasma level is determined by opposing influences between anabolic and catabolic alterations. Rising TTR values indicate that synthetic processes prevail over tissue breakdown with a nitrogen balance (NB) turning positive as a result of efficient nutritional support and / or anti-inflammatory therapy. Declining TTR values are associated with an effect of maladjusted dietetic management and / or further worsening of the morbid condition.

Inflammatory disorders of any cause are initiated by activated leukocytes releasing a shower of cytokines working as autocrine, paracrine and endocrine molecules. Cytokines regulate the overproduction of acute-phase proteins (APPs), notably that of CRP, 1-acid glycoprotein (AGP), fibrinogen, haptoglobin, 1-antitrypsin and antichymotrypsin. APPs contribute in several ways to defense and repair mechanisms, being characterized by proper kinetic and functional properties. Interleukin-6 (IL-6) is regarded as a key mediator governing both the acute and chronic inflammatory processes, as documented by data recorded on burn, sepsis and AIDS patients. IL-6-NF possesses a high degree of homology with C/EBP-NF1 and competes for the same DNA response element of the IL-6 gene. IL-6-NF is not expressed under normal circumstances, explaining why APP concentrations are kept at baseline levels. In stressful conditions, IL-6-NF causes a dramatic surge in APP values with a concomitant suppressed synthesis of TTR.

Inadequate nutritional management, multiple injuries, occurrence of severe sepsis and metabolic complications result in persistent proteolysis and subnormal TTR concentrations. The evolutionary patterns of urinary N output and of TTR thus appear as mirror images of each other, which supports the view that TTR might well reflect the depletion of TBN in both acute and chronic disease processes. Even in the most complex stressful conditions, the synthesis of visceral proteins is submitted to opposing anabolic or catabolic influences yielding ultimately TTR as an end-product reflecting the prevailing tendency. Whatever the nutritional and/or inflammatory causal factors, the actual TTR plasma level and its course in process of time indicates the exhaustion or restoration of the body N resources, hence its likely (in)ability to assume defense and repair mechanisms.

In westernized societies, elderly persons constitute a growing population group. A substantial proportion of them may develop a syndrome of frailty characterized by weight loss, clumsy gait, impaired memory and sensorial aptitudes, poor physical, mental and social activities, depressive trends. Hallmarks of frailty combine progressive depletion of both structural and metabolic N compartments. Sarcopenia and limitation of muscle strength are naturally involutive events of normal ageing which may nevertheless be accelerated by cytokine-induced underlying inflammatory disorders. Depletion of visceral resources is substantiated by the shrinking of FFM and its partial replacement by FM, mainly in abdominal organs, and by the down-regulation of indices of growth and protein status. Due to reduced tissue reserves and diminished efficiency of immune and repair mechanisms, any stressful condition affecting old age may trigger more severe clinical impact whereas healing processes require longer duration with erratical setbacks. As a result, protein malnutrition is a common finding in most elderly patients with significantly increased morbidity and mortality rates.

TTR has proved to be a useful marker of nutritional alterations with prognostic implications in large bowel cancer, bronchopulmonary carcinoid tumor, ovarian carcinoma and squamous carcinoma of bladder. Many oncologists have observed a rapid TTR fall 2 or 3 months prior to the patient’s death. In cancer patients submitted to surgical intervention, most postoperative complications occurred in subjects with preoperative TTR 180 mg/L. Two independent studies came to the same conclusion that a TTR threshold of 100 mg/L is indicative of extremely weak survival likelihood and that these terminally ill patients better deserve palliative care rather than aggressive therapeutic strategies.

Thyroid hormones and retinoids indeed function in concert through the mediation of common heterodimeric motifs bound to DNA response elements. The data also imply that the provision of thyroid molecules within the CSF works as a relatively stable secretory process, poorly sensitive to extracerebral influences as opposed to the delivery of retinoid molecules whose plasma concentrations are highly dependent on nutritional and/or inflammatory alterations. This last statement is documented by mice experiments and clinical investigations showing that the level of TTR production by the liver operates as a limiting factor for retinol transport. Defective TTR synthesis determines the occurrence of secondary hyporetinolemia which nevertheless results from entirely different kinetic mechanisms in the two quoted studies.

Points to consider:

Protein energy malnutrition has an unlikely causal relationship to carcinogenesis. Perhaps the opposite is true. However, cancer has a relationship to protein energy malnutrition without any doubt. PEM is the consequence of cachexia, whether caused by dietary insufficiency, inflammatory or cancer.

Protein energy malnutrition leads to hyperhomocysteinemia, and by that means, the relationship of dietary insufficiency of methionine has a relationship to heart disease. This is the significant link between veganism and cardiovascular disease, whether voluntary or by unavailability of adequate source.

The last portion of these chapters deals with metabolomics and functional nutrition. This is an emerging and important area of academic interest. There is a significant relationship between these emerging studies and pathways to understanding natural products medicinal chemistry.

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Genetic link to sleep and mood disorders

Posted in Behavior, Behavioral Genetics, Gene Regulation, Neuroscience, tagged behavior, brain, Circadian rhythm, health, light, mood, sleep wake cycle on February 27, 2016| Leave a Comment »

Genetic link to sleep and mood disorders

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Scientists identify molecular link between sleep and mood

By Claire AsherFeb. 22, 2016 http://www.sciencemag.org/news/2016/02/scientists-identify-molecular-link-between-sleep-and-mood

A poor night’s sleep is enough to put anyone in a bad mood, and although scientists have long suspected a link between mood and sleep, the molecular basis of this connection remained a mystery. Now, new research has found several rare genetic mutations on the same gene that definitively connect the two.

Sleep goes hand-in-hand with mood. People suffering from depression and mania, for example, frequently have altered sleeping patterns, as do those with seasonal affective disorder (SAD). And although no one knows exactly how these changes come about, in SAD sufferers they are influenced by changes in light exposure, the brain’s time-keeping cue. But is mood affecting sleep, is sleep affecting mood, or is there a third factor influencing both? Although a number of tantalizing leads have linked the circadian clock to mood, there is “no definitive factor that proves causality or indicates the direction of the relationship,” says Michael McCarthy, a neurobiologist at the San Diego Veterans’ Affairs Medical Center and the University of California (UC), San Diego.

To see whether they could establish a link between the circadian clock, sleep, and mood, scientists in the new study looked at the genetics of a family that suffers from abnormal sleep patterns and mood disorders, including SAD and something called advanced sleep phase, a condition in which people wake earlier and sleep earlier than normal. The scientists screened the family for mutations in key genes involved in the circadian clock, and identified two rare variants of the PERIOD3 (PER3) gene in members suffering from SAD and advanced sleep phase. “We found a genetic change in people who have both seasonal affective disorder and the morning lark trait” says lead researcher Ying-Hui Fu, a neuroscientist at UC San Francisco. When the team tested for these mutations in DNA samples from the general population, they found that they were extremely rare, appearing in less than 1% of samples.

Fu and her team then created mice that carried the novel genetic variants. These transgenic mice showed an unusual sleep-wake cycle and struggled less when handled by the researchers, a typical sign of depression. They also had lower levels of PER2, a protein involved in circadian rhythms, than unmutated mice, providing a possible molecular explanation for the unusual sleep patterns in the family. Fu says this supports the link between the PER3 mutations and both sleep and mood. “PER3’s role in mood regulation has never been demonstrated directly before,” she says. “Our results indicate that PER3 might function in helping us adjust to seasonal changes,” by modifying the body’s internal clock.

To investigate further, the team studied mice lacking a functional PER3 gene. They found that these mice showed symptoms of SAD, exhibiting more severe depression when the duration of simulated daylight in the laboratory was reduced. Because SAD affects between 2% and 9% of people worldwide, the novel variants can’t explain it fully. But understanding the function of PER3 could yield insights into the molecular basis of a wide range of sleep and mood disorders, Fu says.

Together, these experiments show that the PERIOD3 gene likely plays a key role in regulating the sleep-wake cycle, influencing mood and regulating the relationship between depression and seasonal changes in light availability, the team reports today in the Proceedings of the National Academy of Sciences. “The identification of a mutation in PER3 with such a strong effect on mood is remarkable,” McCarthy says. “It suggests an important role for the circadian clock in determining mood.”

The next step will be to investigate how well these results generalize to other people suffering from mood and sleep disorders. “It will be interesting to see if other rare variants in PER3 are found, or if SAD is consistently observed in other carriers,” McCarthy says. That could eventually lead to new drugs that selectively target the gene, which McCarthy says, “could be a strategy for treating mood or sleep disorders.”

http://dx.doi.org:/10.1126/science.aaf4095

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New subgroups of ILC immune cells discovered through single-cell RNA sequencing: from Karolinska Institute

Posted in Cell Biology, Genome Biology, Immunology, mRNA Therapeutics, Single Cell Genomics, Single-cell sequencing, Transcriptomics, Variation in human protein-coding regions, tagged Biology, health, immune system, inflammation, Karolinska Institutet, medicine, RNA-Seq clustering machine learning single-cell transcriptomics, single-cell transcriptomics on February 17, 2016| Leave a Comment »

New subgroups of ILC immune cells discovered through single-cell RNA sequencing

Reporter: Stephen J Williams, PhD

UPDATED on 8/8/2020

A Hybrid Deep Clustering Approach for Robust Cell Type Profiling Using Single-cell RNA-seq Data

Suhas Srinivasan1,

Anastasia Leshchyk1,

Nathan J Johnson2 and

Dmitry Korkin1,3

+Author Affiliations

¹ Worcester Polytechnic Institute;

² Harvard Medical School and Dana Farber Cancer Institute

↵* Corresponding author; email: korkin@korkinlab.org

Abstract

Single-cell RNA sequencing (scRNA-seq) is a recent technology that enables fine-grained discovery of cellular subtypes and specific cell states. It routinely uses machine learning methods, such as feature learning, clustering, and classification, to assist in uncovering novel information from scRNA-seq data. However, current methods are not well suited to deal with the substantial amounts of noise that is created by the experiments or the variation that occurs due to differences in the cells of the same type. Here, we develop a new hybrid approach, Deep Unsupervised Single-cell Clustering (DUSC), that integrates feature generation based on a deep learning architecture with a model-based clustering algorithm, to find a compact and informative representation of the single-cell transcriptomic data generating robust clusters. We also include a technique to estimate an efficient number of latent features in the deep learning model. Our method outperforms both classical and state-of-the-art feature learning and clustering methods, approaching the accuracy of supervised learning. We applied DUSC to single-cell transcriptomics dataset obtained from a triple-negative breast cancer tumor to identify potential cancer subclones accentuated by copy-number variation and investigate the role of clonal heterogeneity. Our method is freely available to the community and will hopefully facilitate our understanding of the cellular atlas of living organisms as well as provide the means to improve patient diagnostics and treatment.

Keywords

RNA-Seq

clustering

machine learning

single-cell

transcriptomics

Received January 3, 2020.

Accepted May 22, 2020.

Published by Cold Spring Harbor Laboratory Press for the RNA Society

This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

SOURCE

https://rnajournal.cshlp.org/content/early/2020/06/12/rna.074427.119.abstract

New subgroups of ILC immune cells discovered through single-cell RNA sequencing

SOURCE

http://ki.se/en/news/new-subgroups-of-ilc-immune-cells-discovered-through-single-cell-rna-sequencing?elqTrackId=f79885cef36049e281109c02da213910&elq=ac700a4d4374478b9d6e10e301ae6b90&elqaid=14707&elqat=1&elqCampaignId=14

Updated on 2016-02-15. Published on 2016-02-15Denna sida på svenska

Jenny Mjösberg and Rickard Sandberg are principal investigators at Karolinska Institutet’s Department of Medicine, Huddinge and Department of Cell and Molecular Biology, respectively. Credit: Stefan Zimmerman.

A relatively newly discovered group of immune cells known as ILCs have been examined in detail in a new study published in the journal Nature Immunology. By analysing the gene expression in individual tonsil cells, scientists at Karolinska Institutet have found three previously unknown subgroups of ILCs, and revealed more about how these cells function in the human body.

Innate lymphoid cells (ILCs) are a group of immune cells that have only relatively recently been discovered in humans. Most of current knowledge about ILCs stems from animal studies of e.g. inflammation or infection in the gastrointestinal tract. There is therefore an urgent need to learn more about these cells in humans.

Previous studies have shown that ILCs are important for maintaining the barrier function of the mucosa, which serves as a first line of defence against microorganisms in the lungs, intestines and elsewhere. However, while there is growing evidence to suggest that ILCs are involved in diseases such as inflammatory bowel disease, asthma and intestinal cancer, basic research still needs to be done to ascertain exactly what part they play.

Two research groups, led by Rickard Sandberg and Jenny Mjösberg, collaborated on a study of ILCs from human tonsils. To date, three main groups of human ILCs are characterized. In this present study, the teams used a novel approach that enabled them to sort individual tonsil cells and measure their expression across thousands of genes. This way, the researchers managed to categorise hundreds of cells, one by one, to define the types of ILCs found in the human tonsils.

Unique gene expression profiles

Rickard Sandberg, credit: Stefan Zimmerman,

“We used cluster analyses to demonstrate that ILCs congregate into ILC1, ILC2, ILC3 and NK cells, based on their unique gene expression profiles,” says Professor Sandberg at Karolinska Institutet’sDepartment of Cell and Molecular Biology, and the Stockholm branch of Ludwig Cancer Research. “Our analyses also discovered the expression of numerous genes of previously unknown function in ILCs, highlighting that these cells are likely doing more than what we previously knew.”

By analysing the gene expression profiles (or transcriptome) of individual cells, the researchers found that one of the formerly known main groups could be subdivided.

Jenny Mjösberg, credit: Stefan Zimmerman.

“We’ve identified three new subgroups of ILC3s that evince different gene expression patterns and that differ in how they react to signalling molecules and in their ability to secrete proteins,” says Dr Mjösberg at Karolinska Institutet’s Department of Medicine in Huddinge, South Stockholm. “All in all, our study has taught us a lot about this relatively uncharacterised family of cells and our data will serve as an important resource for other researchers.”

The study was financed by grants from a number of bodies, including the Swedish Research Council, the Swedish Cancer Society, the EU Framework Programme for Research and Innovation, the Swedish Society for Medical Research, the Swedish Foundation for Strategic Research and Karolinska Institutet.

Our press release about this study

Publication

The heterogeneity of human CD127+ innate lymphoid cells revealed by single-cell RNA sequencing
Åsa K. Björklund, Marianne Forkel, Simone Picelli, Viktoria Konya, Jakob Theorell, Danielle Friberg, Rickard Sandberg, Jenny Mjösberg
Nature Immunology, online 15 February 2016, doi:10.1038/ni.3368

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Two New Drugs for Inflammatory Bowel Syndrome Are Giving Patients Hope

Posted in Immunology, Immunotherapy, Inflammasome, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, tagged Actavis, Food and Drug Administration, guanylate cyclase, health, IBS, inflamation, inflammatory bowel disease (IBD), medicine, opiod delta agonist, plecanatide, Synergy Pharmaceuticals, Viberzi on January 7, 2016| Leave a Comment »

Two New Drugs for Inflammatory Bowel Syndrome Are Giving Patients Hope

Reporter: Stephen J. Williams, Ph.D.

Actavis Receives FDA Approval for VIBERZI (eluxadoline) for the Treatment of Irritable Bowel Syndrome with Diarrhea (IBS-D) in Adults -First in class treatment for IBS-D treats hallmark symptoms of IBS-D; abdominal pain and diarrhea

DUBLIN, May 27, 2015 /PRNewswire/ — Actavis plc (NYSE: ACT) announced today that VIBERZI™ (eluxadoline) was approved by the Food and Drug Administration (FDA) as a twice-daily, oral treatment for adults suffering from irritable bowel syndrome with diarrhea (IBS-D). VIBERZI (eluxadoline) has mixed opioid receptor activity, it is a mu receptor agonist, a delta receptor antagonist, and a kappa receptor agonist.

Logo – http://photos.prnewswire.com/prnh/20130124/NY47381LOGO

“The FDA’s approval of VIBERZI is the first step to providing physicians with a new, evidence-based, treatment option for their adult patients with IBS-D,” said David Nicholson, Executive Vice President, Actavis Global Brands R&D. “At Actavis, we are dedicated to providing new treatment options, and the development of new agents that help address the most bothersome symptoms of IBS-D. We are very pleased to be working with the FDA to advance this IBS-D treatment and we eagerly await DEA scheduling determination later this year.”

IBS-D is a multifactorial disorder marked by recurrent abdominal pain or discomfort and altered bowel function that affects as many as 15 million adult Americans, impacting about twice as many women as men.^i,ii,iii There are few treatment options available for IBS-D, particularly options that relieve both the diarrhea and abdominal pain associated with IBS-D.

“The unpredictable symptoms experienced by patients with IBS-D can have a significant impact on everyday life,” said William D. Chey, MD, Nostrant Professor of Gastroenterology at the University of Michigan Health System. “It’s exciting when physicians are able to add an additional treatment option like VIBERZI to their toolbox for patients with IBS-D.”

The FDA has recommended that VIBERZI be classified as a controlled substance. This recommendation has been submitted to the U.S. Drug Enforcement Administration (DEA). Once VIBERZI receives final scheduling designation, the updated label will be available. Pending final scheduling designation, product launch is anticipated in Q1 2016.

About VIBERZI

VIBERZI is an orally active compound indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in men and women. VIBERZI (eluxadoline) has mixed opioid receptor activity, it is a mu receptor agonist, a delta receptor antagonist, and a kappa receptor agonist.

Efficacy was established in two Phase III clinical studies, demonstrating significant superiority over placebo on the composite endpoint of simultaneous improvement in both abdominal pain and diarrhea at both 75 mg and 100 mg twice daily doses. The primary efficacy responder endpoint was evaluated over the duration of double-blind, placebo-controlled treatment. Response rates were compared based on patients who met the daily composite response criteria (improvement in both abdominal pain and stool consistency on the same day) for at least 50% of the days from weeks 1 to 12 (FDA endpoint) and weeks 1 to 26 (European Medicines Agency endpoint).

The most common adverse events in the two Phase III clinical trials were constipation (7% and 8% for eluxadoline 75 mg and 100 mg; 2% for placebo) and nausea (8% and 7% for eluxadoline 75 mg and 100 mg; 5% for placebo). Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg eluxadoline. Rates of discontinuation due to constipation were low for both eluxadoline and placebo (≤2%) and similar rates of constipation occurred between the active and placebo arms beyond 3 months of treatment. A total of 2,426 subjects were enrolled across the two studies.

For more information including full prescribing information about VIBERZI at http://www.actavis.com/Actavis/media/PDFDocuments/VIBERZI_PI.pdf

About IBS-D

Irritable bowel syndrome with diarrhea (IBS-D) is a functional bowel disorder characterized by chronic abdominal pain and frequent diarrhea, which affects approximately 15 million patients in the U.S. Although the exact cause of IBS-D is not known, symptoms are thought to result from a disturbance in the way the gastrointestinal tract and nervous system interact.

IBS-D can be debilitating and there are limited therapeutic options for managing the chronic symptoms. IBS-D is associated with economic burden in direct medical costs and indirect social costs such as absenteeism and lost productivity, along with decreased quality of life.

About Actavis
Actavis plc (NYSE: ACT), headquartered in Dublin, Ireland, is a unique, global pharmaceutical company and a leader in a new industry model—Growth Pharma. Actavis is focused on developing, manufacturing and commercializing innovative branded pharmaceuticals, high-quality generic and over-the-counter medicines and biologic products for patients around the world.

Actavis markets a portfolio of best-in-class products that provide valuable treatments for the central nervous system, eye care, medical aesthetics, gastroenterology, women’s health, urology, cardiovascular and anti-infective therapeutic categories, and operates the world’s third-largest global generics business, providing patients around the globe with increased access to affordable, high-quality medicines. Actavis is an industry leader in research and development, with one of the broadest development pipelines in the pharmaceutical industry and a leading position in the submission of generic product applications globally.

With commercial operations in approximately 100 countries, Actavis is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives.

Actavis intends to adopt a new global name – Allergan – pending shareholder approval in 2015.

For more information, visit Actavis’ website at www.actavis.com.

Actavis Cautionary Statement Regarding Forward-Looking Statements

Statements contained in this communication that refer to Actavis’ estimated or anticipated future results, including estimated synergies, or other non-historical facts are forward-looking statements that reflect Actavis’ current perspective of existing trends and information as of the date of this communication. Actual results may differ materially from Actavis’ current expectations depending upon a number of factors affecting Actavis’ business. These factors include, among others, the timing and success of product launches; the difficulty of predicting the timing or outcome of product development efforts and regulatory agency approvals or actions, if any; market acceptance of and continued demand for Actavis’ products; difficulties or delays in manufacturing; and such other risks and uncertainties detailed in Actavis’ periodic public filings with the Securities and Exchange Commission, including but not limited to Actavis plc’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2015 and from time to time in Actavis’ other investor communications. Except as expressly required by law, Actavis disclaims any intent or obligation to update or revise these forward-looking statements.

ⁱ Camilleri M. Current and future pharmacological treatments for diarrhea-predominant irritable bowel syndrome. Expert Opinion on Pharmacotherapy. 2013;14:1151.

ⁱⁱ Grundmann O, Yoon SL. Irritable bowel syndrome: epidemiology, diagnosis, and treatment: an update for health-care practitioners. Journal of Gastroenterology and Hepatology. 2010;25:691–699.

ⁱⁱⁱ Eluxadoline Xifaxin Summary Final. November 2014.

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Synergy’s Looming FDA Filing Makes It Pharma of the Month

By James Passeri Follow

| Jan 05, 2016 | 8:39 AM EST | 0

Keep an eye on Synergy Pharmaceuticals (SGYP) this month: Analysts like it, its shares have waned since a big spike this summer, and the official filing of its star product is expected any day.

When the New York-based pharmaceutical company, which specializes in gastrointestinal therapy, announced that it passed clinical trials on its flagship drug plecanatide this summer, shares rocketed 95%.

But today analysts appear mystified at why the stock has receded 45% from its July high, especially with plecanatide’s new drug application with the Food and Drug Administration expected this month. (It’s currently trading below $6, and the consensus price target is over $13, according to data provided by Bloomberg.)

Synergy should be raking in $600 million from plecanatide, a daily tablet that treats patients with irritable bowel syndrome (IBS), within five years of obtaining FDA approval (expected in 2017, according to equity research firm BTIG. Synergy currently has a market capitalization of just $645 million.

BTIG’s $11 price target is also buoyed by roughly $142 million on the balance sheet, as well as newly appointed management including CFO Gary Sender and COO Troy Hamilton, both former executives at pharma success story Shire (SHPG). Though Shire shares are down just under 4% over the past 12 month, they have rocketed 112% over the past two years.

Synergy also stands to benefit from a growing demand for gastrointestinal treatments, feeding the appetite of Big Pharma for potential acquisitions, according to BTIG.

“With about 45 million Americans suffering from chronic constipation and IBS, and major companies like Allergan(AGN) and Valeant (VRX) focusing their marketing efforts on GI treatments, it seems logical to imagine SGYP as a takeover candidate,” BTIG analyst Timothy Chiang wrote in a November report.

Whether or not this leads to a buyout or another stock surge, Synergy certainly can be counted on for a healthy dose of small-cap volatility as its chief product takes the final steps toward reaching its customers.

Synergy Pharmaceuticals Announces Successful End-of-Phase 2 Meeting with FDA for Plecanatide in Irritable Bowel Syndrome with Constipation

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Pivotal Phase 3 IBS-C Program to be Initiated in the Fourth Quarter of 2014

NEW YORK– Synergy Pharmaceuticals Inc. (NASDAQ:SGYP) today announced that it has successfully completed an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) on its lead drug plecanatide for the treatment of irritable bowel syndrome with constipation (IBS-C). Agreement was reached with the FDA for the plecanatide pivotal phase 3 IBS-C clinical development program that is scheduled to begin in the fourth quarter of this year.

“We are very pleased with the outcome of our meeting with the FDA and have a clear path forward to start the IBS-C registration program with plecanatide this year,” said Dr. Gary S. Jacob, Chairman and CEO of Synergy. “The pivotal phase 3 IBS-C trials will include both 3.0 mg and 6.0 mg plecanatide, which are consistent with the doses currently being evaluated in our phase 3 chronic idiopathic constipation (CIC) program. Plecanatide has demonstrated a clinical dose-response for efficacy with an excellent tolerability profile that is observed across trials. This is an important advantage as we look to bring two doses to market in both indications and provide physicians with options for addressing individual patient needs.”

Synergy’s pivotal phase 3 IBS-C clinical development program will consist of two registration trials, each including 1,050 patients who will receive either placebo, 3.0 mg or 6.0 mg plecanatide. IBS-C patients successfully completing either of the 12-week placebo-controlled registration trials will be offered enrollment into a long-term safety trial in order to complement and support the ongoing long-term safety database for the CIC indication.

About Plecanatide

Plecanatide is Synergy’s lead uroguanylin analog in late-stage clinical development to treat patients with CIC and IBS-C. Uroguanylin is a natural gastrointestinal (GI) hormone produced by humans in the small intestine and plays a key role in regulating the normal functioning of the digestive tract through its activity on the guanylate cyclase-C (GC-C) receptor. The GC-C receptor is known to be a primary source for stimulating a variety of beneficial physiological responses. Orally administered plecanatide mimics uroguanylin’s functions by binding to and activating the GC-C receptor to stimulate fluid and ion transit required for normal bowel function. Synergy has successfully completed a phase 2b trial of plecanatide in 951 patients with CIC and is currently enrolling patients in two pivotal phase 3 CIC trials. The company also recently announced positive top-line data results from a phase 2b dose-ranging study with plecanatide in patients with IBS-C.

About Synergy Pharmaceuticals

Synergy Pharmaceuticals (NASDAQ:SGYP) is a biopharmaceutical company focused on the development of novel therapies based on the natural human hormone, uroguanylin, to treat GI diseases and disorders. Synergy has created two unique analogs of uroguanylin – plecanatide and SP-333 – designed to mimic the natural hormone’s activity on the GC-C receptor and target a variety of GI conditions. SP-333 is currently in phase 2 development for opioid-induced constipation and is also being explored for ulcerative colitis. For more information, please visit www.synergypharma.com.

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New Data Shows A False-Positive Mammogram May Actually Increase Risk

Posted in Cancer Prevention: Research & Programs, Cancer Screening, tagged breast cancer, breast cancer screening, Cancer - General, cancer prevention, Conditions and Diseases, health, mammography on December 14, 2015| Leave a Comment »

False-Positive Mammogram Results May Be Linked to Higher Risk Later in Life

From BreastCancer.org

While screening mammograms aren’t perfect, they are the best way we have right now to detect breast cancer early, when it’s most treatable.

When a screening mammogram shows an abnormal area that looks like a cancer but turns out to be normal, it’s called a false positive. Ultimately the news is good: no breast cancer. But the suspicious area usually requires follow-up with more than one doctor, extra tests, and extra procedures, including a possible biopsy.

A large study suggests that women with false-positive mammogram results have a slightly higher risk of developing invasive breast cancer within the next 10 years.

The research was published online on Dec. 2, 2015 by the journal Cancer Epidemiology, Biomarkers & Prevention. Read the abstract of “Increased Risk of Developing Breast Cancer after a False-Positive Screening Mammogram.”

To do the study, the researchers looked at information from nearly 1.3 million women ages 40 to 70 with no family history of breast cancer who had screening mammograms from 1994 to 2009. The information came from the Breast Cancer Surveillance Consortium database, which is maintained by the National Cancer Institute.

The researchers found that the 1,297,906 women had a total of 2,207,942 screening mammograms. There were:

159,448 false-positive results with a recommendation for more imaging
22,892 false-positive results with a recommendation for biopsy
2,025,602 negative mammograms

Women ages 40 to 49 made up the largest percentage of false-positive mammogram results with a recommendation for more imaging (33.1%). Women with dense breasts also were more likely to have false-positive results.

The researchers then compared the rates of invasive breast cancer between women who had false-positive mammogram results and women who had negative mammogram results:

there were 3.91 invasive breast cancers per 1,000 person-years of follow-up among women with negative mammogram results
there were 5.51 invasive breast cancers per 1,000 person-years of follow-up among women with false-positive mammogram results with a recommendation for more imaging
there were 7.01 invasive breast cancers per 1,000 person-years of follow-up among women with false-positive mammogram results with a recommendation for biopsy

The researchers said the 10-year risk of invasive breast cancer was:

39% higher in women with false-positive results with a recommendation for more imaging
76% higher in women with false-positive results with a recommendation for biopsy

compared to women with negative results.

It’s important to know that the increases above are increases in relative risk — the risk of a woman with a false-positive result relative to the risk of a woman with a negative result.

In terms of absolute risk, the increase is small:

women with false-positive results have about a 2% risk of developing invasive disease in the 10 years after the false-positive result
women with negative results have about a 1% risk of developing invasive disease in the 10 years after the negative result

The researchers didn’t offer an explanation about why false-positive mammogram results appear to be linked to a slightly higher risk of invasive disease. Many experts think that the subtle changes suggested on the mammogram may be an early clue to cancer before actual cancer exists.

It’s also important to know that this association has been suggested in other studies. But the large number of women in the study and the length of follow-up add more evidence that the link between false-positive results and a somewhat higher risk of invasive disease actually exists.

“The power of this study to show the association is very strong, particularly when you combine it with the results of the other studies that have been done,” said Richard Wender, M.D., chief of cancer control at the American Cancer Society, in an interview. “I think we can now say with confidence that women who have had a previous false-positive mammogram are at somewhat higher risk for breast cancer.”

The researchers who did this study want to incorporate false-positive mammogram results into models that predict breast cancer risk.

“Now that we have this information, our hope is that we can add it into existing risk-prediction models to improve their ability to discriminate between women who will go on to develop breast cancer and those who won’t,” said Louise Henderson, Ph.D., of the University of North Carolina Lineberger Comprehensive Cancer Center, who was the lead author of the study. “We should accept that a false-positive mammogram is a risk factor for predicting future risk of breast cancer.

“In clinical terms, that means women who have a false-positive mammogram need to be particularly vigilant about keeping up with regular mammographic screening,” she continued. “The clinicians caring for these women should have a way to track women who have had a false-positive and make sure that every effort is made to keep up to date with mammography.”

It’s important to know that a false-positive mammogram result doesn’t mean you will be diagnosed with breast cancer.

“Having any history of breast biopsies is associated with a higher risk,” said Breastcancer.org President and Founder Marisa Weiss, M.D. “Breast tissue that is dense or has proliferative changes tends to lead to questions on the breast imaging. Sometimes it leads to biopsies. In contrast, breast tissue that is boring, without any extra activity, rarely leads to any kind of biopsy. That kind of inactive breast tissue is less likely to develop breast cancer.”

“This study doesn’t suggest that having a false-positive leads to breast cancer,” said Brian Wojciechowski, M.D., Breastcancer.org’s medical adviser. “Rather, it reflects an association between breast cancer risk and abnormal breast imaging. Women should not worry that getting mammograms will increase their risk of breast cancer in the future.”

There’s only one of you and you deserve the best care possible. Don’t let any obstacles get in the way of your regular screening mammograms, especially if you’ve had a false-positive result.

If you’re worried about cost, talk to your doctor, a local hospital social worker, or staff members at a mammogram center. Ask about free programs in your area.
If you’re having problems scheduling a mammogram, call the National Cancer Institute (800-4-CANCER) or the American College of Radiology (800-227-5463) to find certified mammogram providers near you.
If you find mammograms painful, ask the mammography center staff members how the experience can be as easy and as comfortable as possible for you.
If you’re concerned about unknown results or being called back for more testing, talk to your doctor about what happens when mammogram results are unclear, as well as what to expect if you’re called back for more testing.

For more information on mammograms and other tests to detect and diagnose breast cancer, visit the Breastcancer.org Screening and Testing section.

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PD1 Inhibitor atezolizumab may show promise in bladder cancer in patients with high PDL1 expression

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Pharmaceutical Drug Discovery, tagged bladder cancer, cancer immunotherapeutics, Clinical trial, health, Immunotherapy, medicine, PDL1/PD1 pathway on November 17, 2015| Leave a Comment »

PD1 Inhibitor atezolizumab may show promise in bladder cancer in patients with high PDL1 expression

Reporter: Stephen J Williams

Updated 4/15/2016

Promising Immunotherapy Agents on Horizon in Bladder Cancer

Reported from OncLive

Virginia Powers, PhD

Published Online: Monday, November 16, 2015 at http://www.onclive.com/web-exclusives/promising-immunotherapy-agents-on-horizon-in-bladder-cancer

thompson

Thomas Powles, MD

The dramatic and often practice-changing findings demonstrated by trials of immunotherapies in melanoma and lung cancer may soon be reflected in the treatment of bladder cancer, according to a summary of ongoing studies¹ presented at the 7th European Multidisciplinary Meeting on Urological Cancers (EMUC).

“Immune therapy is a promising new treatment in transitional cell carcinoma (TCC) of the bladder,” said Thomas Powles, MD, medical oncologist, director of St Bartholomew’s Cancer Centre, London. “Until recently, bladder cancer research has been somehow left behind.”

Powles underscored that immune checkpoint inhibitors are active in urothelial bladder cancer (UBC) and provided an overview of the emergence of immune therapy in bladder cancer that focused on agents targeting the immune checkpoint axis, especially the programed death receptor (PD1) and its ligand (PD-L1).

“Each drug has a unique companion diagnostic but the strongest data so far are seen with blocking PD-L1 and atezolizumab,” he said.

The confirmed overall response rate (ORR) by RECIST to atezolizumab are associated with PD-L1 expression levels in the tumor. In a phase I trial of second line atezolizumab (MPDL3280A) in TCC, a response was demonstrated in patients that had previously showed only a 10% response rate to chemotherapy. The ORRs were 43% for patients with tumors expressing high levels of PD-L1 (IHC 2/3) compared to 11% in patients with tumors having low expression (IHC 0 or 1).²

PD-L1 expression on the immune cells (IC) infiltrating the tumor has also been shown to be associated with response. The PD-L1 expression on ICs was evaluated as low, medium, and high in approximately one-third each of 311 patients with locally-advanced or metastatic urothelial carcinoma (mUC) participating in the phase II IMvigor 210 trial, which corresponded to an ORR with atezolizumab of 9%, 10%, and 27% in the respective expression groups.

Overall survival (OS) at a median follow-up of 7 months (range, 0-11) also correlated with expression levels and was 6.7 months in low (IC0/1), not reached in high (IC2/3) expressing patients, and 7.9 months in overall population. However, no difference was seen in progression-free survival (PFS) according to expression levels; median PFS was 2.1 months in the overall population and in patients having both low (IC0/1) and high (IV2/3) expression levels, respectively. These data were emphasized as early response data that are expected to mature in further analyses.³

Powles commented that his team is beginning a phase III randomized trial of atezolizumab in 767 patients with locally-advanced UBC who were also chemotherapy-resistant following 1 to 2 prior lines of a platinum-based regimen. Patients have been stratified by chemotherapy regimen, PD-L1 expression, IHC status, risk factors, and the presence of liver metastasis. The primary endpoint is OS and secondary endpoints include ORR, PFS, and duration of response (DoR), safety, and tolerability. Other objectives include disease control rate and potential biomarkers.

“PD-L1 expression appears important but we need to find other biomarkers,” he remarked.

Powles moved on to discuss the KEYNOTE-012 phase Ib trial of pembrolizumab, an anti-PD1 antibody that blocks interaction with both PD-L1 and PD-L2. In KEYNOTE, pembrolizumab demonstrated anti-tumor activity in patients with recurrent or metastatic PD-L1–positive UBC in 64% of patients experiencing a decrease in target lesions from baseline.⁴

Combination and adjuvant studies are ongoing, according to Powles. A trial of atezolizumab as adjuvant therapy versus placebo is underway in patients with TCC whose tumors express PD-L1. The trial has a primary endpoint of disease-free survival (DFS).

“Next-generation combination therapy with nivolumab plus ipilimumab is a common sense approach that was tested in advanced melanoma and is now being evaluated in the Danube trial,” Powles said.

Nivolumab, a PD-1 blocking antibody, and ipilimumab, which blocks CTLA-4, will be evaluated in Danube, a randomized phase III study that will enroll 800 patients with untreated metastatic TCC. The endpoints are PFS and OS. Patients are required to have available tissue for PD-L1 testing and no contraindications for immune therapy.

The rationale for the combination was demonstrated in melanoma, where confirmed objective responses were seen in 61% of patients receiving nivolumab plus ipilimumab versus 11% in patients receiving ipilimumab and placebo (P <0.001). Complete responses were reported in 16 patients (22%) with combination compared to no patients receiving ipilimumab monotherapy.⁵

“It looks like checkpoint inhibition works particularly well in node positive patients; in the future we can see treatment with first-line immunotherapeutic agents,” said Powles.

“We hope that immune therapy will identify a subset of patients who get long-term benefits from immune therapy,” Powles said. “The future looks bright for immunotherapy in bladder cancer.”

References

Powles T. Update on systemic treatments in bladder cancer. Presented at: 7th European Multidisciplinary Meeting on Urological Cancers (EMUC), Barcelona, Spain, November 12–15, 2015.
Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558-562.
Rosenberg J, Petrylak D, Abidoye O, et al. Atezolizumab in patients (pts) with locally-advanced or metastatic urothelial carcinoma (mUC): Results from a pivotal multicenter phase II study (IMvigor 210). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 21LBA.
Plimack ER, Bellmunt J, Gupta S, et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J Clin Oncol 33, 2015 (suppl; abstr 4502).
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373:23-34.

– See more at: http://www.onclive.com/web-exclusives/promising-immunotherapy-agents-on-horizon-in-bladder-cancer#sthash.c63jReGo.dpuf

Speedy review for Merck’s Keytruda in head and neck cancer

DAILY NEWS | APRIL 14, 2016

As seen in PharmaTimes.com at http://www.pharmatimes.com/Article/16-04-14/Speedy_review_for_Merck_s_Keytruda_in_head_and_neck_cancer.aspx

SELINA MCKEE

Speedy review for Merck's Keytruda in head and neck cancer

US regulators have agreed to undertake a speedy review of Merck & Co’s application to market immunotherapy Keytruda for the treatment of certain patients with head and neck cancer, it third potential indication in the country.

The company is targeting the drug towards patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Lab Grown Brains and more from Twittersphere on 3D Bio-Printing News

Posted in 3D Plotting Scaffolds, 3D Printing for Medical Application, 4D Printing and Meta Materials, BioPrinting in Regenerative Medicine, tagged 3-D bioprinting, 3D printing, artificial artery, brain, conservation, ethical issues, health, medicine, Social media, Twitter on November 16, 2015| Leave a Comment »

Lab Grown Brains and more from Twittersphere on 3D Bio-Printing News

Curator: Stephen J. Williams, Ph.D

How Tiny Lab-Grown Human Brains Are Giving Big Insights Into Autism and more from the Twittershpere

https://twitter.com/singularityhub/status/664508353771610112

(more…)

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FDA Guidance on Use of Xenotransplanted Products in Human: Implications in 3D Printing

Posted in 3D Plotting Scaffolds, 3D Printing for Medical Application, BioInks, Biopolymer Blend Open Porous, BioPrinting in Regenerative Medicine, Cell Level, FDA, FDA Regulatory Affairs, MicroEngineering Cell-Tissue & Systems, tagged 3-D bioprinting, 3D biological structure, 3D organ, FDA, FDA compliance, FDA guidance, Food and Drug Administration, health, hydrogel, Organ transplantation, porcine models, regenerative medicine, Scaffolding, xenotransplantation on November 9, 2015| Leave a Comment »

FDA Guidance On Source Animal, Product, Preclinical and Clinical Issues Concerning the Use of Xenotranspantation Products in Humans – Implications for 3D BioPrinting of Regenerative Tissue

Reporter: Stephen J. Williams, Ph.D.

The FDA has submitted Final Guidance on use xeno-transplanted animal tissue, products, and cells into human and their use in medical procedures. Although the draft guidance was to expand on previous guidelines to prevent the introduction, transmission, and spread of communicable diseases, this updated draft may have implications for use of such tissue in the emerging medical 3D printing field.

This document is to provide guidance on the production, testing and evaluation of products intended for use in xenotransplantation. The guidance includes scientific questions that should be addressed by sponsors during protocol development and during the preparation of submissions to the Food and Drug Administration (FDA), e.g., Investigational New Drug Application (IND) and Biologics License Application (BLA). This guidance document finalizes the draft guidance of the same title dated February 2001.

For the purpose of this document, xenotransplantation refers to any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs. For the purpose of this document, xenotransplantation products include live cells, tissues or organs used in xenotransplantation. (See Definitions in section I.C.)

This document presents issues that should be considered in addressing the safety of viable materials obtained from animal sources and intended for clinical use in humans. The potential threat to both human and animal welfare from zoonotic or other infectious agents warrants careful characterization of animal sources of cells, tissues, and organs. This document addresses issues such as the characterization of source animals, source animal husbandry practices, characterization of xenotransplantation products, considerations for the xenotransplantation product manufacturing facility, appropriate preclinical models for xenotransplantation protocols, and monitoring of recipients of xenotransplantation products. This document recommends specific practices intended to prevent the introduction and spread of infectious agents of animal origin into the human population. FDA expects that new methods proposed by sponsors to address specific issues will be scientifically rigorous and that sufficient data will be presented to justify their use.

Examples of procedures involving xenotransplantation products include:

transplantation of xenogeneic hearts, kidneys, or pancreatic tissue to treat organ failure,
implantation of neural cells to ameliorate neurological degenerative diseases,
administration of human cells previously cultured ex vivo with live nonhuman animal antigen-presenting or feeder cells, and
extracorporeal perfusion of a patient’s blood or blood component perfused through an intact animal organ or isolated cells contained in a device to treat liver failure.

The guidance addresses issues such as:

REGULATORY RESPONSIBILITY
SOURCE ANIMAL CHARACTERIZATION
CHARACTERIZATION OF XENOTRANSPLANTATION PRODUCTS
MICROBIOLOGICAL TESTING OF XENOTRANSPLANTATION PRODUCTS
MANUFACTURING AND PROCESS-RELATED GMP CONSIDERATIONS FOR HARVEST AND PROCESSING OF XENOTRANSPLANTATION PRODUCTS
PRECLINICAL CONSIDERATIONS FOR XENOTRANSPLANTATION INCLUDING
Issues Related to Infectious Agents
Xenotransplantation Product-Host Interactions
Considerations for the Use of Heterogeneous Xenotransplantation Products
In Vitro and In Vivo Tumorigenicity Models for Xenotransplantation Products Intended for Transplantation
Combinations of Xenotransplantation Products with Devices
CLINICAL ISSUES IN XENOTRANSPLANTATION INCLUDING

Clinical Protocol Review
Xenotransplantation Site
Criteria for Patient Selection
Risk/Benefit Assessment
Screening for Infectious Agents
Patient Follow-up
Archiving of Patient Plasma and Tissue Specimens
Health Records and Data Management
Informed Consent
Responsibility of the Sponsor in Informing the Patient of New Scientific Information

A full copy of the PDF can be found below for reference:

fdaguidanceanimalsourcesxenotransplatntation

An example of the need for this guidance in conjunction with 3D printing technology can be understood from the below article (source http://www.geneticliteracyproject.org/2015/09/03/pig-us-xenotransplantation-new-age-chimeric-organs/)

Pig in us: Xenotransplantation and new age of chimeric organs

David Warmflash | September 3, 2015 | Genetic Literacy Project

Imagine stripping out the failing components of an old car — the engine, transmission, exhaust system and all of those parts — leaving just the old body and other structural elements. Replace those old mechanical parts with a brand new electric, hydrogen powered, biofuel, nuclear or whatever kind of engine you want and now you have a brand new car. It has an old frame, but that’s okay. The frame wasn’t causing the problem, and it can live on for years, undamaged.

When challenged to design internal organs, tissue engineers are taking a similar approach, particularly with the most complex organs, like the heart, liver and kidneys. These organs have three dimensional structures that are elaborate, not just at the gross anatomic level, but in microscopic anatomy too. Some day, their complex connective tissue scaffolding, the stroma, might be synthesized from the needed collagen proteins with advanced 3-D printing. But biomedical engineering is not there yet, so right now the best candidate for organ scaffolding comes from one of humanity’s favorite farm animals: the pig.

Chimera alarmists connecting with anti-biotechnology movements might cringe at the thought of building new human organs starting with pig tissue, but if you’re using only the organ scaffolding and building a working organ from there, pig organs may actually be more desirable than those donated by humans.

How big is the anti-chimerite movement?

Unlike anti-GMO and anti-vaccination activists, there really aren’t too many anti-chemerites around. Nevertheless, there is a presence on the web of people who express concern about mixing of humans and non-human animals. Presently, much of their concern is focussed on the growing of human organs inside non-human animals, pigs included. One anti-chemerite has written that it could be a problem for the following reason:

Once a human organ is grown inside a pig, that pig is no longer fully a pig. And without a doubt, that organ will no longer be a fully human organ after it is grown inside the pig. Those receiving those organs will be allowing human-animal hybrid organs to be implanted into them. Most people would be absolutely shocked to learn some of the things that are currently being done in the name of science.

The blog goes on to express alarm about the use of human genes in rice and from there morphs into an off the shelf garden variety anti-GMO tirade, though with an an anti-chemeric current running through it. The concern about making pigs a little bit human and humans a little bit pig becomes a concern about making rice a little bit human. But the concern about fusing tissues and genes of humans and other species does not fit with the trend in modern medicine.

Utilization of pig tissue enters a new age

A porcine human ear for xenotransplantation. source: The Scientist

For decades, pig, bovine and other non-human tissues have been used in medicine. People are walking around with pig and cow heart valves. Diabetics used to get a lot of insulin from pigs and cows, although today, thanks to genetic engineering, they’re getting human insulin produced by microorganisms modified genetically to make human insulin, which is safer and more effective.

When it comes to building new organs from old ones, however, pig organs could actually be superior for a couple of reasons. For one thing, there’s no availability problem with pigs. Their hearts and other organs also have all of the crucial components of the extracellular matrix that makes up an organ’s scaffolding. But unlike human organs, the pig organs don’t tend to carry or transfer human diseases. That is a major advantage that makes them ideal starting material. Plus there is another advantage: typically, the hearts of human cadavers are damaged, either because heart disease is what killed the human owner or because resuscitation efforts aimed at restarting the heart of a dying person using electrical jolts and powerful drugs.

Rebuilding an old organ into a new one

How then does the process work? Whether starting with a donated human or pig organ, there are several possible methods. But what they all have in common is that only the scaffolding of the original organ is retained. Just like the engine and transmission of the old car, the working tissue is removed, usually using detergents. One promising technique that has been applied to engineer new hearts is being tested by researchers at the University of Pittsburgh. Detergents pumped into the aorta attached to a donated heart (donated by a human cadaver, or pig or cow). The pressure keeps the aortic valve closed, so the detergents to into the coronary arteries and through the myocardial (heart muscle) and endocardial (lining over the muscle inside the heart chambers) tissue, which thus gets dissolved over the course of days. What’s left is just the stroma tissue, forming a scaffold. But that scaffold has signaling factors that enable embryonic stem cells, or specially programed adult pleuripotent cells to become all of the needed cells for a new heart.

Eventually, 3-D printing technology may reach the point when no donated scaffolding is needed, but that’s not the case quite yet, plus with a pig scaffolding all of the needed signaling factors are there and they work just as well as those in a human heart scaffold. All of this can lead to a scenario, possibly very soon, in which organs are made using off-the-self scaffolding from pig organs, ready to produce a custom-made heart using stem or other cells donated by new organ’s recipient.

David Warmflash is an astrobiologist, physician, and science writer. Follow @CosmicEvolution to read what he is saying on Twitter.

And a Great Article in The Scientist by Dr. Ed Yong Entitled

Replacement Parts

To cope with a growing shortage of hearts, livers, and lungs suitable for transplant, some scientists are genetically engineering pigs, while others are growing organs in the lab.

By Ed Yong | August 1, 2012

Source: http://www.the-scientist.com/?articles.view/articleNo/32409/title/Replacement-Parts/

.. where Joseph Vacanti and David Cooper figured that using

“engineered pigs without the a-1,3-galactosyltransferase gene that produces the a-gal residues. In addition, the pigs carry human cell-membrane proteins such as CD55 and CD46 that prevent the host’s complement system from assembling and attacking the foreign cells”

… thereby limiting rejection of the xenotransplated tissue.

In addition to issues related to animal virus transmission the issue of optimal scaffolds for organs as well as the advantages which 3D Printing would have in mass production of organs is discussed:

To Vacanti, artificial scaffolds are the future of organ engineering, and the only way in which organs for transplantation could be mass-produced. “You should be able to make them on demand, with low-cost materials and manufacturing technologies,” he says. That is relatively simple for organs like tracheas or bladders, which are just hollow tubes or sacs. Even though it is far more difficult for the lung or liver, which have complicated structures, Vacanti thinks it will be possible to simulate their architecture with computer models, and fabricate them with modern printing technology. (See “3-D Printing,” The Scientist, July 2012.) “They obey very ordered rules, so you can reduce it down to a series of algorithms, which can help you design them,” he says. But Taylor says that even if the architecture is correct, the scaffold would still need to contain the right surface molecules to guide the growth of any added cells. “It seems a bit of an overkill when nature has already done the work for us,” she says.

Volume 4: Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices.

On Amazon.com since since 12/30/2017 at https://www.amazon.com/dp/B078QVDV2W

Use of 3D Bioprinting for Development of Toxicity Prediction Models

Global Technology Conferences on 3D BioPrinting 2015 – 2016

New Scaffold-Free 3D Bioprinting Method Available to Researchers

New FDA Draft Guidance On Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products – Implications for 3D BioPrinting of Regenerative Tissue

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FDA Guidance Documents Update Nov. 2015 on Devices, Animal Studies, Gene Therapy, Liposomes

Posted in FDA, FDA Regulatory Affairs, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Lipidomics, Liposome, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Uncategorized, tagged animal testing, Clinical trial, FDA, Food and Drug Administration, gene therapy, health on November 3, 2015| Leave a Comment »

FDA Guidance Documents Update

Reporter: Stephen J. Williams, Ph.D.

10/30/2015

You are subscribed to FDA Guidance Documents for U.S. Food & Drug Administration (FDA).

This information has recently been updated and is now available.

Recently posted guidance documents

10/14/15: General Considerations for Animal Studies for Medical Devices – Draft Guidance for Industry and Food and Drug Administration Staff

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

Posted in Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Disease Biology, tagged anti-cancer therapeutics, beta adrenergic, Biology, Cancer - General, cell signaling, Clinical trial, Conditions and Diseases, DNA, gene expression, health, MD Anderson Cancer center, norepinephrine, ovarian cancer on October 26, 2015| Leave a Comment »

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

Curator: Stephen J. Williams, Ph.D.

This post is a follow-up on the two reports found in this Open Access Journal

http://pharmaceuticalintelligence.com/2015/09/16/ovarian-cancer-survival-increased-5-months-overall-with-beta-blockers-study-the-speaker/

AND

http://pharmaceuticalintelligence.com/2013/04/08/beta-blockers-help-in-better-survival-in-ovarian-cancer/

in order to explain some of the background which went into the development of these reports.

A recent paper by Anil Sood’s group at MD Anderson in Journal of Cancer: Clinical impact of selective and nonselective beta-blockers on survival in patients with ovarian cancer describes a retrospective pathologic evaluation of ovaries from patients taking various beta blockers for currently approved indications.

The history of this finding is quite interesting and, as I remember in a talk given by Dr. Sood in mid-2000’s, a microarray conducted by his lab had showed overexpression of the β2-AR (β2 adrenergic receptor in ovarian cancer cells relative to normal epithelium. At the time it appeared an interesting result however most of the cancer (and ovarian cancer) field were concentrating on the tyrosine kinase signaling pathways as potential therapeutic targets, as much promising translational research in this area was in focus at the time. As a result of this finding and noticing that sustained β-adrenergic stimulation can promote ovarian cancer cell growth (Sood, 2006), Dr. Sood’s group have been studying the effects of β-adrenergic signaling om ovarian cancer. In addition it has been shown that propanalol can block VEGF signaling and norepinephrine increased MMP2 and MMP9 expression, an effect mediated by the β2-AR.

The above re-post of a Scoop-IT describes promising results of a clinical trial for use of selective beta blockers in ovarian cancer. As to date, there have been many clinical trials initiated in ovarian cancer and most have not met with success for example the following posts:

Good and Bad News Reported for Ovarian Cancer Therapy

a follow-up curation on the problems encountered with the PARP-inhibitor olaparib

enough is enough: Treat ‘Each Patient as an Individual’

which contains an interview with Dr. Maurie Markman (Vice President, Patient Oncology Services, and National Director for Medical Oncology, Cancer Treatment Centers of America) and Dr. Kathy D. Miller, Indiana University School of Medicine) and discusses how each patient’s ovarian cancer is genetically unique and needs to be treated as such

Therefore the mainstay therapy is still carboplatin plus a taxane (Taxotere, Abraxane). The results of this clinical trial show a 5 month improvement in survival, which for a deadly disease like ovarian cancer is a significant improvement.

First below is a SUMMARY of the paper’s methodology and findings.

Methods:

Four participating institutions collected retrospective patient data and pathology reports from 1425 patients diagnosed with epithelial ovarian cancer (EOC)
Medical records were evaluated for use of both selective and nonselective β-blockers
β-blockers were used for various indications however most common indication was treatment for hypertension (71% had used β1 selective blockers while rest of patients taking β blockers were given nonselective blockers for a host of other indications)
most patients had stage III/IV disease and in general older (median age 63 years)

The authors looked at overall survival (OS) however progression free survival PFS) was not calculated

Results:

Hypertension was associated with decreased survival (40.1 monts versus 47.4 months for normotensive patients)
Overall Survival for patients on any β blockers was 47.8 months versus 42.0 months for nonusers
Patients receiving nonselective β blockers has an OS of 94.9 months versus 38 months for EOC patients receiving β1-selective blockers
No effect of diabetes mellitus on survival

Authors Note on Limitations of Study:

Retrospective in nature
Lack of documentation of dosage, trade-name and duration of β-blocker use
Important to stratify patients on selectivity of β-blocker since Eskander et. al. found no difference of Progression Free Survival and non-selective β-blocker
Several β adrenergic receptor polymorphisms may exist and no downstream biomarker evaluated to determine effect on signaling; could it be a noncanonical effect?

The goal of this brief, added curation is to paint a historical picture, and highlight the scientific findings which led up to the rationale behind this clinical trial.

How the βeta Adrenergic Receptor (βAR) Became a Target for Ovarian Cancer

A. βAR and its signaling over-expressed in ovarian cancer

Role of mitogen-activated protein kinase/extracellular signal-regulated kinase cascade in gonadotropin-releasing hormone-induced growth inhibition of a human ovarian cancer cell line.

Kimura A, Ohmichi M, Kurachi H, Ikegami H, Hayakawa J, Tasaka K, Kanda Y, Nishio Y, Jikihara H, Matsuura N, Murata Y.

Cancer Res. 1999 Oct 15;59(20):5133-42.

Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the beta 2-adrenergic receptor.

Rangarajan S, Enserink JM, Kuiperij HB, de Rooij J, Price LS, Schwede F, Bos JL.

J Cell Biol. 2003 Feb 17;160(4):487-93. Epub 2003 Feb 10.

B. Mechanistic Link Between Chronic Stress From Excess Adrenergic Stimulation and Angiogenesis and Metastasis

Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Jabbari S, Rainwater K, Ritchie JM, Yang M, Sood AK.

Clin Cancer Res. 2003 Oct 1;9(12):4514-21.PMID:

Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells.

Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB, Jewell S, Flavahan NA, Morrison C, Yeh PE, Lemeshow S, Glaser R.

Cancer Res. 2006 Nov 1;66(21):10357-64.

VEGF is differentially regulated in multiple myeloma-derived cell lines by norepinephrine.

Yang EV, Donovan EL, Benson DM, Glaser R.

Brain Behav Immun. 2008 Mar;22(3):318-23. Epub 2007 Nov 5.

Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.

Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK.

Nat Med. 2006 Aug;12(8):939-44. Epub 2006 Jul 23.

Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells.

Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB, Jewell S, Flavahan NA, Morrison C, Yeh PE, Lemeshow S, Glaser R.

Cancer Res. 2006 Nov 1;66(21):10357-64.

C. In Vivo Studies Confirm In Vitro Findings That Chronic Stress Via Adrenergic overstimulation Increases Ovarian Cancer Growth

Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.

Nat Med. 2006 Aug;12(8):939-44. Epub 2006 Jul 23.

Stress hormone-mediated invasion of ovarian cancer cells.

Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker PH, Li Y, Gershenson DM, Lutgendorf S, Cole SW.

Clin Cancer Res. 2006 Jan 15;12(2):369-75.

The neuroendocrine impact of chronic stress on cancer.

Thaker PH, Lutgendorf SK, Sood AK.

Cell Cycle. 2007 Feb 15;6(4):430-3. Epub 2007 Feb 9. Review.

Surgical stress promotes tumor growth in ovarian carcinoma.

Lee JW, Shahzad MM, Lin YG, Armaiz-Pena G, Mangala LS, Han HD, Kim HS, Nam EJ, Jennings NB, Halder J, Nick AM, Stone RL, Lu C, Lutgendorf SK, Cole SW, Lokshin AE, Sood AK.

Clin Cancer Res. 2009 Apr 15;15(8):2695-702. doi: 10.1158/1078-0432.CCR-08-2966. Epub 2009 Apr 7.

Sood group wanted to mimic the surgical stress after laparoscopic surgery to see if surgical stress would promote the growth of micrometasteses remaining after surgical tumor removal. Propranolol completely blocked the effects of surgical stress on tumor growth, indicating a critical role for beta-adrenergic receptor signaling in mediating the effects of surgical stress on tumor growth. In the HeyA8 and SKOV3ip1 models, surgery significantly increased microvessel density (CD31) and vascular endothelial growth factor expression, which were blocked by propranolol treatment. Tumor growth after surgery was decreased in a mouse null for βAR. Levels of cytokines G-CSF, IL-1a, IL-6, and IL-15were increased after surgery

Stress effects on FosB- and interleukin-8 (IL8)-driven ovarian cancer growth and metastasis J Biol Chem. 2010 Nov 12;285(46):35462-70. doi: 10.1074/jbc.M110.109579. Epub 2010 Sep 8.

Shahzad MM¹, Arevalo JM, Armaiz-Pena GN, Lu C, Stone RL, Moreno-Smith M, Nishimura M, Lee JW, Jennings NB, Bottsford-Miller J, Vivas-Mejia P, Lutgendorf SK, Lopez-Berestein G, Bar-Eli M, Cole SW, Sood AK.

Free PMC Article

Abstract

A growing number of studies indicate that chronic stress can accelerate tumor growth due to sustained sympathetic nervous system activation. Our recent findings suggest that chronic stress is associated with increased IL8 levels. Here, we examined the molecular and biological significance of IL8 in stress-induced tumor growth. Norepinephrine (NE) treatment of ovarian cancer cells resulted in a 250-300% increase in IL8 protein and 240-320% increase in its mRNA levels. Epinephrine treatment resulted in similar increases. Moreover, NE treatment resulted in a 3.5-4-fold increase in IL8 promoter activity. These effects were blocked by propranolol. Promoter deletion analyses suggested that AP1 transcription factors might mediate catecholamine-stimulated up-regulation of IL8. siRNA inhibition studies identified FosB as the pivotal component responsible for IL8 regulation by NE. In vivo chronic stress resulted in increased tumor growth (by 221 and 235%; p < 0.01) in orthotopic xenograft models involving SKOV3ip1 and HeyA8 ovarian carcinoma cells. This enhanced tumor growth was completely blocked by IL8 or FosB gene silencing using 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoliposomes. IL8 and FosB silencing reduced microvessel density (based on CD31 staining) by 2.5- and 3.5-fold, respectively (p < 0.001). Our findings indicate that neurobehavioral stress leads to FosB-driven increases in IL8, which is associated with increased tumor growth and metastases. These findings may have implications for ovarian cancer management.

Dopamine blocks stress-mediated ovarian carcinoma growth.

Moreno-Smith M, Lu C, Shahzad MM, Pena GN, Allen JK, Stone RL, Mangala LS, Han HD, Kim HS, Farley D, Berestein GL, Cole SW, Lutgendorf SK, Sood AK.

Clin Cancer Res. 2011 Jun 1;17(11):3649-59. doi: 10.1158/1078-0432.CCR-10-2441. Epub 2011 Apr 29.

D. Additional mechanisms iincluding JAK/STAT modulation, prostaglandin synthesis, AKT, and Slug implicated in Stress (norepinephrine) induced increase in Ovarian Tumor Growth

Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis.

Nagaraja AS, Dorniak PL, Sadaoui NC, Kang Y, Lin T, Armaiz-Pena G, Wu SY, Rupaimoole R, Allen JK, Gharpure KM, Pradeep S, Zand B, Previs RA, Hansen JM, Ivan C, Rodriguez-Aguayo C, Yang P, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK.

Oncogene. 2015 Aug 10. doi: 10.1038/onc.2015.302. [Epub ahead of print]

The antihypertension drug doxazosin suppresses JAK/STATs phosphorylation and enhances the effects of IFN-α/γ-induced apoptosis.

Park MS, Kim BR, Kang S, Kim DY, Rho SB.

Genes Cancer. 2014 Nov;5(11-12):470-9.

hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness.

Choi MJ, Cho KH, Lee S, Bae YJ, Jeong KJ, Rha SY, Choi EJ, Park JH, Kim JM, Lee JS, Mills GB, Lee HY.

Oncogene. 2015 Jun;34(26):3402-12. doi: 10.1038/onc.2014.270. Epub 2014 Aug 25.

The antihypertension drug doxazosin inhibits tumor growth and angiogenesis by decreasing VEGFR-2/Akt/mTOR signaling and VEGF and HIF-1α expression.

Park MS, Kim BR, Dong SM, Lee SH, Kim DY, Rho SB.

Oncotarget. 2014 Jul 15;5(13):4935-44.

Meeting Abstracts on the Subject

From 2007 AACR Meeting

Neuroendocrine Modulation of Signal Transducer and Activator of Transcription-3 in Ovarian Cancer

Requests for reprints:
Anil K. Sood, Departments of Gynecologic Oncology and Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1155 Herman Pressler, CPB6.3244, Unit 1362, Houston, TX 77230-1439. Phone: 713-745-5266; Fax: 713-792-7586; E-mail: asood@mdanderson.org.

Abstract

There is growing evidence that chronic stress and other behavioral conditions are associated with cancer pathogenesis and progression, but the mechanisms involved in this association are poorly understood. We examined the effects of two mediators of stress, norepinephrine and epinephrine, on the activation of signal transducer and activator of transcription-3 (STAT3), a transcription factor that contributes to many promalignant pathways. Exposure of ovarian cancer cell lines to increasing concentrations of norepinephrine or epinephrine showed that both independently increased levels of phosphorylated STAT3 in a dose-dependent fashion. Immunolocalization and ELISA of nuclear extracts confirmed increased nuclear STAT3 in response to norepinephrine. Activation of STAT3 was inhibited by blockade of the β1- and β2-adrenergic receptors with propranolol, and by blocking protein kinase A with KT5720, but not with the α receptor blockers prazosin (α1) and/or yohimbine (α2). Catecholamine-mediated STAT3 activation was not inhibited by pretreatment with an anti–interleukin 6 (IL-6) antibody or with small interfering RNA (siRNA)–mediated decrease in IL-6 or gp130. Regarding the effects of STAT3 activation, exposure to norepinephrine resulted in an increase in invasion and matrix metalloproteinase (MMP-2 and MMP-9) production. These effects were completely blocked by STAT3-targeting siRNA. In mice, treatment with liposome-incorporated siRNA directed against STAT3 significantly reduced isoproterenol-stimulated tumor growth. These studies show IL-6–independent activation of STAT3 by norepinephrine and epinephrine, proceeding through the β1/β2-adrenergic receptors and protein kinase A, resulting in increased matrix metalloproteinase production, invasion, and in vivo tumor growth, which can be ameliorated by the down-regulation of STAT3. [Cancer Res 2007;67(21):10389–96]

From 2009 AACR Meeting

Abstract #2506: Functional \#946;2 adrenergic receptors (ADRB2) on human ovarian tumors portend worse clinical outcome

Abstract

Objective: Stress hormones such as catecholamines can augment tumor metastasis and angiogenesis; however, the prevalence and clinical significance of adrenergic receptors in human ovarian cancer is unknown and is the focus of the current study. Methods: After IRB approval, paraffin-embedded samples from 137 patients with invasive epithelial ovarian carcinoma were examined for \#946;1- and \#946;2-adrenergic receptor (ADRB1 and ADRB2, respectively) expression. Correlations with clinical outcomes were determined using parametric and non-parametric tests. Survival analyses were performed using the Kaplan-Meier method. Expression of ADRB1 and -2 was examined by quantitative RT-PCR in 15 freshly extracted human ovarian carcinoma cells. Human ovarian carcinoma cells then underwent time-variable adrenergic stimulation, and tumorigenic and angiogenic cytokine levels were examined by ELISA. Results: Sixty-six percent of the tumors had high expression of ADRB1; 80% of specimens highly expressed ADRB2. Univariate analyses demonstrated that high ADRB1 expression was associated with serous histology (p=0.03) and the presence of ascites (p=0.03), while high expression of ADRB2 was associated with advanced stage (p=0.008). Moreover, high ADRB2 expression was associated with the lower overall survival (2.2 vs. 6.5 years; p<0.001). In multivariate analysis, controlling for FIGO stage, grade, cytoreduction, age, and ADRB expression, only FIGO stage, cytoreduction status, age, and ADRB status retained statistical significance in predicting overall survival. In tumor cells freshly isolated from human ovarian cancers, 75% of samples had high expression of ADRB2 while most lacked ADRB1 compared to normal surface epithelium. Stimulation of the freshly isolated ADRB2-positive human ovarian cancer cells with norepinephrine resulted in increased levels of cAMP and increased angiogenic cytokines IL-6 and VEGF. Conclusions: ADRB2 are frequently found on human ovarian tumors and are strongly associated with poor clinical outcome. These findings support a direct mechanism by which stress hormones modulate ovarian cancer growth and metastasis as well as provide a basis for therapeutic targeting.

And from the 2015 AACR Meeting:

Abstract 3368: Sustained adrenergic signaling activates pro-inflammatory prostaglandin network in ovarian carcinoma

Archana S. Nagaraja 1,

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA

Abstract

Purpose: Catecholamine mediated stress effects are known to induce production of various pro-inflammatory cytokines. However, the mechanism and functional effect of adrenergic signaling in driving inflammation via pro-inflammatory metabolites is currently unknown. Here we address the functional and biological consequences of adrenergic-induced Cox2/PGE2 axis activation in ovarian cancer metastasis.

Methods: We first analyzed global metabolic changes in tumors isolated from patients with known Center for Epidemiologic Studies Depression Scale (CES-D; depressive) scores and tumoral norepinephrine (NE) levels. Beta-adrenergic receptor (ADRB) positive cells (Skov3 and HeyA8) were used to study gene and protein levels of PTGS2 (cyclooxygenase2), PTGES (prostaglandin E synthase) and metabolite PGE2 in vitro and in vivo. To study tumor-specific effects on catecholamine-derived expression of PTGS2, we used a novel DOPC delivery system of PTGS2 siRNA.

Results: Our results revealed that levels of PGs were significantly increased in patients with high depressive scores (>16). PGE2 was upregulated by 2.38 fold when compared to the low CES-D scores. A similar trend was also observed with other pro-inflammatory eicosanoids, such as 6-keto prostaglandin F1 Alpha (2.03), prostaglandin A2 (1.39) and prostaglandin E1 (1.39). Exposure to NE resulted in increased PTGS2 and PTGES (prostaglandin E2 synthase) gene expression and protein levels in Skov3 and HeyA8. PGE2 ELISA confirmed that upon treatment with NE, PGE2 levels were increased in conditioned medium from Skov3 and HeyA8 cells. Treatment with a broad ADRB agonist (isoproterenol) or ADRB2 specific agonist (terbutaline) led to increases in expression of PTGS2 and PTGES as well as PGE2 levels in supernatant. Conversely, treatment with a broad antagonist (propranolol) or an ADRB2 specific antagonist (butoxamine) in the presence of NE abrogated gene expression changes of PTGS2 and PTGES. ChIP analysis showed enrichment of Nf-kB binding to the promoter region of PTGS2 and PTGES by 2.4 and 4.0 fold respectively when Skov3ip1 cells were treated with NE. Silencing PTGS2 resulted in significantly decreased migration (40%) and invasion (25%) of Skov3 cells in the presence of NE. Importantly, in the Skov3-ip1 restraint stress orthotopic model, silencing PTGS2 abrogated stress mediated effects and decreased tumor burden by 70% compared to control siRNA with restraint stress.

Conclusion Increased adrenergic stimulation results in a pro-inflammatory milieu mediated by prostaglandins that drives tumor progression and metastasis in ovarian cancer.

Citation Format: Archana S. Nagaraja, Piotr Dorniak, Nouara Sadaoui, Guillermo Armaiz-Pena, Behrouz Zand, Sherry Y. Wu, Julie K. Allen, Rajesha Rupaimoole, Cristian Rodriguez-Aguayo, Sunila Pradeep, Lin Tan, Rebecca A. Previs, Jean M. Hansen, Peiying Yang, Garbiel Lopez-Berestein, Susan K. Lutgendorf, Steve Cole, Anil K. Sood. Sustained adrenergic signaling activates pro-inflammatory prostaglandin network in ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3368. doi:10.1158/1538-7445.AM2015-3368

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

How the βeta Adrenergic Receptor (βAR) Became a Target for Ovarian Cancer

A. βAR and its signaling over-expressed in ovarian cancer

B. Mechanistic Link Between Chronic Stress From Excess Adrenergic Stimulation and Angiogenesis and Metastasis

C. In Vivo Studies Confirm In Vitro Findings That Chronic Stress Via Adrenergic overstimulation Increases Ovarian Cancer Growth

Abstract

D. Additional mechanisms iincluding JAK/STAT modulation, prostaglandin synthesis, AKT, and Slug implicated in Stress (norepinephrine) induced increase in Ovarian Tumor Growth

Neuroendocrine Modulation of Signal Transducer and Activator of Transcription-3 in Ovarian Cancer

Abstract

Abstract

And from the 2015 AACR Meeting:

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Other Article in This Open Access Journal on Ovarian Cancer Include

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