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Showing posts with label Biology. Show all posts
Showing posts with label Biology. Show all posts

Saturday, 30 May 2020

Cells Inside Cells: The Bacteria That Live in Cancer Cells


Cancer cells are comfy havens for bacteria. That conclusion arises from a rigorous study of over 1,000 tumor samples of different human cancers. The study, headed by researchers at the Weizmann Institute of Science, found bacteria living inside the cells of all the cancer types – from brain to bone to breast cancer – and even identified unique populations of bacteria residing in each type of cancer. The research suggests that understanding the relationship between a cancer cell and its “mini-microbiome” may help predict the potential effectiveness of certain treatments or may point, in the future, to ways of manipulating those bacteria to enhance the actions of anticancer treatments.

Dr. Ravid Straussman of the Institute’s Molecular Cell Biology Department had, several years ago, discovered bacteria lurking within human pancreatic tumor cells; these bacteria were shown to protect cancer cells from chemotherapy drugs by “digesting” and inactivating these drugs. When other studies also found bacteria in tumor cells, Straussman and his team wondered whether such hosting might be the rule, rather than the exception. To find out, Drs. Deborah Nejman and Ilana Livyatan in Straussman’s group and Dr. Garold Fuks of the Physics of Complex Systems Department worked together with a team of oncologists and researchers around the world. The work was also led by Dr. Noam Shental of the Mathematics and Computer Science Department of the Open University of Israel.



Ultimately, the team would produce a detailed study describing, in high resolution, the bacteria living in these cancers – brain, bone, breast, lung, ovary, pancreas, colorectal and melanoma. They discovered that every single cancer type, from brain to bone, harbored bacteria and that different cancer types harbor different bacteria species. It was the breast cancers, however, that had the largest number and diversity of bacteria. The team demonstrated that many more bacteria can be found in breast tumors compared to the normal breast tissue surrounding these tumors, and that some bacteria were preferentially found in the tumor tissue rather than in the normal tissue surrounding it.

To arrive at these results, the team had to overcome several challenges. For one, the mass of bacteria in a tumor sample is relatively small, and the researchers had to find ways to focus on these tiny cells-within-cells. They also had to eliminate any possible outside contamination. To this end they used hundreds of negative controls and created a series of computational filters to remove the traces of any bacteria that could have come from outside the tumor samples.

The team was able to grow bacteria directly from human breast tumors, and their results proved that the bacteria found in these tumors are alive. Electron microscopy visualization of these bacteria demonstrated that they prefer to nestle up in a specific location inside the cancer cells – close to the cell nucleus.

This electron microscope image reveals the bacteria living in a tumor cell


Different cells for different bacteria

The team also reported that bacteria can be found not only in cancer cells, but also in immune cells that reside inside tumors. “Some of these bacteria could be enhancing the anticancer immune response, while others could be suppressing it – a finding that may be especially relevant to understanding the effectiveness of certain immunotherapies,” says Straussman. Indeed, when the team compared the bacteria from groups of melanoma samples, they found that different bacteria were enriched in those melanoma tumors that responded to immunotherapy as compared to those that had a poor response.

Straussman thinks that the study can also begin to explain why some bacteria like cancer cells and why each cancer has its own typical microbiome: The differences apparently come down to the choice of amenities offered in each kind of tumor-cell environment. That is, the bacteria may live off certain metabolites that are overproduced by or stored within the specific tumor types. For example, when the team compared the bacteria found in lung tumors from smokers with those from patients who had never smoked, they found variances. These differences stood out more clearly when the researchers compared the genes of these two groups of bacteria: Those from the smokers’ lung cancer cells had many more genes for metabolizing nicotine, toluene, phenol and other chemicals that are found in cigarette smoke.

In addition to showing that some of the most common cancers shelter unique populations of bacteria within their cells, the researchers believe that the methods they have developed to identify signature microbiomes with each cancer type can now be used to answer some crucial questions about the roles these bacteria play: Are the bacteria freeloaders on the cancer cell’s surplus metabolites, or do they provide a service to the cell? At what stage do they take up residence? How do they promote or hinder the cancer’s growth? What are the effects that they have on response to a wide variety of anticancer treatments?



“Tumors are complex ecosystems that are known to contain, in addition to cancer cells, immune cells, stromal cells, blood vessels, nerves, and many more components, all part of what we refer to as the tumor microenvironment. Our studies, as well as studies by other labs, clearly demonstrate that bacteria are also an integral part of the tumor microenvironment. We hope that by finding out how exactly they fit into the general tumor ecology, we can figure out novel ways of treating cancer,” Straussman says.


Bibliography:

Nejman, D., Livyatan, I., Fuks, G., Gavert, N., Zwang, Y., Geller, L. T., . . . Straussman, R. (2020).

The human tumor microbiome is composed of tumor type–specific intracellular bacteria.

Science, 368(6494), 973-980.

doi: 10.1126/science.aay9189

Friday, 29 May 2020

Exploiting viruses to attack cancer cells


An adenovirus is now better able to target and kill cancer cells due to the addition of an RNA stabilizing element.

Hokkaido University scientists have made an adenovirus that specifically replicates inside and kills cancer cells by employing special RNA-stabilizing elements. The details of the research were published in the journal Cancers.

Much research in recent years has investigated genetically modifying adenoviruses to kill cancers, with some currently being tested in clinical trials. When injected, these adenoviruses replicate inside cancer cells and kill them. Scientists are trying to design more efficient viruses, which are better able to target cancer cells while leaving normal cells alone.



Hokkaido University molecular oncologist Fumihiro Higashino led a team of scientists to make two new adenoviruses that specifically target cancer cells. To do this, they used ‘adenylate-uridylate-rich elements’ (AREs), which are signals in RNA molecules known to enhance the rapid decay of messenger RNAs (mRNAs) in human cells. “AREs make sure that mRNAs don’t continue to code for proteins unnecessarily in cells,” explains Higashino. “Genes required for cell growth and proliferation tend to have AREs.”

Under certain stress conditions, however, ARE-containing mRNAs can become temporarily stabilized allowing the maintenance of some necessary cell processes. ARE-mRNAs are also stabilized in cancer cells, supporting their continuous proliferation.

Higashino and his team inserted AREs from two human genes into an adenovirus replicating gene, making the new adenoviruses: AdARET and AdAREF. “The idea behind the insertion is that the AREs will stabilize the killer adenoviruses, allowing them to replicate only inside cancer cells but not in normal healthy ones,” says Higashino.

Indeed, AdARET and AdAREF were both found to replicate inside and kill cancer cells in the laboratory, while they hardly affected normal cells. Tests confirmed that the specific replication in cancer cells was due to stabilization of the viral genes with AREs, which did not happen in the healthy cells.

The AdARET killed cancer cells (A549, H1299, and C33A) in a dose-dependent manner while normal cells (BJ and WI38) were largely unaffected particularly with small doses of AdARET. Living cells were stained blue. MOI indicates the number of virus particles per cell. (Yohei Mikawa et al., Cancers, May 11, 2020)

The scientists then injected human cancer cells under the skin of nude mice, which then developed into tumors. When AdARET and AdAREF were injected into the tumors, they resulted in a significant reduction in tumor size.

This wasn’t the first time for the team to test the use of AREs in adenoviruses. In a previous study, another scientist used an ARE belonging to a different gene and found this adenovirus worked specifically in cancers containing a mutation in a gene called RAS. AdARET and AdAREF, on the other hand, were found to be effective against cancer cells without a mutated RAS gene, making the viruses applicable to a wider range of cancer cells.



“Since ARE-mRNA stability has also been reported in diseases other than cancer, we think the viruses we engineered could also have potential for treating diseases related to inflammations, viral infection, hypoxia, and ultraviolet irradiation,” says Higashino.


Bibliography:

Yohei Mikawa, Mohammad Towfik Alam, Elora Hossain, Aya Yanagawa-Matsuda, Tetsuya Kitamura, Motoaki Yasuda, Umma Habiba, Ishraque Ahmed, Yoshimasa Kitagawa, Masanobu Shindoh, Fumihiro Higashino.

Conditionally Replicative Adenovirus Controlled by the Stabilization System of AU-Rich Elements Containing mRNA. 

Cancers, 2020; 12 (5): 1205

DOI: 10.3390/cancers12051205

Wednesday, 27 May 2020

Researchers Discover How Protein Can Inhibit Cancer Development in Mice


Proteins are found throughout our cells and regulate a lot of biological processes that are important for our survival. But some of them also regulate processes that can make us sick. Now, an international research team, with researchers from the University of Copenhagen at the forefront, has achieved a much better understanding of one such protein.

In a new study, the researchers discovered how the protein PP2A works at the molecular level, and how it inhibits the development of tumors in mice. The new results have been published in the scientific journal, the EMBO Journal.



“We call PP2A a household protein because it is found almost everywhere. In everything living – from simple yeast cells to complex cells in humans. PP2A removes phosphate groups on other proteins, and now we have found these proteins and how PP2A, via one of these proteins, inhibits cancer development”, says Jakob Nilsson, Professor at the Novo Nordisk Foundation Center for Protein Research.


Turned-off enzyme

According to the researchers, there is a great deal of interest from both the academic research community and from the pharmaceutical industry for the protein PP2A because it is well-known that PP2A is a so-called tumor suppressor that suppresses tumors. But precisely which proteins PP2A regulates in order to inhibit cancer have so far not been known. Now, the researchers have gained detailed insight into this.

“The new thing about our study is that we show how PP2A selects the phosphate groups that shall be removed from other proteins. And then at the same time, we show that PP2A turns off an enzyme named ADAM17. This shutdown of ADAM17 results in inhibition of tumour growth in mice”, explains Associate Professor Marie Kveiborg from the Biotech Research and Innovation Centre.

The researchers have used advanced methods to show that PP2A can turn off the activity of ADAM17 on the outside of the cell by removing phosphate groups from the part of ADAM17 that is located inside the cell.

The researchers' illustration of PP2A binding to ADAM17 whcich cleaves other proteins such as the growth factor EGF which again binds the receptor EGFR and stimulates cell growth.

The function is inhibited

Normally, ADAM17 sits as a pair of molecular scissors in the cell's outer membrane and cleaves other proteins from the cell surface – for example, growth factors that will then stimulate cell growth. But that function ceases when PP2A removes the phosphate groups from ADAM17.

The researchers already knew from previous studies that ADAM17 stimulates a variety of cancers, including breast and bowel cancer. But this is the first time that PP2A has been shown to actively turn off ADAM17 activity.



Going forward, the researchers hope that their new cancer discovery will also apply to human tumors. For now, the next step for the researchers is to clarify whether substances that activate PP2A can be used to regulate ADAM17 activity. In addition, the researchers also want to look at how PP2A regulates other proteins that may be important for the understanding of its tumor suppressor function.


Bibliography:

Kruse et al. (2020). Mechanisms of Site-Specific Dephosphorylation and Kinase Opposition Imposed by PP2A Regulatory Subunits.

The EMBO Journal.

DOI: https://doi.org/10.15252/embj.2019103695

Friday, 22 May 2020

RESEARCHERS MAY HAVE UNCOVERED THE ACHILLES HEEL OF VIRUSES


Viruses have an exceptional ability to circumvent the body's immune system and cause diseases. The majority of people recover from a viral infection such as influenza, although the current COVID-19 pandemic demonstrates how dangerous viruses are when there is no effective vaccine or treatment.

Professor and virologist Søren Riis Paludan from the Department of Biomedicine at Aarhus University, Denmark, has been leading a research partnership between Aarhus University, the University of Oxford and the University of Gothenburg, which has brought us one step closer to understanding the tactics used by viruses when they attack the immune system.



Søren Riis Paludan heads a laboratory which carries out research into the immune system's ability to fight diseases caused by the herpes virus, influenza viruses and, most recently, SARS-CoV2, more commonly known as coronavirus.

In the new study, which has just been published in the scientific journal Journal of Experimental Medicine, the researchers have investigated how the herpes simplex virus circumvents the immune system in order to cause infections of the brain. This is a rare infection but one which has a high mortality rate among those who are affected.

"In the study, we found that the herpes simplex virus is capable of inhibiting a protein in the cells, known as STING, which is activated when there is a threat. When STING is inhibited, the body's immune system is also inhibited - the virus thereby puts the brakes on the body's brake, which is supposed to prevent us from becoming ill. Other viruses also make use of the same principle," says Søren Riis Paludan.

Søren Riis Paludan points out that though the study focuses on herpesviruses, there are parallels to the coronavirus. Interestingly, the same protein is also inhibited by many different viruses, including the coronavirus.

"This suggests that we have found an Achilles heel in the virus and the way it establishes infections in the body. Our results lead us to hope that if we can prevent viruses from blocking STING, then we can prevent the virus from replicating. That could pave the way for new principles for treatment of herpes, influenza and also the coronavirus," says Søren Riis Paludan.



He hopes that the research results can be used in the development of antiviral drugs and vaccines in the future.

"Previous studies have also shown that the coronavirus inhibits STING in the same way as the herpes virus. This suggests that we have found a common denominator for several types of virus, and that this is probably an important element in the development of treatment," he says.



Bibliography:

HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
Chiranjeevi Bodda,

 Line S. Reinert, Stefanie Fruhwürth, Timmy Richardo, Chenglong Sun, Bao-cun Zhang, Maria Kalamvoki, Anja Pohlmann, Trine H. Mogensen, Petra Bergström, Lotta Agholme, Peter O’Hare, Beate Sodeik, Mads Gyrd-Hansen, Henrik Zetterberg, Søren R. Paludan

Exp Med (2020) 217 (7): e20191422. 

DOI: https://doi.org/10.1084/jem.20191422.

Wednesday, 20 May 2020

Researchers have discovered the 'Off-Switch' for Pain in the Brain

A Duke University research team has found a small area of the brain in mice that can profoundly control the animals’ sense of pain.

Somewhat unexpectedly, this brain center turns pain off, not on. It’s also located in an area where few people would have thought to look for an anti-pain center, the amygdala, which is often considered the home of negative emotions and responses, like the fight or flight response and general anxiety.



“People do believe there is a central place to relieve pain, that’s why placebos work,” said senior author Fan Wang, the Morris N. Broad Distinguished Professor of neurobiology in the School of Medicine. “The question is where in the brain is the center that can turn off pain.”

“Most of the previous studies have focused on which regions are turned ON by pain,” Wang said. “But there are so many regions processing pain, you’d have to turn them all off to stop pain. Whereas this one center can turn off the pain by itself.”

The work is a follow-up to earlier research in Wang’s lab looking at neurons that are activated, rather than suppressed, by general anesthetics. In a 2019 study,  they found that general anesthesia promotes slow-wave sleep by activating the supraoptic nucleus of the brain. But sleep and pain are separate, an important clue that led to the new finding, which appears online May 18 in Nature Neuroscience.

Neuron cells in the central amygdala of a mouse brain. Red, magenta and yellow cells (but not green or blue) are parts of a collection of neurons called the CeAga that has potent pain-suppression abilities. (Fan Wang Lab)


The researchers found that general anesthesia also activates a specific subset of inhibitory neurons in the central amygdala, which they have called the CeAga neurons (CeA stands for central amygdala; ga indicates activation by general anesthesia). Mice have a relatively larger central amygdala than humans, but Wang said she had no reason to think we have a different system for controlling pain.

Using technologies that Wang’s lab has pioneered to track the paths of activated neurons in mice, the team found the CeAga was connected to many different areas of the brain, “which was a surprise,” Wang said.

By giving mice a mild pain stimulus, the researchers could map all of the pain-activated brain regions. They discovered that at least 16 brain centers known to process the sensory or emotional aspects of pain were receiving inhibitory input from the CeAga.

“Pain is a complicated brain response,” Wang said. “It involves sensory discrimination, emotion, and autonomic (involuntary nervous system) responses. Treating pain by dampening all of these brain processes in many areas is very difficult to achieve. But activating a key node that naturally sends inhibitory signals to these pain-processing regions would be more robust.”

Using a technology called optogenetics, which uses light to activate a small population of cells in the brain, the researchers found they could turn off the self-caring behaviors a mouse exhibits when it feels uncomfortable by activating the CeAga neurons. Paw-licking or face-wiping behaviors were “completely abolished” the moment the light was switched on to activate the anti-pain center.

“It’s so drastic,” Wang said. “They just instantaneously stop licking and rubbing.”

When the scientists dampened the activity of these CeAga neurons, the mice responded as if a temporary insult had become intense or painful again. They also found that low-dose ketamine, an anesthetic drug that allows sensation but blocks pain, activated the CeAga center and wouldn’t work without it.



Now the researchers are going to look for drugs that can activate only these cells to suppress pain as potential future pain killers, Wang said.

“The other thing we’re trying to do is to (transcriptome) sequence the hell out of these cells,” she said. The researchers are hoping to find the gene for a rare or unique cell surface receptor among these specialized cells that would enable a very specific drug to activate these neurons and relieve pain.


Bibliography:

Thuy Hua, Bin Chen, Dongye Lu, Katsuyasu Sakurai, Shengli Zhao, Bao-Xia Han, Jiwoo Kim, Luping Yin, Yong Chen, Jinghao Lu, Fan Wang.

General anesthetics activate a potent central pain-suppression circuit in the amygdala. 

Nature Neuroscience, 2020;

DOI: 10.1038/s41593-020-0632-8

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