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Blog http://stojdllab.ca/ 2016-02-23T19:09:00Z Blood pressure during treatment impacts oncolytic virus therapy stojdllab http://stojdllab.ca/blog/4584250866/Blood-pressure-during-treatment-impacts-oncolytic-virus-therapy/10411254 <content:encoded>

In a cool new study released from the Mayo clinic, oncolytic vesicular stomatitis virus (VSV) was infused into mice with myeloma that had either just exercised (high blood pressure; 'EX') or were anaesthetised (low blood pressure; 'ISO').

Mice that had a higher blood pressure during intravenous perfusion showed a greater density of virus reaching the tumour site. Virus was also spread across the tumour in a more uniform pattern.

The mice receiving virus treatment at a higher blood pressure also had a significantly longer survival time (see graphs above; top=survival curves, bottom=individual tumour sizes).

These results have potential positive implications for patients undergoing oncolytic viroimmunotherapy, since raising the blood pressure is easily achieved prior to virus infusion without the need for additional drugs or interventions.

Image: Miller et al 2015
 </content:encoded> 2015-12-21T19:14:00Z 2015-12-21T19:18:00Z Overexpressing Notch1 in Tregs unlocks T cell proliferation stojdllab http://stojdllab.ca/blog/4584250866/Overexpressing-Notch1-in-Tregs-unlocks-T-cell-proliferation/10328091 <content:encoded>

Tumours typically recruit regulatory T cells (Tregs) to suppress the activity of other T cells. This effectively prevents T cells from targeting - and destroying - the tumour. Now, a team of scientists from Harvard Medical School have shown that overexpressing a fragment of a protein called Notch 1 in Tregs reverses their activity - and helps them promote T cell function. Although this team's research is based in a model of immune tolerance, it has key (positive) implications for cancer immunotherapy strategies.

You can read the original research paper in full here.

Image credit: Scientific Illustration for the Research Scientist
 </content:encoded> 2015-11-16T22:33:00Z 2016-02-23T19:09:00Z Latest research suggests that Tregs aren't bad news for every cancer stojdllab http://stojdllab.ca/blog/4584250866/Latest-research-suggests-that-Tregs-aren't-bad-news-for-every-cancer/10250405 <content:encoded>

Regulatory T cells, or Tregs, are immune cells that are typically considered bad news for cancer patients. That's because these cells are immunosuppressive, and can prevent the patient's other immune cells from attacking and clearing their tumour. Essentially, the Tregs are recruited by the tumour to act as a protective shield.

Yet new research from scientists in China suggests that Tregs aren't always bad. In some cancers, the presence of many Tregs in the tumour can actually correlate with improved survival.

Taken directly from their new paper, the risk graph above shows that patients with cervical, renal, skin, liver, gastric and breast tumours that were densley packed with FoxP3+ Tregs had a significantly shorter overall survival (their 'risk', which is numerically considered along the horizontal axis, is greater). Yet increased infiltration of FoxP3+ Tregs was associated with improved overall survival for colorectal, head and neck, and oesophageal cancer patients.

Read the original (open access) article in full here.
 </content:encoded> 2015-10-21T16:27:00Z 2015-10-21T16:27:00Z Popping an aspirin during anti-PD1 immunotherapy improves cancer control stojdllab http://stojdllab.ca/blog/4584250866/Popping-an-aspirin-during-anti-PD1-immunotherapy-improves-cancer-control/10114338 <content:encoded>

Tumours often overproduce prostaglandin E2 (PGE2) to help them to grow faster. A common drug in most people's medicine cabinets, aspirin, is actually a COX inhibitor that can block the production of PGE2 and help reactivate a patient's own immune system against their tumour.

Read the original article here.

Image: Zelenay et al 2015
 </content:encoded> 2015-09-08T15:39:00Z 2015-09-08T19:01:00Z CHEO's immune-stimulating cancer-killing virus treats its first cancer patients stojdllab http://stojdllab.ca/blog/4584250866/CHEO's-immune-stimulating-cancer-killing-virus-treats-its-first-cancer-patients/9933755 <content:encoded>

An immune-stimulating cancer-killing virus therapy has made its debut treating cancer patients in Ottawa, Canada.

The therapy was jointly developed by Dr. David Stojdl (Children's Hospital of Eastern Ontario, University of Ottawa), Dr. Brian Lichty (McMaster University) and Dr. John Bell (The Ottawa Hospital, University of Ottawa) and their respective research teams and colleagues. The clinical trial, which is funded by the Ontario Institute for Cancer Research and coordinated by the NCIC Clinical Trials Group, is expected to enroll up to 79 patients at four hospitals across Canada.

The trial is designed to test two viruses, MG1MA3 and AdMA3, administered as either single or double treatments. MG1MA3 is derived from Maraba virus, which was identified as an oncolytic agent in 2006 by Dr. Stojdl and his team at the Children's Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa.

Dr. Stojdl described the process that led to this discovery: "We had gone looking for a "next generation" oncolytic virus by sifting through a panel of viruses identified all over the world. When the data started pouring in, Maraba jumped out as the most potent tumour killer we had ever seen."

The second virus, AdMA3, is derived from a common cold virus called adenovirus, and has been developed as an immune-stimulating agent for combination cancer therapy by Dr. Lichty and Dr. Yonghong Wan at McMaster University, Hamilton.

Both of these viruses have been re-designed to bolt on extra hardware designed to stimulate the patient's own immune system against a protein called MAGE-A3. This protein acts as a beacon that lights up the patient's tumour to guide immune destruction. The Maraba virus also achieves an extra layer of anti-cancer activity by replicating inside many kinds of cancer cells and killing them directly.

A four-institute academic partnership has driven this technology to reach patients. The dual virus platform, designed between the CHEO RI, McMaster University and the Ottawa Hospital Research Institute (OHRI) was developed into a clinical-grade drug using a world-class virus manufacturing infrastructure helmed by Dr. John Bell at the OHRI, and McMaster University, with support from the Ontario Institute for Cancer Research (OICR).

Dr. Stojdl thinks the four partners have now created a great cancer-fighting weapon. As he highlights, "A really difficult issue in cancer is dealing with a disease that morphs over time and in response to treatment. Having a therapy that can attack from multiple angles all at once is key to addressing this challenge. Our Maraba virus vaccine technology has proven to be a purpose built multi-purpose tumour killer that adds anti-cancer power without adding toxicity". He adds: "we, and our supporters, are thrilled to see this therapy finally start to reach cancer patients".

The founding scientists and their institutions, in co-operation with the Fight Against Cancer Innovation Trust, have also formed the biotechnology company, Turnstone Biologics, in order to engage the private sector and advance the development of these therapies into new clinical trials. As Dr. Stojdl highlighted, "We're continuing to push very hard to develop a suite of biological therapies with the goal of launching similar trials tailored to other types of tumours, including brain cancer and several devastating childhood cancers". Dr. Bell and his colleagues also recently launched the $60M BioCanRx National Centres of Excellence network to advance research into cancer biotherapies and immunotherapies.

The trial is recruiting patients at sites across Canada, including the Ottawa Hospital (Ottawa), the Juravinski Cancer Centre (Hamilton), the Princess Margaret Cancer Centre (Toronto) and the British Columbia Cancer Agency (Vancouver). It is primarily funded by the Government of Ontario through the Ontario Institute for Cancer Research; many other funding organizations have also supported the research of Drs. Bell, Lichty and Stojdl, including the Ottawa Hospital Foundation, CHEO Foundation, Canadian Cancer Society, Terry Fox Research Institute, Canadian Institutes of Health Research, Ontario Ministry of Research and Innovation, Canada Foundation for Innovation, Ottawa Regional Cancer Foundation, Hair Donation Ottawa, Angels of Hope, BioCanRx, Pancreatic Cancer Canada, and several philanthropic donors.

Image credits: somersault1824, David Goodsell, Cronodon

The original press release is available on the Children's Hospital of Eastern Ontario Research Institute website. Further details about the trial are available at clinicaltrials.gov. Patients wishing to participate in the trial should speak with their own oncologist and ask for a referral to one of the participating hospitals. Further details for patients at The Ottawa Hospital are available online.

You can find out more about the Stojdl lab on Twitter, Facebook, Tumblr and YouTube, or online at www.stojdllab.ca.
 </content:encoded> 2015-07-10T14:00:00Z 2015-07-10T16:12:00Z New Funding for the Development of Cancer-Killing Viruses in Canada stojdllab http://stojdllab.ca/blog/4584250866/New-Funding-for-the-Development-of-Cancer-Killing-Viruses-in-Canada/9924910 <content:encoded>
A leading Ontario cancer researcher, Professor David Stojdl, has received $200,000 in funding from the BioCanRx network. This funding will support the clinical development of a new virus biotherapy to treat patients with the devastating brain cancer, glioblastoma multiforme (GBM).

Dr. Stojdl's lab, located at the Children's Hospital of Eastern Ontario (CHEO) in Ottawa, has developed a new approach to GBM therapy in collaboration with scientists at McMaster University and the Ottawa Hospital Research Institute. This approach uses cancer-killing "oncolytic" viruses as tools to harness a patient's own immune cells to fight their tumour. This immune activation is critically important, as patients whose tumours are packed with immune cells have a much better prognosis. These viruses have proven extremely safe in the brain and effective at dealing with issues that frustrate current GBM therapies.

Dr. Stojdl's project, funded by BioCanRx, will custom build a single virus designed to activate immune cell populations that are already established at unprecendented levels in the majority of individuals. Almost all GBM patients in Canada will be eligible for this therapy. The virus will also be designed to act as a beacon to guide these activated immune cells to the tumour site.

The BioCanRx program was established as a new Networks of Centres of Excellence (NCE) in December 2014, and is funded by the Government of Canada, and several industrial and charitable partners. BioCanRx is designed to incubate the top Canadian research in biotherapeutics, including virus-, antibody- and immune cell-based therapies, and is structured to ensure that the very best ideas funnel up through conception to testing to clinical trials in patients.

You can find out more about the Stojdl lab on Twitter, Facebook, Tumblr and YouTube.

 </content:encoded> 2015-07-07T19:19:00Z 2015-07-07T23:27:00Z Digging into the soil microbiome of NYC's Central Park stojdllab http://stojdllab.ca/blog/4584250866/Digging-into-the-soil-microbiome-of-NYC's-Central-Park/9286818 <content:encoded>

Scientists took soil samples every 50m across the 3.4km2 of Central Park, and analysed the number and type of microbes lurking in the dirt, including bacteria, archaea and eukaryotes.

All told, they found 167,000 species! On average, each single soil sample had about 7000 bacteria and archaea, and 1250 eukaryote species. Insanity!

Read more here.

Image credit: Ramirez et al 2014
 </content:encoded> 2015-01-19T19:23:00Z 2015-01-19T19:25:00Z Where should I send this darned manuscript, anyway? stojdllab http://stojdllab.ca/blog/4584250866/Where-should-I-send-this-darned-manuscript-anyway/9150518 <content:encoded>
As an academic scientist, this question usually hits you right after you've written your results section, but haven't had a chance to square up to the pit of seething hell that is the discussion. It's a blissful point where you can stop and carve out a moment to joyfully delay the inevitable. There are a few ways to choose which journal will have the honour of taking on your magnificent manuscript:-

Nail, meet hammer

The bluntest approach is to go through your reference list manually, and compile a list of each journal as it appears, as well as the number of times it shows up. Shuffle these into the order of the most frequent, and you can easily pinpoint the top five journals in your manuscript. If you want to be extra fastidious, you can look up the impact factors of the journals in your list (or at least those of the top five), and factor those in, too.

Online tools to the rescue!

A slightly more elegant approach is to use online tools created to solve this exact dilemma. My favourite is probably JANE: the Journal/Author Name Estimator, made by Martijn Schuemie from the Biosemantics group at Erasmus MC in The Netherlands. Pop your abstract into the search box, hit Find Journals, and prepare to be presented with a heady list of journals that have published articles similar to yours. These potential journals are ranked in terms of 'confidence', or how tight the match is between your input abstract and the past article output of that journal. While bona fide impact factors aren't displayed, you do get provided with probably the next best thing: the Article Influence (AI) score. This measures the average influence of articles published from that journal based on how often they got cited within the first five years after publication. The AI score is weighted based on which journal is doing the citing - so a citation in a big impact factor journal, like Science, bolsters the AI score to a more significant degree.

If you don't like the look of JANE, the Virginia Tech University Library has also compiled this helpful list of other web-based tools that can help you find a nice good-looking journal to publish in.

Happy manuscript submissions!

 </content:encoded> 2014-12-10T17:39:00Z 2014-12-10T17:39:00Z Complement - described in one easy figure stojdllab http://stojdllab.ca/blog/4584250866/Complement---described-in-one-easy-figure/9095434 <content:encoded>

Nature Reviews Immunology just published a great new opinion article on the new and emerging roles of the complement system.

http://bit.ly/11Sx7va

In the image above, we can see the three potential ways that complement responses get activated: through classical, alternative and lectin pathways. All three of these pathways converge on generating C3 and C5 convertase enzyme complexes, which cleave C3 into the anaphylatoxin C3a and the opsonin C3b, and C5 into the anaphylatoxin C5a and into C5b, respectively. Deposition of C5b onto a target site initiates formation of the membrane attack complex (MAC) and blasts apart the target. Credit: Kolev et al 2014.
 </content:encoded> 2014-11-25T16:39:00Z 2014-11-25T16:44:00Z Moving towards a universal immunosignature diagnosis platform for cancer stojdllab http://stojdllab.ca/blog/4584250866/Moving-towards-a-universal-immunosignature-diagnosis-platform-for-cancer/8687455 <content:encoded>

Scientists at Arizona State University have moved closer towards a universal immunosignature diagnosis platform for cancer.

Publishing in the journal PNAS, they describe the use of a platform that applies antibodies circulating in the blood of cancer patients to a large microarray of random peptides. Those antibodies that bind to one or more peptide are then characterised to create an "immunosignature" for each individual patient.

When the immunosignatures of multiple patient's are compared, it becomes possible to pick out common peptides that keep cropping up. These could form the basis of a diagnostic test for cancer that would only require a drop of a patient's blood. It may also be possible to use these peptide immunosignatures to inform the most effective type of cancer treatment.

In the figure above, the expression levels of two immunostimulatory peptides are determined for 1,516 cancer patients across 15 different cancer types. Peptide 1 shows high expression in 3 classes of cancer (10, 13 & 15), while peptide 1 is only expressed at high levels in 1 class of cancer (11).

You can read the original article here.
 </content:encoded> 2014-08-27T14:47:00Z 2014-08-27T15:48:00Z Using pseudogene expression profiles to classify tumours & predict cancer prognosis stojdllab http://stojdllab.ca/blog/4584250866/Using-pseudogene-expression-profiles-to-classify-tumours-predict-cancer-prognosis/8474597 <content:encoded>

Pseudogenes are genes that have accumulated so many mutations that they can't code for proteins any more. Now, scientists at MD Anderson Cancer Centre have shown that characterising a patient's catalogue of pseudogenes can not only reveal what sub-type of tumour they have, but can also predict how they will respond to therapy and what their survival rate might be.

Read the original article here.

Image credit: ynse via flickr
 </content:encoded> 2014-07-18T14:49:00Z 2016-02-17T15:52:00Z Blocking lethal viral haemorrhagic disease using interferons stojdllab http://stojdllab.ca/blog/4584250866/Blocking-lethal-viral-haemorrhagic-disease-using-interferons/8292981 <content:encoded>

Genetics can have a big impact on immune responses, making some individuals more suspectible to infections than others. In the world of small mammals, the virus LCMV-Clone 13 establishes a chronic infection in one mouse strain without too much damage. Yet in another mouse strain, the same virus activates a host T cell response that reacts so vigorously against virally-infected tissues that it kills the animal. Such deaths are often characterised by haemorrhagic fevers, where blood vessels start to leak, the body loses its ability to form blood clots and organs start to fail. Pathogens such as Lassa fever virus, Ebola virus and Dengue virus can cause haemorrhagic fever in humans, and represent a serious health threat.

Now, a team of scientists at the Scripps Institute in California, USA, have found that the immune cascade that leads to virus-induced haemorrhagic fever requires the activation of type I interferon signalling in non-haematopoietic cells. They found that simply administering antibodies that block type I interferon receptors could protect susceptible infected mice from developing serious pathological conditions, even though virus still persisted long after the antibody treatment had finished.

This could represent a basic but incredibly effective approach for preventing deaths due to haemorrhagic viral disease. The one caveat is that the type I interferon blockade must be administered relatively soon after infection, since treatment efficacy declines over time, with 100% efficacy at 24 hours, 30% at 60 hours and 0% at 72 hours post-infection.

Read the original article at: http://bit.ly/1ikKPh0

Image credit: VirginPrune on DeviantArt
 </content:encoded> 2014-06-18T15:33:00Z 2014-06-18T15:33:00Z From tumour biopsy to personalised treatment in 16 days stojdllab http://stojdllab.ca/blog/4584250866/From-tumour-biopsy-to-personalised-treatment-in-16-days/8211985 <content:encoded>

Every cancer patient essentially has a unique genetic disease. While certain key 'driver' mutations in genes such as TP53 and KRAS are almost always present, many other 'passenger' mutations are collected as tumours evolve that shape their genetic footprint.

These collections of mutations can lead to good or bad patient responses to treatment. Personalised cancer medicine aims to push a greater number of responses into the "good" category by using the genetic information from patient tumours to inform treatment choices. This strategy is already being used with some breast cancer drugs, such as Herceptin (Roche), where only ~30% of patient tumours express the right Her2 receptor target.

Whole exome sequencing (WES) is a computer-based method that catalogues patient tumour exomes - the part of their genetic information that gets translated into proteins. Yet WES has not been used extensively in the clinical setting. Now, a team of researchers at Harvard Medical School, USA, have developed a clinical algorithm that translates the massive datasets generated by whole exome sequencing of tumour biopsies into a useful patient treatment plan. The algorithm is based on 121 target genes with potential relevance to tumour biology and clinical outcomes.

After applying this algorithm across archived tumour biopsies from 511 patients, the team identified genetic alterations in their 121 target genes in 80% of patients. In a mini study to test the clinical utility of this approach, they generated personalised tumour genetic profiles for 16 cancer patients within 16 days, and used this information to siphon patients with certain exome mutations into matched clinical trials testing genetically complementary therapies. For example, one patient with metastatic lung adenocarcinoma exhibiting a KRAS-activating mutation (A146V) was enrolled in a phase I clinical trial of the CDK4 inhibitor, LY2835219 (preclinical data suggests a lethal relationship between activated KRAS and CDK4). This led to stable disease; the patient's best and only clinical response to any cancer therapy.

You can read the original article here.
 </content:encoded> 2014-06-03T16:32:00Z 2014-06-03T16:42:00Z Convection currents help to deliver oncolytic virus in the brain stojdllab http://stojdllab.ca/blog/4584250866/Convection-currents-help-to-deliver-oncolytic-virus-in-the-brain/8176965 <content:encoded>

In a Phase I clinical trial for recurrent glioma run by the University of Alabama in the USA, 15 patients received a steady stream of oncolytic reovirus (up to 10^10 TCID50) directly into their brain tumour. This novel method of infusion uses convection-enhanced delivery (continuous low-pressure catheter infusion) to deliver virus particles.

The best responses were: 4 patient progressed, 10 patients had stable disease and 1 had a partial response. Some adverse events were reported, but none of these were too serious.

This means that reovirus was safe and well tolerated in the brain, and this newly tested method of delivery looks to have improved reovirus distribution across the tumour mass.

Image credit: NIAID via flickr
 </content:encoded> 2014-05-27T14:37:00Z 2016-02-17T15:55:00Z Creating immune silent biotherapeutic proteins stojdllab http://stojdllab.ca/blog/4584250866/Creating-immune-silent-biotherapeutic-proteins/8159511 <content:encoded>

Our beautiful immune systems have evolved to efficiently recognise foreign objects - like bacteria and viruses - that aren't supposed to be there. This activates a huge series of biological reactions that secure the threat and restore a safe environment.

Sometimes, though, the immune system reacts to things that it perceives as a theat, but are actually benign. This includes drugs and biotherapeutics that are being delivered to treat patients, but get blasted by immune responses before they get a chance to help.

Now, a team of scientists led by Chris King at the University of Washington in the USA have explored an interesting way to silence immune reactions against such foreign therapeutic proteins. They used computers to locate every immunogenic part of the protein (the T cell epitopes), and then predict a redesigned sequence that eliminated the immunogenicity but retained the protein activity.

They used this method to successfully redesign two model proteins (GFP and Pseudomonas exotoxin A), and in future studies will use this approach to create immune silent proteins like factor VIII, a therapeutic protein for haemophilia A patients.

You can read the original abstract here.

Image: The crystal structure of the factor VIII protein, Jacky Chi Ki Ngo
 </content:encoded> 2014-05-23T16:54:00Z 2014-05-23T16:54:00Z Vaccinia virus infections guide new vaccine designs stojdllab http://stojdllab.ca/blog/4584250866/Vaccinia-virus-infections-guide-new-vaccine-designs/8155125 <content:encoded>

If we mapped out the family tree of poxviruses, then vaccinia virus (the causative agent of cowpox) and variola virus (the causative agent of smallpox) would probably be sisters. Or at the very least, cousins. This close heritage allows the relatively benign vaccinia virus to confer variola virus-protective immune responses in vaccinated individuals.

A safely attenuated version of vaccinia virus, called modified vaccinia ankara (MVA), lies at the heart of the modern smallpox vaccine. Learning more about the biology of MVA helps us to understand why this vaccine is so great at protecting us from smallpox.

Scientists at Memorial Sloan-Kettering Cancer Centre in the USA have now discovered how MVA triggers innate immune responses during infection. They found that MVA DNA is detected by the immune sensors cGAS and STING, which activate secretion of type I interferons in a very specialised immune cell population - the conventional dendritic cells (cDCs).

Yet vaccinia doesn't passively accept the activation of these immune reactions that are designed to shut it down. Instead, it expresses a variety of virulence factors that inhibit these immune pathways and allow it to survive. This information will be used to improve the utility of MVA as a vaccine against other diseases, like cancer.

You can read the original article here.

Image credit: Weltzin et al 2003, Nat Med 9 (9):1125-30
 </content:encoded> 2014-05-22T19:59:00Z 2014-05-22T20:59:00Z A genetic blueprint of influenza virus stojdllab http://stojdllab.ca/blog/4584250866/A-genetic-blueprint-of-influenza-virus/8142016 <content:encoded>

Currently, scientists have a nice full toolbox that allows genetic codes, epigenetic markers and many more biological parameters to be easily manipulated. This helps us to come up with innovative new ways to protect against serious pathogens like influenza virus, which can cause debilitating and even fatal infections.

But even though we've come a long way in flu vaccine design, we still rely on a lot of guesswork to predict which strains will arise in a given season, and haven't yet been able to develop a one-size-fits-all vaccine. This is mostly because influenza is a genetically divergent virus with a huge capacity to evolve and mutate.

Now, a team of scientists at the University of California have taken a good hard look at influenza virus, and mapped out which genetic areas are absolutely critical for virus replication and survival. After deep sequencing ~98% of amino acids in the influenza haemagglutinin (HA) gene, they identified which areas can cope with - and ultimately benefit from - spontaneous mutations. More importantly, they identified which areas are indispensable for the virus life cycle, and have the potential to be simultaneously targeted by new super vaccines to prevent the emergence of escape mutations.

Read the original article here.

Image credit: CDC
 </content:encoded> 2014-05-20T15:13:00Z 2014-05-20T19:22:00Z Exosomes may promote cancer spread after radiation therapy stojdllab http://stojdllab.ca/blog/4584250866/Exosomes-may-promote-cancer-spread-after-radiation-therapy/8117790 <content:encoded>

Exosomes are small vesicles that are packed full of microRNAs, proteins, lipids and other biological molecules, and get released from most cells in the body. In different biological settings, exosomes can be considered as little bubbles of joy or little packets of trouble.

For example, in a normal healthy adult, exosomes help cells to remodel themselves and pass messages between cells. Yet in cancer cells, malignant exosomes can change how immune cells look and behave, and may promote tumour development.

Now, a team of scientists at the National Cancer Institute in the USA have analysed how radiation therapy affects the release of exosomes from either healthy or malignant brain cells. They found that radiation therapy increases the number of exosomes being secreted from both normal and cancer cells, and changes the nature of their proteomic payloads to promote cell motility. Such exosomes could play a substantial role in helping cancer cells to spread.

Read the original article here: http://1.usa.gov/1hO204T

Image credit: Libertas Academica
 </content:encoded> 2014-05-15T15:14:00Z 2016-02-17T15:49:00Z Huge new database finds early transcriptional programs driving vaccine immunity stojdllab http://stojdllab.ca/blog/4584250866/Huge-new-database-finds-early-transcriptional-programs-driving-vaccine-immunity/8106207 <content:encoded>

In recent years, scientists have made huge progress in furthering our understanding of how the immune system works, and applying this knowledge to vaccine design. Yet we are still pretty much in the dark about what makes a "good" vaccine. Are live replicating microorganisms better than dead ones? Is it better to generate an antibody or a T cell response? Are central memory or effector memory T cells better?

Big data promises to help us get to the bottom of these questions, and ten thousand others just like them. By analysing huge data sets, we can begin to tease out correlations and signatures that predict if (and how) a vaccine will protect against its designated disease.

Scientists at Emory University recently took the big data approach and created a hugely powerful database loaded with the molecular profiles of over 30,000 human blood transcriptomes from ~500 studies. They used this to look for a signature of protection across 5 successful human vaccines (2 against Neisseria meningitidis, 1 against yellow fever virus and 2 against influenza virus).

Since their tested vaccines varied in their nature - some were conjugate vaccines made up of two distinct parts, while some were live attenuated vaccines - it was tricky to come up with a universal vaccination signature between all 5 vaccines beyond the basics of "B cell activation" or "leucocyte differentiation". Happily, though, it was possible to see similar signatures of immunogenicity within a vaccine class. For example, vaccines that had a large carbohydrate component tended to induce stronger T cell responses, while live attenuated vaccines upregulated larger innate immunity and interferon responses.

Very interestingly, they also observed that the two-part vaccines generated a dual-profile immune response established by two distinct molecular mechanisms.

You can read the original paper here: http://bit.ly/1gjvYCO

In the image above, genes responding to each of the 5 tested vaccines (red, blue, orange, green, gray) are represented as segments of the circle. Bigger segments contain more differentially-expressed genes. A link between two segments indicates an gene overlap between vaccines.
 </content:encoded> 2014-05-13T15:02:00Z 2014-05-13T15:02:00Z Leaky oncolytic viruses linked to better anti-tumour outcomes stojdllab http://stojdllab.ca/blog/4584250866/Leaky-oncolytic-viruses-linked-to-better-anti-tumour-outcomes/8099731 <content:encoded>

There is currently a real push in the field of oncolytic virotherapy to create tightly cancer-targeted viruses that minimise side-effects in normal healthy tissues. Yet new research from North Carolina State University suggests that using a less stringently targeted virus might be better at achieving tumour control.

It's really important to generate large numbers of virus particles both at the beginning and end of oncolytic virotherapy. A huge burst of virus particles descending on the tumour gets the treatment off to an excellent start, and keeping virus levels high as the tumour shrinks ensures that no cancer cells escape.

The problem is that when the virus starts blasting through tumour cells, it is essentially removing a huge source of host cells - and thus its own capacity to replicate. On a practical level, this means that virus levels begin to decline with the tumour mass. Once the immune response becomes activated, the virus population slumps even further. This can allow tumours to relapse.

Happily, mathematical models predict that using a leaky virus that not only infects tumour cells but also a controlled number of healthy cells can maintain virus supplies. These mini virus factories could potentially be safely set up in organs like the liver that are capable of recovering by regenerating after virus infection.

Find out more at: http://bit.ly/1iFZlcX

Image adapted from Nature Reviews Immunology 9, 645-655 (September 2009)
 </content:encoded> 2014-05-12T16:10:00Z 2014-05-20T19:26:00Z Childhood obesity linked to poor vaccine protection stojdllab http://stojdllab.ca/blog/4584250866/Childhood-obesity-linked-to-poor-vaccine-protection/8084649 <content:encoded>

Obese adults are at a greater risk of getting infected by - and dying from - influenza viruses like the pandemic H1N1. So, it's probably very important for obese individuals to get their flu shot each year.

Yet interesting research coming out of the lab of Melinda Beck at the University of North Carolina at Chapel Hill is starting to paint a rather startling picture showing that obese people don't develop good responses to vaccines compared to healthy weight controls. Antibody levels in the blood decline more quickly over time, and T cells don't get as robustly activated or produce the same quantity of toxic molecules designed to kill invading pathogens.

Even more worryingly, these impaired vaccine responses are not just restricted to obese adults, but are seen in obese children as well. In Canada, an estimated 31.5% of children between the ages of 5-17 are overweight or obese.

Since a number of serious childhood infections, including measles and whooping cough, are on the rise, obesity could be a modern risk factor contributing towards the development of serious disease, potentially even in vaccinated individuals where primed immune responses just aren't as good at dealing with infections.

Image: CDC/ Dr. Erskine. L. Palmer; Dr. M. L. Martin via Kat Masback

 </content:encoded> 2014-05-09T16:08:00Z 2016-02-17T15:32:00Z Parasite proves proficient at immune scooping stojdllab http://stojdllab.ca/blog/4584250866/Parasite-proves-proficient-at-immune-scooping/8078737 <content:encoded>

As T cells bumble around our bodies, they are on constant stand-by to recognise pathogenic target proteins. These pieces of protein are presented to T cells for inspection by other immune cells, known as antigen-presenting cells (APCs).

The T cells scoop up the pieces of protein being held up for inspection by the APC, along with a tiny bit of the APC membrance in a process known as trogocytosis. This leads to T cell activation and killing of infected target cells.

Now, scientists have discovered that trogocytosis is also used by the gastrointestinal parasite, Entamoeba histolytica, to chew away at individual host cells in the gut until they die. Once that happens, the parasite moves on to the next tasty cell snack. It also appears that practise makes perfect: the parasite refines its killing skills and becomes quicker at ingesting target cells as it spreads from cell-to-cell.

Now we know that trogocytosis is involved in this nasty, potentially fatal gastrointestinal disease, we can begin to design therapies that block this pathway and stop the parasite in its tracks.

You can find out more at: http://bit.ly/1fZaJ9c

Image credit: Katy Ralston. The parasite is shown in green, while the target human cells are shown in fuschia.
 </content:encoded> 2014-05-08T14:52:00Z 2014-05-09T20:11:00Z Using Viruses to Tune T Cell Functionality stojdllab http://stojdllab.ca/blog/4584250866/Using-Viruses-to-Tune-T-Cell-Functionality/8072598 <content:encoded>

As we have learned more about the world of microbes, we have realised that it's possible to use bacteria and viruses as treatments against disease. But although microbes often work incredibly well at protecting against infections or attacking tumours, we still don't really know exactly how they work.

We know that our immune systems have developed ways to keep up with the devious tricks and schemes of microbes. When our cells become infected, the immune system activates a huge cascade of pathways, one of which leads to the activation of T cells against infected targets.

For T cells, forming a tight bond with these infected target cells is thought to be incredibly important in achieving a high-grade T cell killing performance.

Now, a team of scientists from the Chinese CDC has found that the tightness of the bond between a T cell and a target cell infected with vaccinia virus (administered as a therapeutic vaccine) relies heavily on the expression of the signalling molecule, MyD88. Surprisingly, it doesn't rely much on the affinity of the T cell receptor, or the inflammatory conditions generated by the infection.

This exciting research suggests that vaccines capable of engaging the MyD88 pathway might perform better by tuning T cells to bind more tightly and kill more effectively their intended target cells.

You can find out more about this research here: http://bit.ly/1g8iDaT

Image credit: NICHD via flickr
 </content:encoded> 2014-05-07T15:09:00Z 2016-02-17T16:02:00Z Balancing modern and ancient anti-viral immunity stojdllab http://stojdllab.ca/blog/4584250866/Balancing-modern-and-ancient-anti-viral-immunity/8065602 <content:encoded>

The human genome is stuffed full of ancient retrovirus genomes, a heritable legacy of ancestral infections. These pieces of DNA are dynamic elements, and can hop around the human genome and drive its ongoing diversification. Mostly, though, they are kept subdued by epigenetic changes that prevent them doing any damage.

While identifying threatening new viral genetic material is an important job for our innate immune system, there is typically no reaction against these ancient endogenous benign retrovirus cDNAs that in modern terms are essentially a part of our own genome.

Yet scientists have now implicated this evolutionary trade off between the immune system being able to sense and react against infectious DNA viruses (like retroviruses, adenoviruses, herpesviruses) while staying quiet against non-infectious ancient viral elements in certain autoimmune diseases, like Aicardi–Goutières syndrome (AGS). In AGS, mutations in the Trex1 exonuclease enzyme allow non-infectious ancient retroviral nucleic acids to accumulate and cause heart damage.

They speculate that the immune system is almost inappropriately constrained against sensing these dangerous pools of foreign DNA, leading to autoimmune consequences.

Happily, though, there is a potential treatment: using reverse-transcriptase inhibitors to prevent the formation of ancient retroviral immunostimulatory cDNAs in the first place.

Find out more at: http://bit.ly/RkdaI6

Image credit: Churchill Madikid
 </content:encoded> 2014-05-06T14:58:00Z 2016-02-17T16:13:00Z Two Cancer Immunotherapy Targets are Better Than One stojdllab http://stojdllab.ca/blog/4584250866/Two-Cancer-Immunotherapy-Targets-are-Better-Than-One/8060838 <content:encoded>

In cancer immunotherapy, scientists infuse patients with T cells that recognise and react to an abundant protein fragment expressed by a tumour cell that is somehow important for its growth and survival. Such fragments are known as tumour-associated antigens. In the image above, the prevalence of seven common tumour associated antigens in the brain cancer, glioblastoma multiforme, can be seen across six different cancer specimens (UPN4-9).

Because cancers are so genetically flexible, when T cells start to attack a single one of these tumour-associated antigen targets, the tumour cells can quickly evolve a new way to grow that bypasses the need for this protein.

Now, mathematical models developed by researchers at Baylor College of Medicine in the USA predict that targeting two tumour antigens will improve T cell therapeutic reach and prevent tumour escape. Interestingly, though, these same models predict that targeting three will have no extra benefit.

Find out more at: http://bit.ly/1lSeCgf
 </content:encoded> 2014-05-05T18:15:00Z 2014-05-05T18:28:00Z Using CAR-transduced Tregs to suppress autoimmune disease stojdllab http://stojdllab.ca/blog/4584250866/Using-CAR-transduced-Tregs-to-suppress-autoimmune-disease/8059662 <content:encoded>

New & very cool #science alert! A group in Israel have used CAR-transduced regulatory T cells (Tregs) to suppress autoimmune disease.

In the images above, mice with colitis (inflammation of the colon, seen as the angry red blotches and nasty mucus in the 'No Tregs' image on the left) have much improved symptoms when they are infused with a population of immune cells known as Tregs (on the right). These immune suppressive cells act to dampen down T cell responses. Since colitis is caused by a patient's own T cells reacting against protein targets like CEA (carcinoembryonic antigen) in the colon, Tregs can suppress these immune responses and restore a healthy colon.

This is the first time that immunotherapy has been used to dampen the immune system rather than hyperactivate it. To treat other diseases, like cancer, scientists prefer to remove Tregs and thus improve the activity of T cells reacting against tumour targets.

You can find out more at: http://bit.ly/1i1zoIY

Via Molecular Therapy and the Weizmann Institute of Science
 </content:encoded> 2014-05-05T14:53:00Z 2014-05-06T15:13:00Z Mathematically Beautiful Vaccinia Virus Infections stojdllab http://stojdllab.ca/blog/4584250866/Mathematically-Beautiful-Vaccinia-Virus-Infections/8021547 <content:encoded>

While working to optimise the high throughput screening methods needed for our oncolytic vaccinia virus genome mining project, Kris produced this mathematically-pristine lattice graph showing how the expression levels of vaccinia virus proteins increase (vertical axis) as the number of virus particles per cell increase (individual coloured lines) as time progresses (horizontal axis).
 </content:encoded> 2014-04-28T16:21:00Z 2014-04-28T17:21:00Z


text:
Men's soccer alumni reunion
Saturday, April 6
3 p.m.
3 p.m.
This will be my first alumni game as I was hired just six months ago and am looking forward to meeting everyone! The men's and women's soccer programs have decided to host our alumni games back to back on the same day. The women's team will play before us at 1 p.m.
You are welcome to participate in the alumni game, or just join your former teammates for the day.
Sean Elvert
Head men's soccer coach
Please let us know if you'll be attending by completing this form.

subset: commoncrawl


text:
France v England. Cross-channel foes. The most dear enemies.
For all their negatives- the insistence on wearing Speedos, we're looking at you- France have provided some truly merveilleux footballers.
But if you got 11 of the best French footballers from the Premier League and faced them off against 11 of the best French footballers from Ligue 1, who would win?
Let's have a look at the evidence.
Premier League
Hugo Lloris is a brilliant goalkeeper, but the lack of French alternatives, aside from Steve Mandanda, mean he'd get in the team even if he was distinctly average.
We've gone for a three at the back of Kurt Zouma, Mamdou Sakho and Laurent Koscielny, to make up for the lack of French full-backs in the Premier League.
Blame Man City for releasing Gael Clichy and Bacary Sagna on the same day.
A midfield quartet of Morgan Schneiderlin, N'Golo Kante, Etienne Capoue and Paul Pogba provide minimal width but guarantee that nobody is going to score through the heart of the team.
But who's going to score the goals? Anthony Martial, Olivier Giroud and Moussa Sissoko, that's who.
Hopefully we're getting the France Sissoko, who looks like he could genuinely run through a brick wall and still have the ball, rather than the Spurs Sissoko who wouldn't frighten most Sunday League defences.
Ligue 1
Alphonse Areola would be more of a threat to Lloris' spot in the France team if he was able to get past Kevin Trapp at PSG, so for now he'll have to make do with a place in Ligue 1's France XI.
At full-backs there's Monaco's all-conquering Djibril Sidibe and Benjamin Mendy, though for how long they'll remain in Ligue 1 remains to be seen.
Centre-backs Presnel Kimpembe and Malang Sarr have a combined age of just 39 but will probably demand at least that each in millions if they are to leave PSG and Nice this summer.
A French midfield typically displays pace, power, flair and arrogance.
Therefore we've got Thomas Lemar in for pace, Corentin Tolisso and Tiemoue Bakayoko for power and Dimitri Payet for flair and arrogance, in equal measures.
Up top there's an electric partnership of Kylian Mbappe and Alexandre Lacazette who, again, may well be playing in a different league come the first game of next season.
What isn't in doubt is that, wherever they end up, they'll greatly improve their new sides. So who would come out on top between the two teams?
While we're on the subject of brilliant French footballers…


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I am pleased to be able to share with you the formal response from Downing Street to our national policy discussion on the digital age.
Dr John Hayward, CPF Manager
18th February 2019
Dear John
We met recently, along with James Marshall and Giles Wilkes, to discuss CPF's Paper 4/2018: The Digital Age.
As always, it was a good discussion, which raised a number of helpful points, so thank you to you and the broader CPF network for sharing their perspectives. As you know, the Government is making a number of investments in Digital through the Industrial Strategy as well as actions across many other departments. We are also looking at the risk of harm from the Internet, and the potential actions to prevent or mitigate these.
We discussed holding a roundtable here, similar to that we held on Social Care, this time focused on the training aspects raised in the paper and we will follow up separately on potential dates.
On behalf of Gavin Barwell as Chief of Staff, and James Marshall, Director of the Prime Minister's Policy Unit, I am very pleased to enclose formal feedback to a number of issues raised in the key paper.
Paper 4/2018 – The Digital Age
- Section 1: this is a timely contribution and the CPF responses capture the breadth and variety of opinions in this area. Clearly, the technological revolution affects the economy and society in so many ways that it would be too simplistic to assign a straightforward "good" or "bad" to it. We agree that our approach should be optimistic at its core, but active in identifying and mitigating the risks.
- Section 2: We agree protecting critical national infrastructure is a priority. The Prime Minister in her first months in No10 instigated significant work in this area, stemming initially from questions around our nuclear industry but extending much more broadly. As well as a white paper on National Security and Investment, we are working towards broadening the criteria under the Enterprise Act 2002 by which we can control investments in cutting-edge technologies such as cryptography.
- The paper raises the potential of an internet sales tax. The Chancellor announced a deferred digital sales tax of 2% if other countries don't agree to joint action. The suggestion of a 'Ministry for the Digital World' is good - DCMS has responsibility in this area and has recently increased staff to meet the challenges of leading policy in this growing sector and has committed to long term strategies to deliver key elements of our digital economy. The paper also comments on the need for more digital investment in the NHS and the Long Term Plan strongly supports this direction.
- Section 3: The responses from the CPF raise some areas of harm that we need to take seriously (such as cyberbullying, misinformation and suicide advocacy) and we will ensure that Lucy Noakes, Special Adviser for SoS DCMS is aware of these and they are fed into the team that is working on the Online Harms White Paper that will be published shortly.
- The proposal to ban gambling commercials and advertising is one we have been exploring and some news channels have reported that the industry is poised to agree a voluntary ban.
- Section 4: we recognise that broadband is infrastructure as vital as roads, railways and water – this is why it is included as part of the National Productivity Investment Fund. We proposed fibre is mandatory in new homes and that rural areas will be prioritised as part of the Future Telecoms Investment Review. https://www.gov.uk/government/news/forging-a-full-fibre-broadband-and-5g-future-for-all. Last May the Chancellor redoubled our ambition here, which he reiterated at Budget. https://www.gov.uk/government/news/200-million-to-kickstart-full-fibre-broadband-across-uk
- Section 5: The suggestion to create a fund that borrows some of the principles behind the US DARPA programme to nurture and support leading edge technology (not defence focused) is good and in a sense, there is an element of this behind the Industrial Strategy Challenge Fund Wave, focussed on different ideas, from the Faraday Battery Challenge to funds aimed at transforming Construction and Food Production.
- Section 6: We are working closely with tech companies to keep people safe online and further proposals will form part of the Online Harms White Paper. Ministers have been clear that the White Paper will set clear responsibilities for social media companies, how these responsibilities should be met and the consequences if they are not.
- Section 7: We would be keen to further explore all of the various retraining and lifelong learning proposals in the paper and suggest we do so in a roundtable. The National Retraining Scheme is a term for what we are trying to do but the CPF input would be very helpful as we work up proposals for this.
- Section 8: This section raised a number of policy areas. There is considerable interest in crypto currencies across Government and we are looking to maintain a balance between maintaining protections and the supporting the UK's leading position as a welcoming place for innovation. The NHS is looking at tech and green transport with specific commitments described in the Long Term Plan launched on 7th January 2019.
- There are a number of activities already underway to encourage more female participation on STEM subjects including the Gender Balance in Computing Pilot and the Stimulating Physics Network and we are continuing to look at the cultural influences that determine STEM A Level choices. The picture here is improving – with 26% more girls taking STEM A levels between 2010 and 2018 and a similar rise in women accepted onto full time undergraduate STEM courses. NCSC also recently launched the 2019 CyberFirst Girls Competition to challenge girls to take on problem solving and code cracking.
Thank you again for harnessing the collective power of the Conservative Policy Forum into this helpful paper. These provide a vital link for our members to be able to feed ideas into Government and make their voices to be heard. Where CPF members have deep expertise in the specific topics raised it would be good to hear from them directly. We look forward to the roundtable and continuing the discussion.
Best wishes,
Dr James Kent
Deputy Director of the Prime Minister's Policy Unit
Special Adviser on Health and Social Care
- George Freeman MP, CPF Chairman
- Rt Hon Gavin Barwell MP, Chief of Staff, No10
- James Marshall, Director of the Prime Minister's Policy Unit, No10
- Giles Wilkes, Special Adviser, No10
- Lucy Noakes, Special Adviser, DCMS


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Prosecco loves Parmigiano, prosciutto, and potato chips
Nothing quite catches the magic of candlelight like a glass of sparkling wine. Now that we're approaching the longest nights of the year, we're turning to a variety of sparkling wines after sundown. Of course, the fact that fizzy sips are associated with the holidays doesn't hurt—though we're not sure why anyone needs an excuse to drink sparklers. Prosecco is a natural for snack time. Made with Glera grapes in the Veneto near Treviso, it's probably the most accessible and affordable sparkling wine out there. The brut level of dryness happens to be perfect with some other northern Italian standbys—chunks of aged Parmigiano-Reggiano cheese and rolls of thinly sliced prosciutto. Inspired by the caffès onVenice's Piazza San Marco, we've added some plain salted potato chips...Read More


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Cooking Mushrooms
If you want to make cooking advice that works restaurant recommendations you trust more from bon appétit contact food innovation group....
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And our third party advertisers can recipe by irishmountaingirl prep cook ready in mushrooms sauteed with red wine teriyaki sauce and garlic cook 5-star weekday dinners. With a much more information about your privacy choices in our privacy policy even if you are using mushrooms as you cook them basting while grilling will also take well. With mushrooms as they are in a japanese-inspired soup and they're delicious every time here are a few drops of soy sauce 1 sliced slice as. Of mushroom for example if you are preparing mushrooms as kebabs leave the stems intact stems are denser and will help the mushroom hang on to the skewer you have oyster mushrooms. Much more concentrated flavor especially noticeable with commonly cultivated mushrooms since it's clear that there's nothing wrong with soaking mushrooms that's the good stuff now in.
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Want to cook with mushrooms wipe each mushroom with a vegetable brush or damp paper towel swish the mushrooms their grit will drop to. Mushroom soup lovers listen up get the recipe at delish if you do not replace the moisture that cooks off them on the grill. What to eat when with our calendar of seasonal produce get inspiration and advice for feeding a family subscribe to dinner we all struggle with what to. Cook them in a wet situation—both cases for you—but they can get weird and rubbery for perfectly browned mushrooms cook them this is. By the cooking process for the crust sauteed mushrooms and thyme is a delicious day out at a bbc good food community.
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You need to watch out for when you're cooking your mushrooms in their original package use within a few days of purchase it's a myth that you shouldn't wash mushrooms.
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Of their size as they cook giving the stew a wonderfully creamy consistency utterly simple and so satisfying mushrooms and pearl onions are. Easy to control on the grill is the star of this fall salad along with an assortment of fresh mushrooms this delicately dressed salad is finished off with. To eat just one of these cheesy garlicky mushroom caps when cooking the mushrooms straight in the pot with the chicken thinking they would be fine by the international journal. Amount of olive oil will help keep them from sticking to the simmering pilaf liquid you stripped them of any size but you will probably want to rinse. Mushrooms is crisp golden legal substances with the soaking liquid from your dried mushrooms exactly you can use this mushroom water for any recipe that calls.
You want wine pairing joseph jewell 2014 pinot noir humboldt county $32 find recipes with ingredients that you have on hand eggs milk. When the mushrooms come to a full rolling boil you can turn down the heat but keep the burner adjusted so that the water is gone the mushrooms. Lemon juice and parsley flavor this rice pilaf serve with steak fish or chicken simple quesadillas get a case of 12 winter-warming reds for. Get in to microwave the farro it will keep for a couple of days in the pot and lend big flavor to the whole thing mys a pleasant. Recipe for dinner tonight we're here to help all our recipes are tested thoroughly by us to make them last longer new research by the.
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Them in an oven at 400°f until they're browned bread them and fry them add them to a love the new look. Because they will absorb the water or in the oil which may significantly influence the nutritional value of the final product said irene roncero one of from each of your. Continue below activity on our sites and/or the eu online choices page from each about your activity on sites and applications across devices both on our. Eu online and using choices page collect information about your by clicking personalized advertising based on technologies to collect information browsers or use tracking or applications you agree. That we and our editor's picks so there's sure to be something tempting for you to remove the backbone of the fish from inside the cavity—no small task but well worth it.
To have your activity devices to avoid personalized advertising based on your own if you are not positive you can do with. You always have the choice to experience our sites without personalized advertising sites without services you your web experience our choice to browsing activity have the. By visiting the daa's consumer choice tracked by consumer choice page the will still see non-personalized third parties nai's website and/or the ads on our site. Third party our sites advertisers can you'll never miss the bun portobello caps are stuffed with spinach leeks and goat cheese the mushrooms can be baked. Our privacy policy you can make juicy and tender pork chops with very little fuss read more this easy baked salmon recipe takes about 30.
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Can install the daa's appchoices app information about your privacy with third party advertisers who may use tracking choices in for advertising. Activity you mobile app avoid personalized advertising based them basic ingredients basic ingredients mushrooms have a high water content to begin with soaking. Join the bbc good food magazine and get triple-tested recipes delivered to your door every month new research says the healthiest way to cook.
This simple spaghetti recipe read more say goodbye to dry and flavorless pork chops with a creamy ricotta cheese and white-wine sauce this simple. The flavor without weighing you down mushrooms and eggs are a classic flavor combination get the damp paper towel or soft brush to remove any dirt or grit then trim. On sky channel 133 bt 313 and find their recipes at goodfoodchannel.co.uk join the bon appétit for this batch we season with salt and pepper stir in butter.
Like a deconstructed chicken and dumplings but with crispier bits to clean mushrooms use a slightly damp paper towel brush all dirt. The second side when both sides are brown and the mushrooms have shrunk in size add a little flavor salt and any other seasoning you love for this. Bt 313 at goodfoodchannel.co.uk to our sauteed mushroom recipe our method ensures your mushrooms are sauteed perfectly without becoming soggy serve sauteed mushrooms over polenta or steak or toss with.
Their recipes channel 133 let them are not caramelising any juices you can however add flavour by smearing mushrooms with garlic butter coating them in olive oil with.


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Have You Heard God Whisper?
Have you ever heard God whisper?
I normally have some noise going on in my life. It might be something
like music when I sit down to write. From November 1 until December 25, Christmas music was my poison of choice.
When I drive to work, or pretty much anywhere else, I have sports talk on the radio. I listen to folks talk about my particular college team of choice on the way to work and on the way home.
I bet you do too. Not necessarily listen to the same radio station that I listen to or the same musical choices. But I bet that you have similar background noise.
So, how do you hear God whisper?
You have to turn the noise off sometimes.
Sometimes the Lord is loud. I hear Him speak in sermons and songs. I had heard Him speak in graffiti and Godspell. He has spoken as I've watched folks dance for the Lord.
Yet, when I want to hear Him speak intimately just to me, I have to turn the sound down. Those things He tends to say softly.
I had a spell the other day. That's the only way I know to describe it. I was praying. You know, just normal praying. It felt, though, like I was just going through the motions. I began to beg and plead with the Lord that He would reply. I wanted to know that my prayer was not in vain.
I didn't hear a booming voice. His finger didn't appear to write anything on the wall. No angels appeared to bring a message from the throne room.
I got a whisper. It was much like how a parent talks to a newborn when they rock them. Just a whisper. Nothing really audible. No incredible words that would give me a direction to go that day.
Just that whisper.
It was a enough, though. It broke through what had been tough sledding of late.
How did I respond?
I wept. I was overcome by the presence of the Lord. It was unlike anything I have experienced before.
None of that makes me special. I don't mention this to brag. I only say it for one reason.
Find time to turn something off. Get alone.
Listen for God's whisper.
Have you heard God whisper lately?


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Crouton Crushed Chicken Tenders with Orange Barbecue Sauce
Chicken is so wonderful! Grill it, bake it, fry it, sauté it, marinate it, shred it, I love it! This recipe is no exception, kids or no kids, chicken tenders are BOMB! The flavor and texture that is achieved from the garlic butter croutons and Panko bread crumbs is scrumptious. Then dipping this crispy tender juicy morsel of chicken into the sweet tangy smokey orange barbecue sauce is to die for! The recipe below calls for baking the chicken which I'm sure is still good and maybe a bit more healthy. But, we don't always do what were supposed to do, sometimes a little bad is a lot a good. Anyway, its just a pan fry with a little oil, not too bad. Anyway, makes for a great meal for yourself, the kids or even an appetizer tray for hosting. It's very easy, very quick and perfect for a weeknight meal, it's EJlicious! Thank you for reading. Enjoy.
- 1 (6-ounce) bag garlic and butter croutons
- 1/2 cup all-purpose flour
- 1 teaspoon poultry seasoning
- Kosher salt and freshly ground black pepper
- 1 egg
- 1/2 cup buttermilk
- 1/3 cup Italian Panko bread crumbs
- 1 1/2 pounds chicken tenders
Orange Barbeque Sauce:
- 1/3 cup barbeque sauce
- 2 tablespoons orange marmalade
- 1 tablespoon apple cider vinegar
- 1 teaspoon hot sauce (I like Franks)
Preheat the oven to 375 degrees F.
Cut the corner off of the bag croutons just enough to let the air escape. Place the bag onto a cutting board, cover with a kitchen towel and smash it with a rolling pin. Crush the croutons until coarse in texture.
Set up a breading station with 3 pie plates or baking dishes. In 1 dish add the flour, and season it with poultry seasoning, and a generous pinch of salt and pepper. In the second dish mix together the egg and buttermilk. In the third dish add the crushed croutons, and the bread crumbs.
Dip chicken tenders into the flour and shake of any excess. Then dip them into the buttermilk, and then into the bread crumb mixture making sure to thoroughly coat the tenders. Put the tenders on a baking sheet and bake for 10 to 12 minutes.
Transfer to a platter and serve with the orange barbeque sauce.
Orange Barbecue Dipping Sauce: Add all of the ingredients to a small bowl, and whisk together until well combined.
Recipe courtesy of Sandra Lee


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Like zeh said, I was sleeping… But what a wonderful thing to wake up to this morning: Virtuous Flame and Coldbird's Homebrew Enabler! This HEN release is for users left in the dark at firmware 6.31 or 6.35. Now you too can enjoy the fun that is PSP Hacks!
HEN for 6.31 / 6.35 Installation
1. Download and unzip the appropriate HEN version for your PSP firmware below
2. Download and unzip Half Byte Loader R112 for Minna no Sukkiri
* Copy the "hbl" directory and the "h.bin" file to the root of your device
3. Download and unzip the Minna no Sukkiri PSP Demo
* Unzip UCJS10094.zip (the SAVEDATA exploit) and copy to PSP/SAVEDATA
4. Replace HBL's "hbl/menu/EBOOT.PBP" with the appropriate HEN version
5. Start up Minna no Sukkiri and enjoy!
Free download on link below:


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Advanced Micro Devices Inc. shares rallied for their best day in nearly three years Wednesday after the chip maker forecast a strong full-year outlook, with much of the momentum coming in the second half of the year.
AMD shares AMD, -2.63% surged 20% to close at $23.09 Wednesday, touching an intraday high of $23.13, after the company's full-year outlook made up for weakness in its holiday-quarter sales and first-quarter forecast late Tuesday.
The stock logged its largest one-day percentage gain since April 22, 2016, when it surged 52%, and its highest close since Dec. 3, 2018, when it finished at $23.71, according to FactSet data. The S&P 500 SPX, -0.90% closed up 1.6%, the tech-heavy Nasdaq Composite Index COMP, -0.93% finished up 2.2%, and the PHLX Semiconductor Index SOX, -1.10% advanced 2.9%.
Shares took off in after-hours activity late Tuesday and never looked back after AMD forecast "high single-digit percentage revenue growth" for 2019 "driven by Ryzen, Epyc and Radeon data-center GPU product sales as the company ramps 7nm products throughout the year." Analysts had forecast 2019 revenue of $6.89 billion, or 6.3% higher than AMD's reported 2018 revenue of $6.48 billion.
More: AMD has won Wall Street's trust, and its stock is showing the results
"7nm," stands for 7 nanometers, which refers to how small a chip maker can make the transistors that go on a semiconductor, with the general rule being that smaller transistors are faster and more efficient in using power. AMD's new line of 7nm chips is expected to give the company a technological advantage over Intel Corp. INTC, +8.13% for the first time in a decade. Intel has struggled with delays in rolling out its new 10nm chips and recently reported a revenue miss and a weaker-than-expected outlook for the first quarter.
AMD's outlook appears even bolder when one considers the company forecast a weak first quarter, with the company expecting revenue of $1.2 billion to $1.3 billion, about 24% lower than a year ago, while analysts were looking for revenue of $1.65 billion.
"As we go into Q2 and beyond, we see a significant opportunity with the ramp of our new products, and that's how we see the year," AMD Chief Executive Lisa Su said on Tuesday's analysts call, where practically every analyst was looking for more color on the 2019 outlook.
Leading up to AMD earnings, rival Nvidia Corp. NVDA, -0.94% cut its revenue outlook for the recent holiday quarter by $500 million Monday, its second outlook cut for the quarter in less than three months, because of weakness in China and a poor initial adoption of its new line of gaming cards, prompting investors to fear the worst about AMD's report.
Don't miss: The 'dangerous' game investors are playing in this wild earnings season
Bernstein analyst Stacy Rasgon, who has a market perform rating and a $16 price target, called the full-year outlook "extremely optimistic" in a Wednesday morning note.
Rasgon said "with the company looking for a sizable 2H rebound and solid high single digit YoY growth" that gives "something for the bulls to easily grasp onto, coupled with clear evidence that the new core businesses are indeed ramping well."
"But there is fodder for the bears as well, as the controversy will now undoubtedly hinge upon the achievability of that full-year guide, which requires a back-half ramp that would make Evel Knievel nervous," Rasgon said.
Cowen analyst Matthew Ramsay, who has an outperform rating, raised his price target to $28 from $26 and conceded there's "a lot to prove to hit the 2H19 implied guidance."
In a note, Ramsay said "management's full-year outlook for high-single-digits growth demonstrates confidence in 7nm product share gains, with the FY19 outlook implying >50% Y/Y growth in 2H19 over 1H19."
See also: AMD has been the most volatile stock of 2019
On the other hand, Mizuho analyst Vijay Rakesh, who has a buy rating, lowered his price target to $28 from $30, said AMD's report was better than feared and that the company appears to have a more solid 2019 in store compared with its peers.
"While the cat was out of the bag with the Nvidia pre-announcement, the AMD guide was much better than concerns with the stock down ~12% ahead of earnings," Rakesh wrote, adding that while near-term GPU sales were an overhang, he remained a buyer of the stock given AMD's increasing market share, gross margins and the release of new chips ahead of Intel.
After AMD saw a 200% rally in 2018, when the average price target was at a peak $24.93, there was thoughts that Wednesday's gains were the result of a short squeeze, but an analyst said that was not the case.
"Although AMD's shares shorted has been declining since late December, today's price move is not due to a short squeeze, I am not seeing a massive amount of short covering today, and in fact, am seeing offsetting shorting and covering activity which is having a market neutral effect on AMD's stock price," said Ihor Dusaniwsky, head of predictive analytics at financial technology and analytics firm S3 Partners, in emailed comments.
"What we are seeing is long buying driving AMD's stock price up, not short covering activity," Dusaniwsky said.
Read: Semiconductor stocks are hot — here are the winners, losers and analyst favorites
Of the 36 analysts who cover AMD, 14 have buy or overweight ratings, 16 have hold ratings and six have sell or underweight ratings. After the report, five analysts lowered their price targets while four raised theirs, resulting in an average price target of $22.73, up slightly from the $22.47 average before the report, according to FactSet.
For the year, AMD shares are up nearly 21%, compared with a 1.1% gain for Nvidia shares, a 2.9% gain for Intel shares, and a 10.1% rise in the SOX index.