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Argos starts Phase II clinical trial with Dendritic Cell Immunotherapy AGS-003 in Non Small Cell Lung Cancer in conjunction with standard platinum therapy

Reporter: Stephen J. Williams, Ph.D.

Argos Announces Start of Phase II AGS-003 Trial in NSCLC

Reported from source http://www.oncotherapynetwork.com/lung-cancer-targets/argos-announces-start-phase-ii-ags-003-trial-nsclc?GUID=D63BFB74-A7FD-4892-846F-A7D1FFE0F131&rememberme=1&ts=29032016

by Stephen J. Williams, Ph.D.

News | March 28, 2016 | Lung Cancer Targets
By Bryant Furlow
The Cancer Research Network of Nebraska has initiated a phase II clinical trial of the autologous dendritic cell immunotherapy AGS-003 with standard platinum-doublet chemotherapy, for non-small cell lung cancer (NSCLC), Argos Therapeutics, Inc. has announced.
AGS-003 is produced using RNA from a patient’s tumor sample, and dendritic cells. It is designed to provoke memory T-cell immune responses specifically targeting an individual patient’s tumor neoantigens, which arise from tumor-specific gene mutations.

“The standard of treatment of NSCLC has been chemotherapy after surgery, but now we can offer this exciting new option of individualized immunotherapy,” said co-principal investigator Stephen Lemon, MD, Oncology Associates in Omaha.

The nonrandomized, open-label, phase II safety study will enroll 20 patients newly diagnosed with stage III NSCLC, administering AGS-003 either concurrently or sequentially with standard carboplatin and paclitaxel chemotherapy regimens, with or without radiotherapy. The primary study endpoint is the effect of AGS-003 on the toxicity associated with standard chemotherapy. Secondary endpoints include memory T-cell activation among patients who complete induction therapy and are administered five or more doses of AGS-003.

AGS-003 is also under study in the phase III ADAPT clinical trial for patients with metastatic renal cell carcinoma (mRCC). Argos is an immuno-oncology firm developing and commercializing “truly individualized” anticancer immunotherapies.

– See more at: http://www.oncotherapynetwork.com/lung-cancer-targets/argos-announces-start-phase-ii-ags-003-trial-nsclc?GUID=D63BFB74-A7FD-4892-846F-A7D1FFE0F131&rememberme=1&ts=29032016#sthash.I9FPkdTf.dpuf

A Message from Faculty Director Lee Fleming on Latest Issue of Crowdfunding

Reported from source: http://funginstitute.berkeley.edu/directors-blog/message-faculty-director-lee-fleming-latest-issue-crowdfunding/

I would like to announce our special issue in the California Management Review on CrowdFunding (thank you to Olav Sorenson for co-editing and the Kauffman Foundation for support).  We have a broad and practical set of articles that should appeal to practitioners and academics alike (please see this linkfor the special issue introduction by Olav and myself).

The landscape of CF can be quite confusing; Peter Younkin and Keyvan Kashkooli give us a mapping of the landscape by asking a simple question, namely, what problems does CF solve?  Gary Dushnitsky and his co-authors provide a rich description of CF in Europe; they identify the surprising strength of national boundaries.  Ethan Mollick and Alicia Robb provide us an easily understood synopsis of their research on the importance of CF for under-served entrepreneurs.  Carina Thurridl and Bernadette Kamleitner help aspiring entrepreneurs understand how to bundle the optimal set of rewards to attract backers.  Ajay Agrawal and co-authors describe a recent trend in CF, namely, the emergence of lead investors and syndicates.  Finally, Valentina Assenova and Olav lead a round table discussion of industry leaders, including Jason Best, Mike Cagney, Douglas Ellenoff, Kate Karas, Jay Moon, Sherwood Neiss, and Ron Suber.  Happy reading!

Here is a short video based on our article:

 

Brain Biobank

Brain Biobank and studies of disease structure correlates

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Unveiling Psychiatric Diseases

Researchers create neuropsychiatric cellular biobank

Image: iStock/mstroz
Image: iStock/mstroz
Researchers from Harvard Medical School and Massachusetts General Hospital have completed the first stage of an important collaboration aimed at understanding the intricate variables of neuropsychiatric disease—something that currently eludes clinicians and scientists.

The research team, led by Isaac Kohane at HMS and Roy Perlis at Mass General, has created a neuropsychiatric cellular biobank—one of the largest in the world.

It contains induced pluripotent stem cells, or iPSCs, derived from skin cells taken from 100 people with neuropsychiatric diseases such as schizophrenia, bipolar disorder and major depression, and from 50 people without neuropsychiatric illness.

In addition, a detailed profile of each patient, obtained from hours of in-person assessment as well as from electronic medical records, is matched to each cell sample.

As a result, the scientific community can now for the first time access cells representing a broad swath of neuropsychiatric illness. This enables researchers to correlate molecular data with clinical information in areas such as variability of drug reactions between patients. The ultimate goal is to help treat, with greater precision, conditions that often elude effective management.

The cell collection and generation was led by investigators at Mass General, who in collaboration with Kohane and his team are working to characterize the cell lines at a molecular level. The cell repository, funded by the National Institutes of Health, is housed at Rutgers University.

“This biobank, in its current form, is only the beginning,” said Perlis, director of the MGH Psychiatry Center for Experimental Drugs and Diagnostics and HMS associate professor of psychiatry. “By next year we’ll have cells from a total of four hundred patients, with additional clinical detail and additional cell types that we will share with investigators.”

A current major limitation to understanding brain diseases is the inability to access brain biopsies on living patients. As a result, researchers typically study blood cells from patients or examine post-mortem tissue. This is in stark contrast with diseases such as cancer, for which there are many existing repositories of highly characterized cells from patients.

The new biobank offers a way to push beyond this limitation.

 

A Big Step Forward

While the biobank is already a boon to the scientific community, researchers at MGH and the HMS Department of Biomedical Informatics will be adding additional layers of molecular data to all of the cell samples. This information will include whole genome sequencing and transcriptomic and epigenetic profiling of brain cells made from the stem cell lines.

Collaborators in the HMS Department of Neurobiology, led by Michael Greenberg, department chair and Nathan Marsh Pusey Professor of Neurobiology,  will also work to examine characteristics of other types of neurons derived from these stem cells.

“This can potentially alter the entire way we look at and diagnose many neuropsychiatric conditions,” said Perlis.

One example may be to understand how the cellular responses to medication correspond to the patient’s documented responses, comparing in vitro with in vivo. “This would be a big step forward in bringing precision medicine to psychiatry,” Perlis said.

“It’s important to recall that in the field of genomics, we didn’t find interesting connections to disease until we had large enough samples to really investigate these complex conditions,” said Kohane, chair of the HMS Department of Biomedical Informatics.

“Our hypothesis is that here we will require far fewer patients,” he said. “By measuring the molecular functioning of the cells of each patient rather than only their genetic risk, and combining that all that’s known of these people in terms of treatment response and cognitive function, we will discover a great deal of valuable information about these conditions.”

Added Perlis, “In the early days of genetics, there were frequent false positives because we were studying so few people. We’re hoping to avoid the same problem in making cellular models, by ensuring that we have a sufficient number of cell lines to be confident in reporting differences between patient groups.”

The generation of stem cell lines and characterization of patients and brain cell lines is funded jointly by the the National Institute of Mental Health, the National Human Genome Research Institute and a grant from the Centers of Excellence in Genomic Science program.

 

On C.T.E. and Athletes, Science Remains in Its Infancy

Se Hoon ChoiYoung Hye KimMatthias Hebisch, et al.

http://www.nature.com/articles/nature13800.epdf

Alzheimer’s disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles1. The amyloid hypothesis of Alzheimer’s disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau2, 3. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer’s disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer’s disease, including distinct neurofibrillary tangle pathology4, 5. Human neurons derived from Alzheimer’s disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles6, 7, 8, 9, 10, 11. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer’s disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.

 

 

Figure 2: Robust increases of extracellular amyloid-β deposits in 3D-differentiated hNPCs with FAD mutations.close

Robust increases of extracellular amyloid-[bgr] deposits in 3D-differentiated hNPCs with FAD mutations.

a, Thin-layer 3D culture protocol. HC, histochemistry; IF, immunofluorescence; IHC, immunohistochemistry. b, Amyloid-β deposits in 6-week differentiated control and FAD ReN cells in 3D Matrigel (green, GFP; blue, 3D6; scale bar, …

 

Stem Cell-Based Spinal Cord Repair Enables Robust Corticospinal Regeneration

 

Novel use of EPR spectroscopy to study in vivo protein structure

http://www.news-medical.net/whitepaper/20160315/Novel-use-of-EPR-spectroscopy-to-study-in-vivo-protein-structure.aspx

α-synuclein

α-synuclein is a protein found abundantly throughout the brain. It is present mainly at the neuron ends where it is thought to play a role in ensuring the supply of synaptic vesicles in presynaptic terminals, which are required for the release of neurotransmitters to relay signals between neurons. It is critical for normal brain function.

However, α-synuclein is also the primary protein component of the cerebral amyloid deposits characteristic of Parkinson’s disease and its precursor is found in the amyloid plaques of Alzheimer’s disease. Although α-synuclein is present in all areas of the brain, these disease-state amyloid plaques only arise in distinct areas.

Alpha-synuclein protein. May play role in Parkinson’s and Alzheimer’s disease.  © molekuul.be / Shutterstock.com

Imaging of isolated samples of α-synuclein in vitro indicate that it does not have the precise 3D folded structure usually associated with proteins. It is therefore classed as an intrinsically disordered protein. However, it was not known whether the protein also lacked a precise structure in vivo.

There have been reports that it can form helical tetramers. Since the 3D structure of a biological protein is usually precisely matched to the specific function it performs, knowing the structure of α-synuclein within a living cell will help elucidate its role and may also improve understanding of the disease states with which it is associated.

If α-synuclein remains disordered in vivo, it may be possible for the protein to achieve different structures, and have different properties, depending on its surroundings.

Techniques for determining protein structure

It has long been known that elucidating the structure of a protein at an atomic level is fundamental for understanding its normal function and behavior. Furthermore, such knowledge can also facilitate the development of targeted drug treatments. Unfortunately, observing the atomic structure of a protein in vivo is not straightforward.

X-ray diffraction is the technique usually adopted for visualizing structures at atomic resolution, but this requires crystals of the molecule to be produced and this cannot be done without separating the molecules of interest from their natural environment. Such processes can modify the protein from its usual state and, particularly with complex structures, such effects are difficult to predict.

The development of nuclear magnetic resonance (NMR) spectroscopy improved the situation by making it possible for molecules to be analyzed under in vivo conditions, i.e. same pH, temperature and ionic concentration.

More recently, increases in the sensitivity of NMR and the use of isotope labelling have enabled determinations of the atomic level structure and dynamics of proteins to be determined within living cells1. NMR has been used to determine the structure of a bacterial protein within living cells2 but it is difficult to achieve sufficient quantities of the required protein within mammalian cells and to keep the cells alive for NMR imaging to be conducted.

Electron paramagnetic resonance (EPR) spectroscopy for determining protein structure

Recently, researchers have managed to overcome these obstacles by using in-cell NMR and electron paramagnetic resonance (EPR) spectroscopy. EPR spectroscopy is a technique that is similar to NMR spectroscopy in that it is based on the measurement and interpretation of the energy differences between excited and relaxed molecular states.

In EPR spectroscopy it is electrons that are excited, whereas in NMR signals are created through the spinning of atomic nuclei. EPR was developed to measure radicals and metal complexes, but has also been utilized to study the dynamic organization of lipids in biological membranes3.

EPR has now been used for the first time in protein structure investigations and has provided atomic-resolution information on the structure of α-synuclein in living mammalians4,5.

Bacterial forms of the α-synuclein protein labelled with 15N isotopes were introduced into five types of mammalian cell using electroporation. Concentrations of α-synuclein close to those found in vivo were achieved and the 15N isotopes allowed the protein to be clearly defined from other cellular components by NMR. The conformation of the protein was then determined using electron paramagnetic resonance (EPR).

The results showed that within living mammalian cells α-synuclein remains as a disordered and highly dynamic monomer. Different intracellular environments did not induce major conformational changes.

Summary

The novel use of EPR spectroscopy has resolved the mystery surrounding the in vivo conformation of α-synuclein. It showed that α-synuclein maintains its disordered monomeric form under physiological cell conditions. It has been demonstrated for the first time that even in crowded intracellular environments α-synuclein does not form oligomers, showing that intrinsic structural disorder can be sustained within mammalian cells.

References

  1. Freedberg DI and Selenko P. Live cell NMR Annu. Rev. Biophys. 2014;43:171–192.
  2. Sakakibara D, et al. Protein structure determination in living cells by in-cell NMR spectroscopy. Nature 2009;458:102–105.
  3. Yashroy RC. Magnetic resonance studies of dynamic organisation of lipids in chloroplast membranes. Journal of Biosciences 1990;15(4):281.
  4. Alderson TA and Bax AD. Parkinson’s Disease. Disorder in the court. Nature 2016; doi:10.1038/nature16871.
  5. Theillet FX, et al. Structural disorder of monomeric α-synuclein persists in mammalian cells. Nature 2016; doi:10.1038/nature16531.

 

More Doctors Are Prescribing Exercise Instead of Medication

Sourced through Scoop.it from: abcnews.go.com

See on Scoop.itCardiovascular Disease: PHARMACO-THERAPY

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:

  1. 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]
  2. Bistrian BR, Blackburn GL, Vitale J, Cochrane D, Naylor J. Prevalence of malnutrition in general medical patients. JAMA. 1976; 235:1567–1570. [PubMed]
  3. Butterworth CE. The skeleton in the hospital closet. Nutrition Today.1974; 9:4–8.
  4. Buzby GP, Mullen JL, Matthews DC, Hobbs CL, Rosato EF. Prognostic nutritional index in gastrointestinal surgery. Am. J. Surg. 1980; 139:160–167.[PubMed]
  5. 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]
  6. 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]
  7. Scrimshaw NS, DanGiovanni JP. Synergism of nutrition, infection and immunity, an overview. J. Nutr. 1997; 133:S316–S321.
  8. Chandra RK. Nutrition and the immune system: an introduction. Am. J. Clin. Nutr. 1997; 66:460S–463S. [PubMed]
  9. Hill GL. Body composition reserach: Implications for the practice of clinical nutrition. JPEN J. Parenter. Enteral Nutr. 1992; 16:197. [PubMed]
  10. Smith PE, Smith AE. High-quality nutritional interventions reduce costs.Healthc. Financ. Manage. 1997; 5:66–69. [PubMed]
  11. Gallagher-Allred CR, Voss AC, Finn SC, McCamish MA. Malnutrition and clinical outcomes. J. Am. Diet. Assoc. 1996; 96:361–366. [PubMed]
  12. Ferguson M. Uncovering the skeleton in the hoapital closet. What next? Aust. J. Nutr. Diet. 2001; 58:83–84.
  13. 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.

 

Epigenetics, Environment and Cancer: Articles of Note @PharmaceuticalIntelligence.com

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

 

Introduction

Author: Larry H. Bernstein, MD, FCAP

The following discussions are presented in two series. The first set of discussions is mainly concerned with the role of genomics in the rapidly emerging research domain of genomics and medicine. The recent advances in genomic research at the end of the 20th century brought into the new millennium a seminal accomplishment because of the mapping of the human genome. This development required advances in technology that touches on biochemistry, organic chemistry, physical chemistry, mathematics and computational sciences that have been followed by a surge of innovation for the last 15 years. This was an accomplishment of basic science research that can be ascribed to substantial leadership from the National Institutes of Health, and to a diversity of research centers within the United States, England, France, and Germany, and Israel among others.

In looking back at this development, it might appear to be weighted heavily in a concentrated work on the genetic code. This was predated by the discovery of genetic inborn errors of metabolism that was at least a half century precedent. Thus a model was constructed for the accounting for many human conditions that are expressed in-utero, perinatal, postnatal, and at critical life stages.   However, even allowing for over-simplification of a model of life reduced to the expression of a genetic code, this has led to the genesis of a concept of genetic clarification of life “maladies”, diagnostic, therapeutic, and prognostic implications. The concept of a “personalized medicine” emerges from such a construct.

I have already ceded considerable ground in an argument of what occurs in life, illness, and death at the cellular, organ, and organ system level. There are indeed gene amplifications and downregulation of genes that are expressed or have an “on-off” nature in transcription, which becomes a major driver of metabolic control. In this respect, the classic model of gene-RNA-protein has been superseded by a much more complicated model, but still in the realm of personalized medicine. The classic model of metabolism is tied to anabolic and catabolic pathways, glycolytic and mitochondrial substrates, amino acids, proteins and 3D-protein aggregates that have functional roles, and that is controlled by allosteric interactions, ion transport, membrane affinity, signaling pathways, and hydrophilic and hydrophobic effects. This leads to the second part of the discussion about epigenetics and environmental impacts on cellular function. It is by no means irrelevant because the evolution of organisms from sea to land, and the existence of living forms in mountainous and desert regions imposed restrictions that required adaptation. A full understanding of these factors is required in the immersion in personalized medicine.

Genetics Impact on Physiology

 

A Perspective on Personalized Medicine

Curator: Larry H. Bernstein, MD, FCAP

 

Precision Medicine for Future of Genomics Medicine is The New Era

Demet Sag, PhD, CRA, GCP

 

Epistemology of the Origin of Cancer: a New Paradigm – New Cancer Theory by two US Scientists in peer-reviewed Cancer Journal

Reporter: Aviva Lev-Ari, PhD, RN

 

A Reconstructed View of Personalized Medicine

Author: Larry H. Bernstein, MD, FCAP

 

Signaling and Signaling Pathways

Curator: Larry H. Bernstein, MD, FCAP

 

Gene Amplification and Activation of the Hedgehog Pathway

Curator: Larry H Bernstein, MD, FCAP

 

Pancreatic Cancer and Crossing Roads of Metabolism

Curator: Demet Sag, PhD

 

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

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

 

Acetylation and Deacetylation of non-Histone Proteins

Author and Curator: Larry H Bernstein, MD, FCAP

 

Pull at Cancer’s Levers

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

 

Epilogue: Envisioning New Insights in Cancer Translational Biology

Author and Curator: Larry H Bernstein, MD, FCAP

 

Directions for Genomics in Personalized Medicine

Author: Larry H. Bernstein, MD, FCAP

 

What is the Future for Genomics in Clinical Medicine?

Author and Curator: Larry H Bernstein, MD, FCAP

 

Environmental Factors Impacting Genetic Mutations

 

Deciphering the Epigenome

Curator: Larry H. Bernstein, MD, FCAP

 

The Underappreciated EpiGenome

Author:  Demet Sag, PhD

 

Introduction to Metabolomics

Curator: Larry H Bernstein, MD, FCAP

 

The Metabolic View of Epigenetic Expression

Writer and Curator: Larry H Bernstein, MD, FCAP

 

Somatic, germ-cell, and whole sequence DNA in cell lineage and disease profiling

Curator: Larry H Bernstein, MD, FCAP

 

RNA and the transcription the genetic code

Curator: Larry H. Bernstein, MD, FCAP

 

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

Author and Curator: Larry H Bernstein, MD, FCAP

 

Genomics and Epigenetics: Genetic Errors and Methodologies – Cancer and Other Diseases

Writer and Curator: Larry H Bernstein, MD, FCAP

 

BET Proteins Connect Diabetes and Cancer

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

Cancer Metastasis

Author: Tilda Barliya PhD

 

Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Curator and Writer: Stephen J. Williams, Ph.D.

 

Immuno therapy at MassBio, 3/31 and 4/1/2016.

2016 MassBio Annual Meeting 03/31/2016 8:00 AM – 04/01/2016 3:00 PM Royal Sonesta Hotel, Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

Plenary Session: Immunotherapy in Combination, 2016 MassBio Annual Meeting 03/31/2016 8:00 AM – 04/01/2016 3:00 PM Royal Sonesta Hotel, Cambridge, MA

Plenary Session: Innovative Pricing Pricing Models: The Future is Now, 2016 MassBio Annual Meeting 03/31/2016 8:00 AM – 04/01/2016 3:00 PM Royal Sonesta Hotel, Cambridge, MA

2-Plenary Session: Advanced Manufacturing, 2016 MassBio Annual Meeting 03/31/2016 8:00 AM – 04/01/2016 3:00 PM Royal Sonesta Hotel, Cambridge, MA

Plenary Session: The 2016 National Landscape, 2016 MassBio Annual Meeting 03/31/2016 8:00 AM – 04/01/2016 3:00 PM Royal Sonesta Hotel, Cambridge, MA – 4/1 @11AM

LIVE @ Congressman Richard Neal – D-MA, Dean of MA Delegation 2016 MassBio Annual Meeting 04/01/2016 11AM Royal Sonesta Hotel, Cambridge, MA

LIVE Remarks by Rachel Kaprielian, Tony Chat and Mike Huckman @ 2016 MassBio Annual Meeting 04/01/2016 12:45 PM Royal Sonesta Hotel, Cambridge, MA

 

Summary

Larry H. Bernstein, MD, FCAP

 

The preceding chapters have provided a substantial insight into the growth and acceleration of work related to translational medicine and personalized medicine. I make note of the fact that a substantial knowledge has been from basic research using animal models, including C. Eligans. The amount of knowledge is quite impressive. Let me review some major points gained from these presentations.

  1. Non-coding areas of our DNA are far from being without function. But the ensuing work with RNAs is captivating. Whether regulating gene expression and transcription, or providing protein attachment sites, this once-dismissed part of the genome is vital for all life.

There are two basic categories of nitrogenous bases: the purines (adenine [A] and guanine [G]), each with two fused rings, and the pyrimidines (cytosine [C], thymine [T], and uracil [U]), each with a single ring. Furthermore, it is now widely accepted that RNA contains only A, G, C, and U (no T), whereas DNA contains only A, G, C, and T (no U).

There is no uncertainty about the importance of “Junk DNA”.  It is both an evolutionary remnant, and it has a role in cell regulation.  Further, the role of histones in their relationship the oligonucleotide sequences is not understood.  We now have a large output of research on noncoding RNA, including siRNA, miRNA, and others with roles other than transcription. This requires major revision of our model of cell regulatory processes.  The classic model is solely transcriptional.

  • DNA-> RNA-> Amino Acid in a protein.

Redrawn we have

  • DNA-> RNA-> DNA and
  • DNA->RNA-> protein-> DNA.

DNA is involved mainly with genetic information storage, while RNA molecules—mRNA, rRNA, tRNA, miRNA, and others—are engaged in diverse structural, catalytic, and regulatory activities, in addition to translating genes into proteins. RNA’s multitasking prowess, at the heart of the RNA World hypothesis implicating RNA as the first molecule of life, likely spurred the evolution of numerous modified nucleotides. This enabled the diversified complementarity and secondary structures that allow RNA species to specifically interact with other components of the cellular machinery such as DNA and proteins. The alphabet of RNA consists of at least 140 alternative nucleotide forms.

Among the 140 modified RNA nucleotide variants identified, methylation of adenosine at the N6 position (m6A) is the most prevalent epigenetic mark in eukaryotic mRNA. Identified in bacterial rRNAs and tRNAs as early as the 1950s, this type of methylation was subsequently found in other RNA molecules, including mRNA, in animal and plant cells as well. In 1984, researchers identified a site that was specifically methylated—the 3′ untranslated region (UTR) of bovine prolactin mRNA.1 As more sites of m6A modification were identified, a consistent pattern emerged: the methylated A is preceded by A or G and followed by C (A/G—methylated A—C).

Although the identification of m6A in RNA is 40 years old, until recently researchers lacked efficient molecular mapping and quantification methods to fully understand the functional implications of the modification. In 2012, we (D.D. and G.R.) combined the power of next-generation sequencing (NGS) with traditional antibody-mediated capture techniques to perform high-resolution transcriptome-wide mapping of m6A, an approach we termed m6A-seq.2 Briefly, the transcriptome is randomly fragmented and an anti-m6A antibody is used to fish out the methylated RNA fragments; the m6A-containing fragments are then sequenced and aligned to the genome, thus allowing us to locate the positions of methylation marks.

  1. The work of Warburg and Meyerhoff, followed by that of Krebs, Kaplan, Chance, and others built a solid foundation in the knowledge of enzymes, coenzymes, adenine and pyridine nucleotides, and metabolic pathways, not to mention the importance of Fe3+, Cu2+, Zn2+, and other metal cofactors.

Of huge importance was the work of Jacob, Monod and Changeux, and the effects of cooperativity in allosteric systems and of repulsion in tertiary structure of proteins related to hydrophobic and hydrophilic interactions, which involves the effect of one ligand on the binding or catalysis of another, demonstrated by the end-product inhibition of the enzyme, L-threonine deaminase (Changeux 1961), L-isoleucine, which differs sterically from the reactant, L-threonine whereby the former could inhibit the enzyme without competing with the latter. The current view based on a variety of measurements (e.g., NMR, FRET, and single molecule studies) is a ‘‘dynamic’’ proposal by Cooper and Dryden (1984) that the distribution around the average structure changes in allostery affects the subsequent (binding) affinity at a distant site.

Present day applications of computational methods to biomolecular systems, combined with      structural, thermodynamic, and kinetic studies, make possible an approach to that question, so as to provide a deeper understanding of the requirements for allostery. The current view is that a variety of measurements (e.g., NMR, FRET, and single molecule studies) are providing additional data beyond that available previously from structural, thermodynamic, and kinetic results. These should serve to continue to improve our understanding of the molecular mechanism of allostery

  1. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. The measurement of free radicals has increased awareness of radical-induced impairment of the oxidative/antioxidative balance, essential for an understanding of disease progression. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Various studies have confirmed that metals activate signaling pathways and the carcinogenic effect of metals has been related to activation of mainly redox sensitive transcription factors, involving NF-kappaB, AP-1 and p53.
  1. There is heterogeneity in the immediate interstices between cancer cells, which may seem surprising, but it should not be.  This refers to the complexity of the cells arranged as tissues and to their immediate environment, which I shall elaborate on. Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups.

IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are heterozygous in cancer, and they catalyze the production of α-2-hydroxyglutarate. The study found human IDH1 transitions between an inactive open, an inactive semi-open, and a catalytically active closed conformation. In the inactive open conformation, Asp279 occupies the position where the isocitrate substrate normally forms hydrogen bonds with Ser94. This steric hindrance by Asp279 to isocitrate binding is relieved in the active closed conformation.

There are allelic variations that underlie common diseases and complete genome sequencing for many individuals with and without disease is required. However, there are advantages and disadvantages as we can carry out partial surveys of the genome by genotyping large numbers of common SNPs in genome-wide association studies but there are problems such as computing the data efficiently and sharing the information without tempering privacy.

Since the first report of p53 as a non-histone target of a histone acetyltransferase (HAT), there has been a rapid proliferation in the description of new non-histone targets of HATs. Of these,

  • transcription factors comprise the largest class of new targets.

The substrates for HATs extend to

  1. cytoskeletal proteins,
  2. molecular chaperones and
  3. nuclear import factors.
  • Deacetylation of these non-histone proteins by histone deacetylases (HDACs) opens yet another exciting new field of discovery in
  • the role of the dynamic acetylation and deacetylation on cellular function.

We capture the dynamic interactions between the systems under stress that are elicited by cytokine-driven hormonal responses, long thought to be circulatory and multisystem, that affect the major compartments of fat and lean body mass, and are as much the drivers of metabolic pathway changes that emerge as epigenetics, without disregarding primary genetic diseases.

The greatest difficulty in organizing such a work is in whether it is to be merely a compilation of cancer expression organized by organ systems, or whether it is to capture developing concepts of underlying stem cell expressed changes that were once referred to as “dedifferentiation”. In proceeding through the stages of neoplastic transformation, there occur adaptive local changes in cellular utilization of anabolic and catabolic pathways, and a retention or partial retention of functional specificities.

This effectively results in the same cancer types not all fitting into the same “shoe”. There is a sequential loss of identity associated with cell migration, cell-cell interactions with underlying stroma, and metastasis., but cells may still retain identifying “signatures” in microRNA combinatorial patterns. The story is still incomplete, with gaps in our knowledge that challenge the imagination.

What we have laid out is a map with substructural ordered concepts forming subsets within the structural maps. There are the traditional energy pathways with terms aerobic and anaerobic glycolysis, gluconeogenesis, triose phosphate branch chains, pentose shunt, and TCA cycle vs the Lynen cycle, the Cori cycle, glycogenolysis, lipid peroxidation, oxidative stress, autosomy and mitosomy, and genetic transcription, cell degradation and repair, muscle contraction, nerve transmission, and their involved anatomic structures (cytoskeleton, cytoplasm, mitochondria, liposomes and phagosomes, contractile apparatus, synapse.

We are a magnificent “magical” experience in evolutionary time, functioning in a bioenvironment, put rogether like a truly complex machine, and with interacting parts. What are those parts – organelles, a genetic message that may be constrained and it may be modified based on chemical structure, feedback, crosstalk, and signaling pathways. This brings in diet as a source of essential nutrients, exercise as a method for delay of structural loss (not in excess), stress oxidation, repair mechanisms, and an entirely unexpected impact of this knowledge on pharmacotherapy.

Despite what we have learned, the strength of inter-molecular interactions, strong and weak chemical bonds, essential for 3-D folding, we know little about the importance of trace metals that have key roles in catalysis and because of their orbital structures, are essential for organic-inorganic interplay. This will not be coming soon because we know almost nothing about the intracellular, interstitial, and intravesicular distributions and how they affect the metabolic – truly metabolic events.

  1. We must translate the sequence information from genomics locus of the genes to function with related polymorphism of these genes so that possible patterns of the gene expression and disease traits can be matched. Then, we may develop precision technologies for:
  1. Diagnostics
  2. Targeted Drugs and Treatments
  3. Biomarkers to modulate cells for correct functions

With the knowledge of:

  1. gene expression variations
  2. insight in the genetic contribution to clinical endpoints ofcomplex disease and
  3. their biological risk factors,
  4. share etiologic pathways

which requires an understanding of both:

  • the structure and
  • the biology of the genome.
  1. A new paradigm is summarized in a sequence of six steps:

“(1) A pathogenic stimulus (biological or chemical) leads at first to a normal reaction seen in wound healing, namely, inflammation. When the inflammatory stimulus is too great or too prolonged, the healing process is unsuccessful, and that results in

(2) chronic inflammation.

“That’s just the beginning. When chronic inflammation persists,

(3) fibrosis [thickening and scarring of the connective tissue,] develops. The fibrosis, with its ongoing alteration of the cellular microenvironment is different and creates

(4) a precancerous niche, resulting in a chronically stressed cellular matrix. In such a situation, the organism deploys

(5) a chronic stress escape strategy. But if this attempt fails to resolve the precancerous state, then

(6) a normal cell is transformed into a cancerous cell.”

Keep in mind:

  1. Nutritional resources that have been available and made plentiful over generations are not abundant in some climates.
  2. Despite the huge impact that genomics has had on biological progress over the last century, there is a huge contribution not to be overlooked in epigenetics, metabolomics, and pathways analysis.

I have provided mechanisms explanatory for regulation of the cell that go beyond the classic model of metabolic pathways associated with the cytoplasm, mitochondria, endoplasmic reticulum, and lysosome, such as, the cell death pathways, expressed in apoptosis and repair.  Nevertheless, there is still a missing part of this discussion that considers the time and space interactions of the cell, cellular cytoskeleton and extracellular and intracellular substrate interactions in the immediate environment.

  1. Signal transduction occurs when an extracellular signaling[1] molecule activates a specific receptor located on the cell surface or inside the cell. In turn, this receptor triggers a biochemical chain of events inside the cell, creating a response.[2] Depending on the cell, the response alters the cell’s metabolism, shape, gene expression, or ability to divide.[3] The signal can be amplified at any step. Thus, one signaling molecule can cause many responses.[4]

In 1970, Martin Rodbell examined the effects of glucagon on a rat’s liver cell membrane receptor. He noted that guanosine triphosphate disassociated glucagon from this receptor and stimulated the G-protein, which strongly influenced the cell’s metabolism. Thus, he deduced that the G-protein is a transducer that accepts glucagon molecules and affects the cell.[5] For this, he shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G. Gilman.

Signal transduction involves the binding of extracellular signaling molecules and ligands to cell-surface receptors that trigger events inside the cell. The combination of messenger with receptor causes a change in the conformation of the receptor, known as receptor activation. This activation is always the initial step (the cause) leading to the cell’s ultimate responses (effect) to the messenger. Despite the myriad of these ultimate responses, they are all directly due to changes in particular cell proteins. Intracellular signaling cascades can be started through cell-substratum interactions; examples are the integrin that binds ligands in the extracellular matrix and steroids.[13] Most steroid hormones have receptors within the cytoplasm and act by stimulating the binding of their receptors to the promoter region of steroid-responsive genes.[14] Examples of signaling molecules include the hormone melatonin,[15] the neurotransmitter acetylcholine[16] and the cytokine interferon γ.[17]

Various environmental stimuli exist that initiate signal transmission processes in multicellular organisms; examples include photons hitting cells in the retina of the eye,[20] and odorants binding to odorant receptors in the nasal epithelium.[21] Certain microbial molecules, such as viral nucleotides and protein antigens, can elicit an immune system response against invading pathogens mediated by signal transduction processes. This may occur independent of signal transduction stimulation by other molecules, as is the case for the toll-like receptor. It may occur with help from stimulatory molecules located at the cell surface of other cells, as with T-cell receptor signaling.

Unraveling the multitude of

  • nutrigenomic,
  • proteomic, and
  • metabolomic patterns

that arise from the ingestion of foods or their

  • bioactive food components

will not be simple but is likely to provide insights into a tailored approach to diet and health. The use of new and innovative technologies, such as

  • microarrays,
  • RNA interference, and
  • nanotechnologies,

will provide needed insights into molecular targets for specific bioactive food components and

  • how they harmonize to influence individual phenotypes(1).
  1. Oct4 has a critical role in committing pluripotent cells into the somatic cellular pathway. When embryonic stem cells overexpress Oct4, they undergo rapid differentiation and then lose their ability for pluripotency. Other studies have shown that Oct4 expression in somatic cells reprograms them for transformation into a particular germ cell layer and also gives rise to induced pluripotent stem cells (iPSCs) under specific culture conditions.

Oct4 is the gatekeeper into and out of the reprogramming expressway. By modifying experimental conditions, Oct4 plus additional factors can induce formation of iPSCs, epiblast stem cells, neural cells, or cardiac cells. Dr. Schöler suggests that Oct4 a potentially key factor not only for inducing iPSCs but also for transdifferention.  “Therapeutic applications might eventually focus less on pluripotency and more on multipotency,

  1. Epigenetics is getting a big attention recently to understand genomics and provide better results. However, this field is studied for many years under functional genomics and developmental biology for cellular and molecular biology. Stem cells have a free drive that we have not figured out yet. So genomics must be studied essentially with people training in developmental biology and comparative molecular genetics knowledge to make heads and tail for translational medicine.

There are three main routes of epigenetic modifications one

  • histone modifications via acetylation and methylation and the other is
  • DNA methylation, which are two classical mechanisms in epigenetics.

The third factor is

  • non-coding RNAs that are usually underestimated even not included.

In 1993, Kavai group showed brain development assays of mice showed that only 0.7% genome has tissue and cellular specificity, and 1.7% of genome was able to turn on and off. This conclusion is relevant to genome sequencing data. Also, previous studies in genome and RNA biology presented that RNA directed DNA modifications lead into splicing and transcriptional silencing for gene regulation in Arapsidosis, mice, and Drosophila. (Borge, F. and. Martiensse, R.A. 2013; Di Croce L, Raker VA, Corsaro M, et al. 2002; Piferrer, F, 2013; Jun Kawai1 et al. 1993)

The environment creates the epigenerators including temperature, differentiation signals and metabolites that trigger the cell membrane proteins for development of signal transduction within the cell to activate gene(s) and to create cellular response.  These changes can be modulated but they are not necessary for modulation. The second step involves epigenetic initiators that require precise coordination to recognize specific sequences on a chromatin in response to epigenerator signals. These molecules are

  • DNA binding proteins and
  • non coding RNAs.

After they are involved they are on for life and controlled by autoregulatory mechanisms, like Sxl (sex lethal) RNA binding protein in somatic sex determination and ovo DNA binding protein in germline sex determination of fruit fly. Both have autoregulation mechanisms, cross talks, differential signals and cross reacting genes since after the final update made the soma has to maintain the decision to stay healthy and develop correctly.  Then, this brings the third level mechanism called epigenetic maintainers that are DNA methylating enzymes, histone modifying enzymes and histone variants.  The good news is they can be reversed. As a result the phonotype establishes either a

  • short term phenotype, transient for transcription,
  • DNA replication and repair or
  • long term phenotype outcomes that are chromatin conformation and heritable markers.

Early in development things are short term and stop after the development seized but be able to maintain the short term phenotype during wound healing, coagulation, trauma, disease and immune responses.

The metabolome for each organism is unique, but from an evolutionary perspective has metabolic pathways in common, and expressed in concert with the environment that these living creatures exist. The metabolome of each has adaptive accommodation with suppression and activation of pathways that are functional and necessary in balance, for its existence.

Most interesting is a recent report from Johns Hopkins in Mar 28, PNAS on breast cancer and stem cell physiology. “Aggressive cancers contain regions where the cancer cells are starved for oxygen and die off, yet patients with these tumors generally have the worst outcome,” Semenza said in a release. “Our new findings tell us that low oxygen conditions actually encourage certain cancer stem cells to multiply through the same mechanism used by embryonic stem cells.”

One of the genes responsible for initiating a stem cell fate under low oxygen conditions is called NANOG. This gene is one of many turned on in oxygen-poor conditions by proteins called hypoxia-inducible factors, or HIFs. NANOG in turn instructs cells to become stem cells to resist the poor conditions and help survival.

NANOG levels can be artificially lowered in embryonic stem cells by experimentally methylating the respective mRNA transcript at the sixth position of its adenine nucleotide. Since this methylation is otherwise thought to stabilize the transcript from degradation, this may help NANOG abandon its proposed stem cell fate for the cell.

In addition to the basic essential nutrients and their metabolic utilization, they are under cellular metabolic regulation that is tied to signaling pathways.  In addition, the genetic expression of the organism is under regulatory control by the interaction of RNAs that interact with the chromatin genetic framework, with exosomes, and with protein modulators. This is referred to as epigenetics, but there are also drivers of metabolism that are shaped by the interactions between enzymes and substrates, and are related to the tertiary structure of a protein.  The framework for diseases in and Pharmaceutical interventions that are designed to modulate specific metabolic targets are addressed as the pathways are unfolded.

Personalized Medicine is here now

Two years ago AJP was found to have a positive test for BRCA1, carrying an 87 percent risk for breast cancer and a 50 percent risk for ovarian cancer. At that time she had a preventive mastectomy. The decision was not easy, but it also brought into consideration that her mother and grandmother both died of breast cancer. She did not have an oophorectomy at that time because on considering the advice of medical experts, she would have been left with no estrogen support. She wanted to delay her early vegetative senescence. She has reached the age of 39 years and on the advice of medical expert opinion, she proceeded with salpingo-oophorectomy, at age 39 years, a decade before her mother had developed cancer. But her delay was to allow her to recover and adjust emotionally to her ongoing situation, with a remaining risk for ovarian cancer.

in a  report in Carcinogenesis back in 2005[3] Lorena Losi, Benedicte Baisse, Hanifa Bouzourene and Jean Benhatter had shown some similar results in colorectal cancer as their abstract described:

“In primary colorectal cancers (CRCs), intratumoral genetic heterogeneity was more often observed in early than in advanced stages, at 90 and 67%, respectively. All but one of the advanced CRCs were composed of one predominant clone and other minor clones, whereas no predominant clone has been identified in half of the early cancers. A reduction of the intratumoral genetic heterogeneity for point mutations and a relative stability of the heterogeneity for allelic losses indicate that, during the progression of CRC, clonal selection and chromosome instability continue, while an increase cannot be proven.”

An article written by Drs. Andrei Krivtsov and Scott Armstrong entitled “Can One Cell Influence Cancer Heterogeneity”[4] commented on a study by Friedman-Morvinski[5] in Inder Verma’s laboratory discussed how genetic lesions can revert differentiated neurons and glial cells to an undifferentiated state [an important phenotype in development of glioblastoma multiforme].

In particular it is discussed that epigenetic state of the transformed cell may contribute to the heterogeneity of the resultant tumor.  Indeed many investigators (initially discovered and proposed by Dr. Beatrice Mintz of the Institute for Cancer Research, later to be named the Fox Chase Cancer Center) show the cellular microenvironment influences transformation and tumor development [6-8].

The mechanism by which tissue microecology influences invasion and metastasis is largely unknown. Recent studies have indicated differences in the molecular architecture of the metastatic lesion compared to the primary tumor, however, systemic analysis of the alterations within the activated protein signaling network has not been described. Using laser capture microdissection, protein microarray technology, and a unique specimen collection of 34 matched primary colorectal cancers (CRC) and synchronous hepatic metastasis, the quantitative measurement of the total and activated/phosphorylated levels of 86 key signaling proteins was performed. Activation of the EGFR-PDGFR-cKIT network, in addition to PI3K/AKT pathway, was found uniquely activated in the hepatic metastatic lesions compared to the matched primary tumors. If validated in larger study sets, these findings may have potential clinical relevance since many of these activated signaling proteins are current targets for molecularly targeted therapeutics. Thus, these findings could lead to liver metastasis specific molecular therapies for CRC.

2016 Bio-IT World Best Practices Finalists Announced

Reporter: Aviva Lev-Ari, PhD, RN

2016 Bio-IT World Best Practices Finalists Announced

Winners to Be Announced at Bio-IT World 2016 – Just 3 Weeks Away!

March 15, 2015 | The Editors announced the finalists today in the Bio-IT World Best Practices competition. Entries from 17 groups made it to the final round of competition. Winners will be announced live at the plenary session at the Bio-IT World Conference & Expo on April 6, at 9:30 am. View details at Bio-ITWorldExpo.com.

Since 2003, the Best Practices Awards have highlighted outstanding examples of how technology innovations and strategic initiatives can be powerful forces for change in the life sciences, from basic biomedical research to drug development and beyond. This year’s field featured a unique class of entrepreneurs and innovators, from the clinic, lab and board room, who have developed new approaches to some of the key pain points in research, discovery, and clinical development.

“Fourteen years after our first Best Practices competition, I continue to be inspired by the work done in our field,” said Bio-IT World Editor Allison Proffitt. “The Bio-IT World Community is increasingly open, and the partnerships and projects showcased here prove our dedication to collaborative excellence.”

2016 Finalists

Amgen

Real World Data Platform and Analytics

AstraZeneca

CI360 (Competitive Intelligence 360)

AstraZeneca nominated by Bina

NGS production informatics: Developing AZ wide capabilities for NGS analytics

Biogen nominated by inviCRO

MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions): Automated quality control pipeline for MRI data in a learning health system

Certara nominated by Rana Healthcare Solutions

New PBPK Model Seeks to Bring More Efficacious Antibody Drug Conjugates to Market

FDA nominated by DNAnexus

FDA advancing precision medicine with precisionFDA: a collaborative informatics community to explore regulatory science

Human Longevity

HLI Knowledgebase & Health Nucleus

ICON Firecrest

eConsent

Pfizer

Academix: A Worldwide, Real-Time “Collaborative Intelligence” Platform

Pfizer nominated by Linguamatics 

A comprehensive approach to identifying relevant patent literature using an integrated text mining solution

Providence Medical Technology nominated by Clinovo

Disrupting Clinical Trials in The Cloud

XOMA

XAbTracker & SeqAgent: Integrated LIMS and sequence analysis tools for Antibody Phage Display

 

SOURCE

From: Bio-IT World <jaimeh@healthtech.com>

Date: Tuesday, March 15, 2016 at 11:10 AM

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

Subject: 2016 Bio-IT World Best Practices Finalists Announced

Portfolio Management: Define Assess & Create Value March 31st 2016 | 12pm EST by eyeforpharma

Reporter: Aviva Lev-Ari, PhD, RN

 

SOURCE

 

Done right, portfolio management is where value originates. Great portfolio managers are able to create and maximize value as fluently as any leading scientist. However, are you confident you and your company are able to define, measure and realize value in early development phases every single time?

Any executive with responsibility for their company’s pipeline will benefit from a new multi-perspective panel discussion we are assembling. Assessment of value has shifted hugely amongst payers, patients and physicians in the past few years and will only accelerate. We’re going to help you better understand how to get real impact from your R&D and Licensing resources. The exclusive panel will help you understand:

  • What is the definition for the value we are trying to create? – Witness the different points of view when it comes to defining and assessing value of your compound pipeline according to varying company objectives.
  • How can we manage it and measure it? – Improve accuracy on key metrics: attrition rates of compounds in R&D pipelines, number of compounds are in production, productivity, and translation of results into value.
  • How can we improve? – Compare traditional methods to a new, broader vision based on qualitative parameters that will give you a clearer conclusion on whether to pursue a produce at preclinical stage

You can’t make it? Sign up for free and I will send you the recording.

Forward to a colleague

SOURCE

Brain and behavior

Brain and behavior

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Behavior Brief

A round-up of recent discoveries in behavior research

By Catherine Offord | March 25, 2016

http://www.the-scientist.com/?articles.view/articleNo/45665/title/Behavior-Brief

Manta in the mirror

http://www.the-scientist.com/images/News/March2016/mantamain.jpg

The mirror self-recognition (MSR) test is commonly used to evaluate nonhuman animals’ self-awareness, and has been reportedly passed by several mammals and birds including apes, elephants, dolphins, and magpies. According to a study published earlier this month (March 11) in The Journal of Ethology, there’s now evidence to add manta rays to that list.

Contingency checking and self-directed behaviors in giant manta rays: Do elasmobranchs have self-awareness?

Csilla Ari  , Dominic P. D’Agostino     Journal of Ethology   11 March 2016: 1-8    http://link.springer.com/article/10.1007%2Fs10164-016-0462-z    doi:10.​1007/​s10164-016-0462-z

Elaborate cognitive skills arose independently in different taxonomic groups. Self-recognition is conventionally identified by the understanding that one’s own mirror reflection does not represent another individual but oneself, which has never been proven in any elasmobranch species to date. Manta rays have a high encephalization quotient, similar to those species that have passed the mirror self-recognition test, and possess the largest brain of all fish species. In this study, mirror exposure experiments were conducted on two captive giant manta rays to document their response to their mirror image. The manta rays did not show signs of social interaction with their mirror image. However, frequent unusual and repetitive movements in front of the mirror suggested contingency checking; in addition, unusual self-directed behaviors could be identified when the manta rays were exposed to the mirror. The present study shows evidence for behavioral responses to a mirror that are prerequisite of self-awareness and which has been used to confirm self-recognition in apes.

X-RAY MAG: How did you become interested in studying the behavior of manta rays?

CA: I knew that I wanted to dedicate my life to study and protect marine life since I was 13 years old. It was during a family vacation in Croatia when I first had the chance to try scuba diving. I was so mesmerized by the experience that when I surfaced I decided to try to find out more about this magical world. I became especially fascinated by the majestic and mysterious manta rays after watching a nature documentary, soon after this first dive. It described how little we know about them and how vulnerable they are.

But growing up in Hungary, a landlocked country, I did not have much option to pursue my dream as a marine biologist, so I got my master’s degree in zoology and my doctorate in neurobiology, while volunteering at oceanography institutes in different countries during the summers. During my PhD studies, I worked on the neuroanatomy and neurohistology of several shark and ray species, including mobulids (mantas and mobulas). During these years, I had the chance to explore the brain structures of mantas and mobulas, which reflected some very unique and surprising features. It was the unusual enlargement of some of their brain parts that got me interested in focusing on their behavior.

“Manta rays are likely the first fish species found to exhibit self-awareness, which implies higher order brain function, as well as sophisticated cognitive and social skills,” study coauthor Csilla Ari told X-Ray Mag.

COGNITION AND SELF AWARENESS IN MANTA RAYS   

Observing two rays in a tank at the Atlantis Aquarium in the Bahamas, the researchers noticed that the animals changed their behavior when a mirror was placed on one of the walls. New behaviors included apparently checking out their fins (see this video) and blowing bubbles at their reflections.     https://youtu.be/LQ1KErB_2oU

X-RAY MAG: What were the findings that caused you to conclude that these animals are using cognition?

CA: Animal cognition, often referred to as animal intelligence, is an exciting scientific field that attempts to describe the mental capacity of an animal. It developed from the field of comparative psychology and it includes exciting research questions, such as perception, attention, selective learning, memory, spatial cognition, tool use, problem solving or consciousness.

There are no easy ways to test these on manta rays, but I found a widely-used and well-established test that can give us insight on their cognitive abilities. The mirror self-recognition (MSR) test is considered to be a reliable behavioral index to show the animal’s ability for self-recognition/self-awareness. Recognizing oneself in a mirror is a very rare capacity among animals. Only a few, large-brained species have passed this test so far, including Asian elephants, bottlenose dolphins and great apes, but no fish species so far.

So, employing a protocol adapted from primates and bottlenose dolphin MSR studies, I exposed captive manta rays to a large mirror and recorded their behavior. The manta rays showed significantly higher frequency of repetitive behavior, such as circling at the mirror or high frequency cephalic fin movements when the mirror was placed in the tank. Contingency checking and self-directed behavior included body turns into a vertical direction, exposing the ventral side of the body to the mirror while staying visually oriented to the mirror. Most surprisingly, such self-directed behaviors were sometimes accompanied with bubble blowing front of the mirror and sharp downward swims.

“This new discovery is incredibly important,” Marc Bekoff of the University of Colorado in Boulder who was not involved in the study told New Scientist. “It shows that we really need to expand the range of animals we study.”

But the MSR test’s developer, Gordon Gallup of the State University of New York at Albany, told New Scientist that the observed movements might reflect curious, rather than self-aware, behavior. “Humans, chimpanzees, and orangutans are the only species for which there is compelling, reproducible evidence for mirror self-recognition,” he said.

Manta rays are first fish to recognise themselves in a mirror  https://www.newscientist.com/article/2081640-manta-rays-are-first-fish-to-recognise-themselves-in-a-mirror

Manta Ray (Manta birostris) feeding on plankton in current, Sangalakki Island, Borneo

Manta ray hears the dinner bell    Norbert Wu/Minden Pictures/FLPA

Giant manta rays have been filmed checking out their reflections in a way that suggests they are self-aware.

Harmless but zippy

Rattlesnakes and other vipers are well-known for their lightning-quick bites, but nonvenomous snakes may be just as speedy, according to a study published this month (March 15) in Biology Letters.

Debunking the viper’s strike: harmless snakes kill a common assumption

David A. Penning, Baxter Sawvel, Brad R. Moon

“There’s this kind of pre-emptive discussion that [vipers] are faster,” study coauthor David Penning of the University of Louisiana, Lafayette, told Smithsonian. But, he added, “as sexy as the topic sounds, there’s not that much research on it.”

To Scientists’ Surprise, Even Nonvenomous Snakes Can Strike at Ridiculous Speeds  By Marcus Woo

The Texas rat snake was just as much of a speed demon as deadly vipers, challenging long-held notions about snake adaptations

http://www.smithsonianmag.com/science-nature/scientists-surprise-even-nonvenomous-snakes-can-strike-ridiculous-speeds-180958452

Texas Rat Snake

Read more: http://www.smithsonianmag.com/science-nature/scientists-surprise-even-nonvenomous-snakes-can-strike-ridiculous-speeds-180958452/#XCyQyDlTqj1JWi14.99

To put the assumption to the test, Penning and his colleagues used a high-speed camera to film strikes from three snake species—the western cottonmouth and the western diamond-backed rattlesnake (both vipers), and a relatively harmless Texas rat snake that kills its prey using constriction.

When a snake strikes, it literally moves faster than the blink of an eye, whipping its head forward so quickly that it can experience accelerations of more than 20 Gs. “It’s the lynchpin of their strategy as predators,” says Rulon Clark at San Diego State University. “Natural selection has optimized a series of adaptations around striking and using venom that really helps them be effective predators.”

When Penning and his colleagues compared strike speeds in three types of snakes, they found that at least one nonvenomous species was just as quick as the vipers. The results hint that serpents’ need for speed may be much more widespread than thought, which raises questions about snake evolution and physiology.  They compared the western cottonmouth and the western diamond-backed rattlesnake, which are both vipers, and the nonvenomous Texas rat snake. They put each snake inside a container and inserted a stuffed glove on the end of a stick. They waved the glove around until the animal struck, recording the whole thing with a high-speed camera. The team tested 14 rat snakes, 6 cottonmouths and 12 rattlesnakes, recording several strikes for each individual.

The recordings revealed that although the highest head acceleration—279 meters per second squared, or nearly 29 g—did indeed come from a rattlesnake, one of the rat snakes followed close behind, accelerating its head at 274 meters per second squared.   All the snakes turned out to be speed demons, the team reports this week in Biology Letters. The rattlesnake scored the highest measured acceleration, at 279 meters per second squared. But to their surprise, the nonvenomous rat snake came in a close second at 274 meters per second squared. That’s lightning-quick, considering that a Formula One race car accelerates at less than 27 meters per second squared to go from 0 to 60 in just one second.

“I was really surprised, because this comparison hadn’t been made before,” Rulon Clark of San Diego Statue University who was not involved in the work told Smithsonian. “It’s not that the vipers are slow, it’s that this very high-speed striking ability is something that seems common to a lot of snake species—or a wider array than people might’ve expected.”

Penning told Discover Magazine that the results make sense, since even nonvenomous snakes have to catch their food. “Prey are not passively waiting to be eaten by snakes,” he said.

Even Harmless Snakes Strike at Deadly Speed

Rather than offering the snakes some sacrificial prey animals, the researchers baited the snakes into striking in self-defense. They used a stuffed glove on a stick. The glove would move around the snake until the animal realized the glove was “clearly not going away,” Penning says, and struck at it. High-speed cameras and mirrors captured these attacks, which happened in the blink of an eye.

Early learning

Emerging evidence suggests that both humans and superb fairywrens begin learning the vocal patterns of their mothers even before birth. Now, a study published this month (March 16) in The Auk: Ornithological Advances indicates that the same is true of the red-backed fairywren, offering the possibility of studying the phenomenon across related species.

“Fairywrens have become a new model system in which to test new dimensions in the ontogeny of parent-offspring communication in vertebrates,” study coauthor Mark Hauber of New York City’s Hunter College said in a statement.

Following on their previous discovery of prenatal learning in superb fairywrens, the researchers compared the structure of nestling calls in the red-backed fairywren to the calls of the birds’ mothers. The team found that the more calls per hour that nestlings received when in the egg, the higher the similarity to maternal calls after hatching. (The number of calls received during the nestling period had no effect on call similarity.)

“Prenatal vocal learning has rarely been described in any animal, with the exception of humans and Australian superb fairywrens,” William Feeney of the University of Queensland, Australia, who was not involved in the work said in the statement. “This result is exciting as it opens the door to investigating the taxonomic diversity of this ability, which could provide insights into why it evolves.”

Vocal imitation of mother’s calls by begging Red-backed Fairywren nestlings increases parental provisioning

Red-backed fairywren (Malurus melanocephalus)  J WELKIN

 

Prenatal imitative learning is an emerging research area in both human and non-human animals. Previous studies in Superb Fairywrens (Malurus cyaneus) showed that mothers are vocal tutors to their embryos and that better imitation of maternal calls yields more parental provisions after hatching. To begin to test if such adaptive behavior is widespread amongst Australasian wrens in Maluridae, we investigated maternal in-nest calling patterns in Red-backed Fairywrens (Malurus melanocephalus). We first compared the structure of maternal and nestling call elements. Next, we examined how in-nest calling behavior varied with parental behaviors and ecological contexts (i.e. prevalence of brood parasitism and nest predation). All Red-backed Fairywren females called to their eggs during incubation and they continued to do so for several days after hatching at a lower rate. Embryos that received more calls per hour during the incubation period (but not the nestling period) developed into hatchlings with higher call element similarity between mother and young. Female call rate was mostly independent of nest predation but in years with more interspecific brood parasitism, nestling element similarity was greater and female call rates tended to be higher. Playback experiments showed that broods with higher element similarity to their mother received more successful feeds. The potential for prenatal tutoring and imitative begging calls in 2 related fairywren taxa sets the stage for a full-scale comparative analysis of the evolution and function of these behaviors across Maluridae and in other vocal-learning lineages.

 

Traveling junk-foodies

White storks may be addicted to junk food, in some cases making migratory trips of tens of kilometers to landfill sites during the breeding season, according to a study published earlier this month (March 15) in Movement Ecology.

“We found that the continuous availability of junk food from landfill has influenced nest use, daily travel distances, and foraging ranges,” study coauthor Aldina Franco of the University of East Anglia said in a statement. “Storks now rely on landfill sites for food—especially during the non-breeding season when other food sources are more scarce.”

Using GPS tracking, the researchers focused on 17 storks traveling between nesting and feeding areas over the course of a year. They found that most long-distance trips were made to landfill sites, and that “having a nest close to a guaranteed food supply also means that the storks are less inclined to leave for the winter,” Franco explained in the statement. “They instead spend their non-breeding season defending their highly desirable nest locations.”

“It’s clear migratory behaviors are quite plastic, in that the [storks] are adaptable and can change quickly,” Andrew Farnsworth of the Cornell Lab of Ornithology who was not involved in the work told National Geographic. He added that the new, detailed dataset will help scientists “consider how such changes in behavior may affect the future population of these birds.”

Are white storks addicted to junk food? Impacts of landfill use on the movement and behaviour of resident white storks (Ciconia ciconia) from a partially migratory population

Nathalie I. Gilbert Email authorRicardo A. CorreiaJoão Paulo Silva,…, Jenny A. Gill and Aldina M. A. Franco

Movement Ecology 2016; 4:7      http://dx.doi.org:/10.1186/s40462-016-0070-0

The migratory patterns of animals are changing in response to global environmental change with many species forming resident populations in areas where they were once migratory. The white stork (Ciconia ciconia) was wholly migratory in Europe but recently guaranteed, year-round food from landfill sites has facilitated the establishment of resident populations in Iberia. In this study 17 resident white storks were fitted with GPS/GSM data loggers (including accelerometer) and tracked for 9.1 ± 3.7 months to quantify the extent and consistency of landfill attendance by individuals during the non-breeding and breeding seasons and to assess the influence of landfill use on daily distances travelled, percentage of GPS fixes spent foraging and non-landfill foraging ranges.   Results   Resident white storks used landfill more during non-breeding (20.1 % ± 2.3 of foraging GPS fixes) than during breeding (14.9 % ± 2.2). Landfill attendance declined with increasing distance between nest and landfill in both seasons. During non-breeding a large percentage of GPS fixes occurred on the nest throughout the day (27 % ± 3.0 of fixes) in the majority of tagged storks. This study provides first confirmation of year-round nest use by resident white storks. The percentage of GPS fixes on the nest was not influenced by the distance between nest and the landfill site. Storks travelled up to 48.2 km to visit landfills during non-breeding and a maximum of 28.1 km during breeding, notably further than previous estimates. Storks nesting close to landfill sites used landfill more and had smaller foraging ranges in non-landfill habitat indicating higher reliance on landfill. The majority of non-landfill foraging occurred around the nest and long distance trips were made specifically to visit landfill.  Conclusions   The continuous availability of food resources on landfill has facilitated year-round nest use in white storks and is influencing their home ranges and movement behaviour. White storks rely on landfill sites for foraging especially during the non-breeding season when other food resources are scarcer and this artificial food supplementation probably facilitated the establishment of resident populations. The closure of landfills, as required by EU Landfill Directives, will likely cause dramatic impacts on white stork populations.

WEIRD & WILD   Junk Food-Loving Birds Diss Migration, Live on Landfill    By Brian Handwerk

Spain and Portugal’s white storks are forgoing their annual journeys to African wintering grounds, a new study says

http://news.nationalgeographic.com/2016/03/060315-storks-food-animals-science-urban-food/

You’ve heard of the staycation. Some white storks in Europe are now opting for the staygration. 

The big birds are skipping their annual trip to African wintering grounds to remain year-round in Spain and Portugal, a new study shows.

Why? They’ve developed an addiction to junk food at landfills.

“White storks used to be wholly migratory. Before the 1980s, there were no white storks staying in” Spain and Portugal, says study leader Aldina Franco, a conservation ecologist at the University of East Anglia in the U.K.

“During the 1980s, the first individuals started staying, and now we see those numbers increasing exponentially.” (Related: “Beloved Storks, Emblems of Fertility, Rebounding in France.”)

 

Unlikely allies

Israel’s barren Negev desert is home to striped hyenas and gray wolves—two large scavenger species with considerably overlapping diets. But although such conditions might be expected to create fierce competition, researchers in Israel and the U.S. have now presented evidence that—at least in some cases—these animals form alliances and may even hunt collaboratively for food. The findings were published last month (February 10) in Zoology in the Middle East.

Wolves and hyenas in the desert might “just need each other to survive, because food is so, so limited,” study coauthor Vladimir Dinets of the University of Tennessee in Knoxville told The Washington Post.

Collating observations made over the past two decades (including reports of overlapping paw prints, and sightings of hyenas among packs of wolves), the researchers note that the findings could reflect the behavior of a few, oddly behaving hyenas, or a more widespread commensal, or even cooperative, relationship between the species.

“Animal behavior is often more flexible than described in textbooks,” Dinets said in a press release. “When necessary, animals can abandon their usual strategies and learn something completely new and unexpected. It’s a very useful skill for people, too.”