Cancer-killing virus alerts immune system

A new UC San Francisco study has shown that a cancer-killing ("oncolytic") virus currently in clinical trials may function as a cancer vaccine-in addition to killing some cancer cells directly, the virus alerts the immune system to the presence of a tumor, triggering a powerful, widespread immune response that kills cancer cells far outside the virus-infected region.

Using novel approaches to examine exactly how oncolytic viruses attack tumors, issue of Cancer Research provided surprising insights about how a viral infection can cooperate with the immune system to attack cancer cells. The study highlights an opportunity to combine this form of therapy with cancer immunotherapy drugs such as checkpoint inhibitors, which unleash the immune system's full cancer-fighting power.

The idea that viruses could fight cancer goes back to the early 20th century, when doctors noted that cancer patients sometimes experienced dramatic remission after getting viral infections. Researchers have been developing oncolytic viruses since the 1980s, but following the U.S. Food and Drug Administration's 2015 approval of Amgen's Imlygic (T-Vec) as the first oncolytic viral therapy in the U.S., such viruses have become a closely watched area of therapeutic development.

Viruses appear capable of attacking tumors in a number of different ways by directly infecting them, by releasing tumor proteins that trigger a broad immune response against the cancer, and by damaging the blood supply tumors need to survive. To better understand the underlying mechanisms of these viral therapies, a collaboration was forged between UCSF vascular researcher Donald McDonald, MD, Ph.D., and researchers at San Francisco-based biotech SillaJen Biotherapeutics Inc. (formerly Jennerex Biotherapeutics, Inc.)

SillaJen is developing an oncolytic viral therapy called Pexa-Vec, currently in phase III and phase Ib/II clinical trials for use against primary liver and colorectal cancers, respectively. Pexa-Vec is an engineered virus based on the harmless vaccinia cowpox virus, also the basis for the original smallpox vaccine. Early observations suggesting that the virus might attack cancer in part by damaging blood vessels that feed tumor growth.

To study how the modified virus attacks tumors, researchers in the McDonald lab injected it intravenously into mice genetically modified to develop neuroendocrine pancreatic cancer. They found that the virus failed to infect healthy organs or make the animals ill, but succeeded in infecting blood vessels within tumors. These initial infections caused the vessels to leak and expose the tumor cells to the virus. In these experiments, the virus managed to infect and destroy only a small proportion of tumor cells directly, the researchers found, but within five days of the initial infection, the rest of the tumor began to be killed by a powerful immune reaction.

At first small spots of the tumor were infected, but then most of the tumor started to die. The researchers found that by killing some tumor cells directly, the viral infection exposed tumor proteins that could be detected by the immune system, triggering an immune attack on the rest of the tumor. The researchers demonstrated this by temporarily getting rid of the immune system's cancer-killing cells, called CD8+ or cytotoxic T cells, and showing that without these cells, the virus killed only the initial five percent of cancer cells.

When the researchers examined the tumors, they discovered that the second drug acted by making the immune system hyper-alert to tumor proteins released by the viral infection, rather than through effects on tumor blood vessels. This finding suggests that pairing Pexa-Vec's ability to awaken the immune system to previously ignored signs of cancer with the newest generation of checkpoint inhibitors, which act by unleashing the immune system's full force, might be an extremely potent combination therapy.
           haleplushearty.blogspot.com

Molecular magnet could improve cancer immunotherapy

According to new research in cell, chemicals that attract specialised immune cells toward tumours could be used to develop better immunotherapies for cancer patients Scientists at the Francis Crick Institute have discovered that immune cells called Natural Killer cells accumulate in tumours and release chemicals that attract specialised dendritic cells (cDC1)-white blood cells known for triggering anti-cancer immune responses to the tumour.

Genes associated with Natural Killer cells and cDC1 correlated with cancer patient survival in a dataset of over 2,500 patients with skin, breast, neck and lung cancers. A similar correlation was seen in an independent group of breast cancer patients, with a particularly positive outcome for women with triple negative breast cancer, which typically has a poor prognosis. The findings have given a renewed appreciation of the importance of Natural Killer cells and cDC1 in the immune response against cancer.

The team showed that prostaglandin E2 (PGE2), a molecule produced by some cancer cells, suppresses Natural Killer cell activity and reduces the responsiveness of cDC1 to the chemical attractants. This suggests that blocking PGE2 with aspirin might help boost the effectiveness of immunotherapies by restoring cDC1 levels in tumours. The research reveals more about the way the body's immune system interacts with cancer, exposing one way in which cancer can avoid attack. It highlight the complexity of this relationship and reveal another way in which the immune system can be harnessed to treat cancer.
           haleplushearty.blogspot.com

HIV vaccine production

Research on HIV over the past decade has led to many promising ideas for vaccines to prevent infection by the AIDS virus, but very few candidate vaccines have been tested in clinical trials. One reason for this is the technical difficulty of manufacturing vaccines based on the envelope proteins of the virus, according to Phil Berman, who led development of a major component of the only vaccine to have shown any efficacy against HIV in a clinical trial.

Berman, the Baskin Professor of Biomolecular Engineering at UC Santa Cruz, has now developed new methods for the production of HIV vaccines. His approach solves major technical problems which have bedeviled the field. Berman described the new methods, and the candidate vaccines his lab has produced.

Researcher was able to use robotics to shorten the time required to produce stable cell lines, needed to make the proteins for a vaccine, while at the same time greatly increasing how much of the protein the cell lines can produce. The improved yield makes it possible to reduce the size of the bioreactor needed to make vaccine for large clinical trials—from 200- to 10,000-liter vessels to 50- or 100-liter vessels—resulting in tremendous savings in the equipment required and cost of materials.

They were  able to create cell lines that make HIV envelope proteins with the right kind of carbohydrate components (called glycans) needed for an effective immune response. The carbohydrates attached to the protein are really important, something no one realized until recently. The conventional way of making these envelope protein vaccines incorporated the wrong kind of carbohydrates.

Cell lines derived from Chinese hamster ovary (CHO) cells are the industry standard used to produce complex recombinant proteins for therapeutic use. These cells are also useful for the production of HIV vaccines. The gene for the desired protein is transferred into CHO cells in a process called transfection, and tens of thousands of transfected cells are screened to find the few rare cells that produce large amounts of the protein. The best cell lines are grown in large batches, in a process similar to yeast fermentation for making beer, and the proteins are then isolated and purified.

Berman's lab developed a new robotic method to isolate high-producing cell lines making HIV envelope proteins. This shortened the time required to produce stable cell lines from 18 to 24 months to just 2 or 3 months, while increasing yields by a factor of 100 to 200. Those improvements are in comparison with Berman's previous experience creating the AIDSVAX vaccine, first at Genentech and then at VaxGen.

Fluorescent antibodies were used to label the HIV gp120 protein and identify high-producing cell lines. Credit: Phil Berman, UCSC. AIDSVAX was one component of an experimental vaccine regimen used in a large-scale clinical trial known as RV144, which showed 31 percent efficacy in preventing new HIV infections. The RV144 results showed that protection was correlated with antibodies to a certain segment of an HIV envelope protein called gp120.

 The original AIDSVAX vaccine had the completely wrong type of carbohydrate, and that we might improve the level of protection if we could find a way to make it with the proper type of carbohydrate. They set out to create a cell line that can produce the unusual glycans found on HIV envelope proteins rather than the complex glycans CHO cells normally produce. This was made possible by the powerful new gene editing technology known as CRISPR/Cas9.

 They used CRISPR to create a new cell line they called MGAT CHO, which produces proteins lacking complex glycans containing sialic acid and enriched for the simple "high mannose" type found on HIV envelope proteins. An unexpected benefit of this new cell line was that it enabled a simpler, less expensive process for recovering and purifying the proteins.

Carbohydrates may not be immunogenic, but HIV turns out that the most important antibodies are directed to carbohydrate. It leads to an improved version of the vaccine used in the RV144 trial. Berman's lab currently has two cell lines he said are ready to start producing vaccines on a large scale. He is now looking for partners and funding to bring them into clinical trials. Researchers have continued to use the AIDSVAX vaccine in clinical studies because it has been so hard to make new HIV vaccines.
         haleplushearty.blogspot.com

Gene therapy can destroy HIV infected cells

Through gene therapy, researchers engineered blood-forming stem cells (hematopoietic stem/progenitor cells, or HSPCs) to carry chimeric antigen receptor (CAR) genes to make cells that can detect and destroy HIV-infected cells. These engineered cells not only destroyed the infected cells, they persisted for more than two years, suggesting the potential to create long-term immunity from the virus that causes AIDS.

Antiviral drugs can suppress the amount of HIV in the body to nearly undetectable levels, but only an effective immune response can eradicate the virus. Researchers have been seeking a way to improve the body's ability to combat the virus by engineering blood-forming stem cells to specifically target and kill HIV-infected cells for the life of the individual.

 Although chimeric antigen receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer -- and show promise in treating HIV-1 infection -- the therapy may not impart long-lasting immunity. Researchers, physicians and patients need T cell-based products that can respond to malignant or infected cells that may reappear months or years after treatment.

Because HIV uses CD4 to infect cells, the researchers used a CAR molecule that hijacks the essential interaction between HIV and the cell surface molecule CD4 to make stem cell-derived T-cells target infected cells. When the CD4 on the CAR molecule binds to HIV, other regions of the CAR molecule signal the cell to become activated and kill the HIV infected cell.

The researchers found that, in test animals, modification of the blood-forming stem cells resulted in more than two years of stable production of CAR-expressing cells without any adverse effects. In addition, these cells were widely distributed throughout the lymphoid tissues and gastrointestinal tract, which are major anatomic sites for HIV replication and persistence in infected people. Most important, engineered CAR T-cells showed efficacy in attacking and killing HIV-infected cells.
           haleplushearty.blogspot.com

Effects of circadian rhythms on autoimmune disease

Circadian rhythms are generated by the body clock, allowing human to anticipate and respond to the 24-hour cycle of the planet. Maintaining a good body clock is generally believed to lead to good health for humans, and disrupting the circadian rhythm-or example, working night shifts has been associated with immune diseases such as multiple sclerosis; however, the underlying molecular links have been unclear.

Immune responses and regulation of autoimmunity are affected by the time of the day when the immune response is activated. Using mice as a model organism, they show that a master circadian gene, BMAL1, is responsible for sensing and acting on time-of-the-day cues to suppress inflammation.

Loss of BMAL1, or induction of autoimmunity at midday instead of midnight, causes more severe experimental autoimmune encephalomyelitis, which is essentially an analogue of multiple sclerosis in mice. Immune system is programmed to respond better to infection and insults encountered at different immune in the 24-hour clock.

This has significant implications for the treatment of immune-mediated diseases and suggests there may be important differences in time of day response to drugs used to treat autoimmune diseases such as multiple sclerosis. Disruption of human body clocks, which is quite common now given our 24/7 lifestyle and erratic eating and sleeping patterns, may have an impact on autoimmune conditions.
          haleplushearty.blogspot.com

Hemlibra for treating hemophilia

 The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors. Reducing the frequency or preventing bleeding episodes is an important part of disease management for patients with hemophilia.

Hemophilia A is an inherited blood-clotting disorder that primarily affects males. According to the National Institutes of Health, hemophilia affects one in every 5,000 males born with the condition. Patients with hemophilia A are missing a gene which produces Factor VIII, a protein that enables blood to clot.

Patients may experience repeated episodes of serious bleeding, primarily into their joints, which can be severely damaged as a result. Some patients develop an immune response known as a FVIII inhibitor or antibody. The antibody interferes with the effectiveness of currently available treatments for hemophilia.

Hemlibra is a first-in-class therapy that works by bridging other Factors in the blood to restore blood clotting for these patients. Hemlibra is a preventative (prophylactic) treatment given weekly via injection under the skin (subcutaneous).

Patients treated with Hemlibra reported an improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking) compared to patients who did not receive prophylactic treatment. Common side effects of Hemlibra include injection site reactions, headache, and joint pain (arthralgia).

          haleplushearty.blogspot.com 

IUDs may prevent cervical cancer

IUDs are safe and highly effective contraception method, intrauterine devices (IUDs) may also be quietly offering protection against the third-most common cancer in women worldwide.

The number of women diagnosed with cervical cancer is steadily rising. According to the World Health Organization WHO, approximately 528,000 women were diagnosed with cervical cancer worldwide in 2012, and 266,000 women died from the disease. By 2035, the WHO projects that those numbers will climb to more than 756,000 and 416,000, respectively.

For women in developing countries, where cervical cancer prevention resources such as the human papillomavirus HPV vaccine or regular cervical screenings are scarce, and where populations are increasing rapidly, a contraceptive that offers protection against cervical cancer could have a profound effect.

IUDs could be a tool to combat cervical cancer. Some scientists speculate that the placement of an IUD stimulates an immune response in the cervix, giving the body an opportunity to fight an existing HPV infection that could lead to cervical cancer. Another possibility is that when an IUD is removed, some cervical cells that contain HPV infection or precancerous changes may be scraped off. The body mounts an immune response to having an IUD placed.
           haleplushearty.blogspot.com

Strong persistence of viral infection

Infections caused by viruses, such as respiratory syncytial virus, measles, parainfluenza and Ebola, are acute. These viruses cause disease quickly and live within a host for a limited time. But in some cases the effects of the infection, and presence of the virus can lead to chronic problems.

Viral infection leads to defective viral genomes, DVG which involved in triggering an immune response, can also kick off a molecular pathway that keeps infected cells alive. The study used a novel technique to examine the presence of DVGs on a cell-by-cell basis to show that DVG-enriched cells had strategies to survive during an immune-system attack.

Partial viral genomes are produced in infected cells when a virus begins to replicate rapidly, leading to defective versions that contain large deletions. DVGs are increasingly believed to be important components of viral infections.

DVGs are critical in stimulating an immune response to respiratory viruses, they are also critical for stimulating an immune response to the human virus RSV, the presence of DVGs in human respiratory samples from infected patients correlates with enhanced antiviral immune responses.

Researchers used a sophisticated technique that allowed them to differentiate full-length genomes from the partial genomes of DVGs at the single-cell level. They studied cells in culture infected with the Sendai virus, or with RSV, a virus that often affects infants and can lead to chronic respiratory problems.

To dig deeper into how the DVGs were influencing the course of infection, the researchers infected cells either with a version of the Sendai virus that lacked DVGs or one enriched in DVGs. The cells infected with the virus high in DVGs survived more than twice as long as those infected with virus lacking DVGs.

 Adding purified DVGs boosted the cells' survival time, indicating a direct role for the DVGs in promoting cell survival.
The results were similar in parallel experiments with RSV, suggesting that the pro-survival role of DVGs held across viral types.

The researchers next were curious to know what molecular pathways might enable the DVG-rich cells to avoid apoptosis. An analysis of highly-expressed genes in DVG-enriched cells compared to the cells with full-length viral genomes revealed that a host of pro-survival genes were activated in the DVG-rich cells.
         haleplushearty.blogspot.com

DNA - based Zika vaccine is safe

Zika virus is a mosquito-borne infection associated with birth defects and neurological complications in adults. However, no approved vaccine or treatment is currently available for treatment of Zika virus. A new generation DNA-based Zika vaccine demonstrated both safety and ability to elicit an immune response against Zika in humans in a phase 1 clinical trial.

Synthetic DNA vaccines are an ideal approach for infectious diseases like Zika, this new generation of DNA vaccines can be designed and manufactured rapidly, they appear to be highly predictable for the generation of immunity in humans, having significant conceptual safety advantages, and they are more stable than some of the traditional vaccines, making them exceptionally practical to distribute during outbreaks, especially in regions where resources are limited.

The GLS-5700 vaccine contains the synthetic DNA instructions for the host to learn how to mount an immune response against a specific Zika virus antigen. Researchers enrolled some participants in the safety trial, two groups of different participants received two different doses of the vaccine candidate intradermally at zero, four, and 12 weeks.

 Each dosage was followed by Cellectra delivery which generates small, directional electric currents into the skin to facilitate optimal vaccine uptake, production of the intended antigen, and immune responses. Results showed that two weeks after the final dose 100 percent of study participants developed Zika-specific antibodies and 80 percent developed significant neutralizing antibodies against the virus.

Serum from the study participants was able to protect immunocompromised mice from developing the disease after infection with Zika virus, showing that the vaccine-induced antibodies can prevent infection in living organism. Result of this research showed that DNA vaccine can produce an immune response against the virus with minimal adverse effects.
          haleplushearty.blogspot.com

Vitamin D prevents asthma attack

Taking oral vitamin D supplements in addition to standard asthma medication could reduce the risk of asthma attacks requiring hospital attendance.
Asthma affects more than 300 million people worldwide and is estimated to cause almost 400,000 deaths annually.

Asthma deaths arise primarily during episodes of acute worsening of symptoms, known as attacks which are commonly triggered by viral upper respiratory infections. Vitamin D is thought to protect against such attacks by boosting immune responses to respiratory viruses and dampening down harmful airway inflammation.

Researchers analysed data from many participants in seven randomised controlled trials, which tested the use of vitamin D supplements. They discovered that vitamin D supplementation resulted in:
a 30 per cent reduction in the rate of asthma attacks requiring treatment with steroid tablets or injections - from 0.43 events per person per year to 0.30.
a 50 per cent reduction in the risk of experiencing at least one asthma attack.

Vitamin D supplementation was found to be safe at the doses administered. No instances of excessively high calcium levels or renal stones were seen, and serious adverse events were evenly distributed between participants taking vitamin D and those on placebo.
          haleplushearty.blogspot.com

Potential Zika vaccine prevents pregnancy transmission and testicular damage

Zika infection typically results in mild or symptom-free infections in healthy individuals, infected pregnant women without symptoms may still give birth to a baby with birth defects like microcephaly.

Researchers has shown that a potential Zika vaccine can protect fetuses against infection and  protect males against testicular infection and injury. It also prevents a lowered sperm count after one vaccination.

Infected men without any signs of illness may still incur testicular injury and lowered sperm count. The Zika virus could infect the male reproductive system for several months, posing risk for sexual transmission.

Taking a single-dose vaccine could prevent Zika infection in non-human primates, prevent mother-to-fetus transmission, and stop male testis infection in mice. The vaccine provides a protective immune response, this vaccine exhibited an excellent safety profile in mouse and non-human primate models.
          haleplushearty.blogspot.com

Steroid hormone and age related bone loss

A group of steroid hormones could provide new insight into the bone loss and deterioration that occurs with aging, protein histone deacetylase 3, HDAC3, turns off the genes that encourage the stem cells in our bone marrow to make and store fat instead of making bone. As HDAC3 levels decrease naturally with age, bones become less dense and easily breakable.

 Looking at a group of steroid hormones known as glucocorticoids, which our bodies naturally have in circulation as a response to different stresses to help quiet the immune response, when these hormones enter bone cells, osteoblasts that make bone bind to a receptor that activates the expression of genes related to fat storage.

To get that effect of bone loss and increased marrow fat when you lose HDAC3, glucocorticoids must be present. Releasing glucocorticoids in response to various stimuli is a natural thing that body does, circulating glucocorticoid levels increase with age.

As with a lot of chemicals in the body, too much and not enough of something can be bad. While glucocorticoids occur naturally in the body, they are also used in various immune-suppressive therapies, many of which have osteoporosis as a side effect.

Researchers studied mice without receptors for the steroid hormones. The mice were placed on a calorie-restricted diet to stimulate the aging process which also has been shown to result in lower bone density and increased marrow fat. Extreme caloric restriction, such as with anorexia nervosa, can also lead to weak and brittle bones.

When looking at the bone cells in a culture dish, the receptor deficient mice show less lipid storage than regular mouse models of aging. They also showed more bone matrix, which is the cause of bone formation. Examination of tibia and femur in a living animal showed the receptor deficient mice actually had more marrow fat and lower bone mass.
          haleplushearty.blogspot.com

Immune and nerve cells fight gut infections

Nerve cells in the gut play a crucial role in the body's ability to produce an immune response to infection. The immune system and nervous system worked together to respond to infectious threats.

The immune system and neuronal system don't act independently,
The lining of the gut house many immune system cells, which serve as a defense against parasites and other infections.

It is also loaded with nerve cells, immune system cells in the gut, called group 2 innate lymphoid cells (ILC2s), are intertwined with nerve cells called cholinergic neurons.

The ILC2 cells have a receptor for a protein called neuromedin U (NMU), which acts as a messenger for the nerve cells. Exposing ILC2 cells to NMU causes the ILC2 cells to multiply rapidly and secrete chemicals called cytokines that may help trigger an immune response or cause inflammation.

Administering NMU to mice infected with a gut parasite triggered inflammation and a powerful
immune response that expel the parasites quickly.

This shows that the NMU-producing nerve cells help the ILC2 cells, enabling them to rapidly and effectively respond to infection. The findings may improve fighting and provision of therapies for inflammatory diseases like asthma, food allergies and inflammatory bowel diseases.
          haleplushearty.blogspot.com

Improved, safer Zika vaccine

Scientists have come up with better plant-based Zika vaccine that is more potent, safer and cheaper. It's based on key Zika protein. The vaccine works against a part of a Zika viral protein, called DIII, the part of the virus that infect people.

All flaviviruses have the envelope protein on the outside part of the virus. It has three domains. The domain III has a unique stretch of DNA for the Zika virus, this is used to generate a protective immune response that is unique for Zika.

Scientists carried out immunization experiments in mice, which induced antibody and cellular immune responses that have been shown to confer 100 percent protection against multiple Zika virus strains in a mouse.

The envelope protein were grew in bacteria, then switched to prepare the DIII protein domain in tobacco plants.
Producing plant-based vaccines, especially in tobacco plants, is safer than using chemical-based.

The protein-based vaccine uses the smallest and most unique part of the Zika virus that can still draw out a potent and good immune response.

Scientists made a pseudovirus- fake virus. The pseudovirus displays only the DIII part of the envelope protein on the surface. Making the full native envelope protein as the basis for a vaccine, it induced antibodies against DI, DII and the DIII domains of the protein.

Women were advised not to become pregnant because Zika virus can cause abnormalities in babies. It can cause
severe brain defect known as microcephaly, in which the head and brain don't develop properly.

It can also cause vision, hearing defects and learning disabilities associated with less severe infections. Gullian-Barre syndrome in adults  has also been linked to Zika virus.
            haleplushearty.blogspot.com

Cancer cells suppress the immune system

Human immune systems prevents different diseases including cancer, for cancer to spread and multiply, they must find a way to avoid the body's immune system.

Degenerated cells in the body cause an inflammatory reaction and influence other blood cells to the extent that the immune system is suppressed.

Tumor cells influence their environment in order to avoid an immune response and to facilitate their growth. Solid tumors manipulate macrophages of the immune system.

The relationship between leukemia cells and monocytes becomes a catalyst for cancer development. Programmed death-ligand 1PD-L1 also known as cluster receptor occurs more frequently on the surface of these nourishing cells, and suppresses the immune response for cancer to grow.

The immune response is suppressed so much that the cancer cells can multiply without any hindrance. The monocytes send out semiochemicals, which belong to the inflammation response of the immune system and support the growth and multiplication of the cancer cells.

Scientists treated monocytes and macrophages of humans and mice with suspect exosomes, as well as purified Y RNA from those exosomes, in a culture dish. In both cases, the cells changed similarly to how they would in chronic lymphatic leukemia CLL patients.

They carry more PD-L1 receptors to their surface and emit semiochemicals that accelerate the immune response and create favorable growth conditions for leukemia cells.

Adding Toll-like receptors TLR inhibitors such as Chloroquin, a medication used for malaria and rheumatic inflammation can inhibit YRNA.

CLL cells was able to suppress the reproduction of cancer cells markedly.
This makes Chloroquin a good substance for a combination therapy along with other agents for cancer treatment.
         haleplushearty.blogspot.com

How your brain detects diseases in others

Human sense of vision and smell can detect a disease before it breaks out, and make us avoid sick people.

Researchers injected harmless bacteria on participants and activated the immune response in another participants, who developed the classic symptoms of disease.

Symptoms like tiredness, pain and fever for a few hours, they were photographed and filmed. The injected substance and symptoms then disappeared from their bodies.

Another group of participants were exposed to the images and asked to rate how much they liked the people, while their brain activities were measured in an MR scanner.

They were  asked to look at the photographs and identify sick and healthy participants.

The result shows that brain is good at picking weak signals from multiple senses relating to a person's state of health. Avoidance does not apply if
you have close relationship with the sick person.