New genes out of nothing

 

One key question in evolutionary biology is how novel genes arise and develop. Swedish researchers now show how new genes and functions that are advantageous to bacteria can be selected from random DNA sequences. The results are presented in the scientific journal mBio.

How do new genes and functional proteins arise and develop? This is one of the most fundamental issues in evolutionary biology. Two different types of mechanism have been proposed: (1) new genes with novel functions arise from existing genes, and (2) new genes and proteins evolve from random DNA sequences with no similarity to existing genes and proteins.

In the present study, the researchers explored the latter type of mechanism: evolution of new genes and proteins from randomised DNA sequences as its called as de novo evolution. It is fairly easy to understand that when a gene already exists, it can be modified and acquire a new function. But how does "nothing" turn into a function affording a small advantage that is favoured by natural selection?

The raw material for the experiment was an big library of some 500 million randomised gene sequences, from which peptide sequences with a biological function were identified. In the experiment, random gene sequences were placed on a plasmid and overexpressed. The scientists then investigated whether they could give bacteria a specific, defined property. Were they, for example, able to give the bacteria antibiotic resistance? They identified several short peptides (22-25 amino acids long) that could give the bacteria a high degree of resistance to aminoglycosides, an important class of antibiotics used for severe infections.

"When the project started, we had low expectations. We were amazed when we found peptides able to confer a resistance level 48 times higher," says Dr Michael Knopp, the study's lead author.

Through a combination of genetic and functional experiments, the scientists were able to demonstrate that the peptides cause resistance by attaching themselves to bacterial cell membranes and affecting the proton potential across the membrane. The disruption of the proton potential causes a decrease in antibiotic uptake, rendering the bacteria resistant.

"This study is important because it shows that completely random sequences of amino acids can give rise to new, advantageous functions, and that this process of de novo evolution can be studied experimentally in the laboratory," says Dan I. Andersson, Professor of Medical Bacteriology, who is chiefly responsible for the study.

An important announcement regarding our upcoming conference 12^th World Congress on Cell & Tissue Science (Cell Tissue Science 2019) scheduled on September 13-14,2019 in Singapore. You can also present your latest research at the different topics such as Cancer Cell Biology, Stem Cell & its applications and many more along with other distinguished professors, doctors and researchers from all over the world.

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Source of the article: https://www.sciencedaily.com/releases/2019/06/190604131214.htm

Maternal programming during pregnancy induces long-term postpartum obesity

During normal pregnancy, mothers always gain body weight within a proper range. However, many women worry that extra pounds put on during pregnancy will not be lost after childbirth and, in fact, past studies have shown that excessive gestational weight gain is associated with immediate postpartum weight retention. But in a new study using a mouse model, researchers at University of California San Diego School of Medicine suggest that long-term postpartum weight gain may be due not so much to retained fat as to reprogramming of maternal energy metabolism.

Writing in the January 8 online issue of the International Journal of Obesity, a team of researchers led by senior author Jianhua Shao, MD, PhD, professor in the Department of Pediatrics at UC San Diego School of Medicine, found that pregnant mice fed a high-fat (HF) diet gained significantly more body fat compared to control mice, but quickly lost the added weight after giving birth.

However, even with a normal diet three months after parturition or giving birth, pregnant mice that received a HF diet during pregnancy began gaining more fat again and nine months after delivery weighed two-fold above levels of control mice due to excess fat mass. Notably, the scientists said the metabolism of mice who were fed a HF diet during pregnancy had slowed, measurably reducing their energy expenditure and thus contributing to fatty weight gain.

"Excessive gestational weight gain increases the risk of long-term postpartum obesity," said Shao, "and our study showed that pregnant mice consuming a high fat diet significantly increased white fat cell gain, which is characteristic in humans too.

"But these mice lost that weight gain soon after giving birth, only to become spontaneously obese a few months later. The data demonstrate that excessive gestational weight gain-induced postpartum obesity is not simply an extension of pregnancy-induced fat gain or fat retention, but rather a fundamental change in maternal metabolism that results in less energy expended and more weight added as the result."

Specifically, Shao and colleagues found that while levels of blood estrogen in mice fed HF during pregnancy and three groups of control mice were similar after giving birth, there was a significant decrease in estrogen signaling in both white and brown adipose tissues in the HF fed group. Their study suggests that the reduction of estrogen signaling gradually develops after pregnancy and giving birth due to the slow adipocyte renewal process. Given that estrogen plays an important role in fat development and energy metabolism, the impairment of estrogen signaling within fat may provide a mechanism for excessive weight gain-induced, long-term postpartum obesity.

The authors underscored that their findings are based on studies of mice and will need to be verified in humans. But if they are, said Shao, it "will lead us to define a new cause of obesity in women after pregnancy and will reveal a new vulnerable window for reprogramming of energy metabolism during adult life."

The authors said their findings, if confirmed in humans, could provide an explanation for how women have overtaken men in the obesity epidemic. After similar rising rates of obesity for more than a decade, a 2015 report by the Centers for Disease Control and Prevention found that women had surpassed men in terms of obesity, with 38 percent of adult women in the United States deemed obese compared to 34 percent of men. More recent statistics place those percentages even higher at 41 and 38, respectively. Clinical data have demonstrated that obesity has significant health risks to the mother in later life, including cardiovascular disease and diabetes.

Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019. 

You can submit your abstract on Session or Track : 09. Stem Cells and its Applications

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Citrate-based biomaterial fuels bone healing with less rejection

A material based on a natural product of bones and citrus fruit, called citrate, provides the extra energy that stem cells need to form new bone tissue, according to a team of Penn State bioengineers. Their new understanding of the mechanism that allows citrate to aid in bone regeneration will help the researchers develop slow-release, biodegradable, citrate-releasing scaffolds to act as bone-growth templates to speed up healing in the body.

"In our lab, we have been working with citrate for over a decade," said Jian Yang, Professor of Biomedical Engineering, Penn State. "We knew that in the human body, 90 percent of organic citrate is located in skeletal tissue. But no one had really tried to use citrate as a building block to make bone biomaterials. Our new paper tries to understand how citrate helps in bone healing and uses the understanding to guide the design of new biomimetic biomaterials for better bone repair."

Autografting -- taking bone from another part of the patient's body and grafting it to the wound -- is the method used most for bone regeneration in a hospital setting. This is not always a suitable method, especially in the case of large wounds or bone tissue removed during cancer treatment.

Synthetic biomaterials would be a welcome replacement and many labs are working on developing them. But current synthetic materials cause significant inflammation, and the bone healing rate is slow and healing quality is poor. The body encapsulates the implant with fibrotic tissues that keep the implant from integrating with surrounding bone. With Yang's material, the researchers do not see encapsulation, and chronic inflammation is minimal.

Chuying Ma, a doctoral student in Yang's lab, is lead author on the paper. Ma was given the problem of uncovering the poorly known mechanism underlying the body's use of citrate to regenerate bone. She found that the stem cell membrane has a transporter that is used to transport citrate into the cell to elevate the cellular energy level. When the bone stem cells differentiate to make new bone cells, they require more energy as support for active bone formation. The timing and dosage of citrate supply to stem cells are also critical. Yang and Ma coined the newly identified citrate effect on stem cell differentiation as "metabonegenic regulation" in the paper.

The team also identified a second factor involved in energy production, an amino acid called phosphoserine. With their new understanding of the mechanism for bone regrowth, they developed a biomaterial incorporating both citrate and phosphoserine and tested it on rat models.

"Using our new material, we see the early deposition of new bone at one month," Ma said. "This is much earlier than the biomaterials widely used in FDA-approved devices. In this study we tested two models, the femoral condyle bone and cranial bone defects."

In both animal models we see the new biomaterial is better than the commercial materials in inducing early bone formation and also promoting bone maturation, according to Ma. "To me, this is an important finding," said Yang, who is a faculty member in Penn State's Materials Research Institute and the Huck Institutes of the Life Sciences. "Citrate is now recognized as a central linker between stem cell metabolism and differentiation. We are uncovering the mechanism whereby citrate influences stem cell activity, not only in bone, but by implication extending to other types of cells and tissues. For instance, there is a high concentration of citrate in the cerebrospinal fluid surrounding the brain. People can now use this understanding to start looking at citrate as a metabolism regulator to further regulate stem cells for other types of tissues and organs throughout the body."

We welcome researchers from different part of the to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . 

You can submit your abstract on Session or Track : 10.Biomaterial and Bioengineering

Novel DNA nanoplatform delivers anticancer agents to multidrug-resistant tumors

A tailored DNA nanoplatform carries chemotherapeutic drugs and RNA interference toward multidrug-resistant tumors

One of the most successful techniques to combat multidrug resistance in cancer cells is the downregulation of those genes responsible for drug resistance. Chinese scientists have now developed a nanoplatform that selectively delivers small hairpin RNA transcription templates and chemotherapeutics into multidrug-resistant tumors. A deadly cocktail of gene-silencing elements and chemotherapeutic drugs effectively and selectively kills cells, they reported in the Journal Angewandte Chemie. The nanoplatform was assembled using established DNA origami techniques.

Multidrug-resistant cancer cells often remove potent drugs from the cell before they can become effective. As several genes for proteins that perform this job are known, scientists attempt to interfere on the gene expression level, which is possible with RNA interference (RNAi) techniques: small RNAi strands combine with messenger RNA and inhibit transcription. However, RNA transcription templates must be delivered and released into the cytoplasm of the cell, and at the same time, a potent drug must be present to kill the cell.

Baoquan Ding at the National Center for Nanoscience and Technology, Beijing, China, and his colleagues have now designed and built a platform that includes every item needed to intrude into tumor cells and release gene-silencing elements and chemotherapeutic drugs. They built the platform using the DNA origami technique, which allows the construction of nanosized DNA objects in multiple, and even very complicated shapes. In this case, the scientists constructed a relatively simple DNA origami structure, which self-assembled into a triangular nanoplatform with various sites to bind multiple functional units.

One of the key features of the platform was that it could include the hydrophobic potent drug doxorubicin (DOX), a cytostatic that is especially useful against malign tumors. Here, DOX did not bind to the nanoplatform by any covalent linkage, but was loaded onto it through intercalation (which is the way DOX works in the cell: it intercalates into DNA, inhibiting transcription). Instead, what was covalently linked to the platform was the multiple gene silencing and cell-targeting site, which consisted of two linear small hairpin RNA transcription templates for RNAi and gene therapy, a cell-specific unit for specific recognition and insertion by the tumor cell, and a disulfide linkage to be cleaved by cellular glutathione.

 

The authors examined their multipurpose nanoplatform with an in vitro assay (on cell cultures) and by administering it into mice containing multidrug-resistant tumors. They found both a high and selective delivery and release rate of DOX and RNA transcription templates, and a high and selective tumor-killing efficiency. In addition, the multifunctional platform itself was not harmful to mice; however, filled with drugs and delivery sites, it was effective and deadly to multidrug-resistant tumors, the authors reported.

This research demonstrates what is possible in cancer therapy. The scientists have designed a nanostructure that not only specifically targets cancer cells, thus reducing severe side effects in chemotherapy, but also carries a drug and everything needed to suppress resistance in the cell when releasing the drug. And the platform itself is modifiable; adaption to other delivery strategies and other therapeutic components is easily possible, according to the authors.

We welcome researchers from different part of the to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . 

You can submit your abstract on Session or Track : 8.Advancement in Cancer Treatment

People with rare cancers can benefit from genomic profiling

New research has shown that many Australians with rare cancers can benefit from genomic profiling. The findings of the patient-driven trial are being presented today at the Clinical Oncology Society of Australia Annual Scientific Meeting and could result in dramatic changes to the way those with rare cancers are diagnosed and treated. 

The initial data from the pilot study for Nominator Trial is being presented by Professor Clare Scott from the Walter and Eliza Hall Institute of Medical Research and Peter MacCallum Cancer Centre, and was funded in part by Rare Cancers Australia. 

The data shows that genomic profiling provides meaningful information that influences diagnosis and treatment in approximately 50 percent of people with rare cancers. 20 percent of those tested got a new treatment plan as a result and 6 percent of participants were given a new diagnosis. 

The aim of the national initiative is to trial the use of genomic testing to match rare cancers to cancer treatments. Testing is used to identify molecular features of the cancer or genetic mutations that can be targeted with existing treatments used in other cancer types with the same characteristics.

While genomic testing is becoming increasingly used in other cancer types, this is one of the first Australian studies of its kind to look at the potential benefits for those with rare cancers, which have very low survival rates.

Professor Clare Scott says the initial pilot data is exciting and proves that there is a current unmet need."The treatment options for Australians with rare cancers are currently extremely limited and this ultimately leads to poor survival rates. Research has also typically been restricted because of the challenges of finding enough of each type of cancer patient to design appropriate clinical trials."Australians in this trial came to us after they had exhausted all their options. The cancers they had are extremely rare - the chances of being diagnosed with these cancer types are often around one in a million."Using genomic profiling we were able to uncover new information that gave many patients new treatment options - and ultimately, new hope."

Professor Scott says."In one case we were able to identify that a rare heart tumour actually had a genetic profile most closely resembling a melanoma. Using that information we were able to get access to the latest treatments that are benefiting melanoma patients - which we hope will provide better outcomes for this patient."

The Nominator Pilot Study results released today included 36 patients. The two-year study will eventually include 100 patients and will lay the groundwork for other national initiatives looking into genomic profiling across a range of cancer types. Professor Phyllis Butow, President, Clinical Oncology Society of Australia said one of the impressive things about the study was that it was driven by Australians directly affected by rare cancers.

"Around 52,000 Australians are diagnosed with rare or less common cancers each year. Those directly affected by the disease, led by Kate and Richard Vines from Rare Cancers Australia, helped call for and fund this research, so it's great to see these initial promising results being presented to cancer experts from across the country." 

We welcome researchers from different part of the to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatmentand many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” .  You can submit your abstract on Session or Track :08- Advancement in Cancer Treatments

New methods to identify AD drug candidates with anti-aging properties

Long thought to suppress cancer by slowing cellular metabolism, the protein complex AMPK also seemed to help some tumors grow, confounding researchers. Now, Salk Institute researchers have solved the long-standing mystery around why AMPK can both hinder and help cancer.

The lab of Salk Professor Reuben Shaw showed that late-stage cancers can trigger AMPK's cellular recycling signal to cannibalize pieces of the cell, supplying large lung tumors with the nutrients they need to grow. The work was published in  Cell Metabolism suggests that blocking AMPK in some conditions could stop the growth of advanced tumors in the most common type of lung cancer.

"Our study shows that the same dysfunction in a genetic circuit that causes non-small-cell lung cancer to begin with is necessary for more mature tumor cells to survive when they don't have enough nutrients," says Shaw, Director of the Salk Cancer Center. "It's exciting because not only does it solve a genetic 'whodunnit,' but it also points to a potential new therapeutic target for a cancer that is often diagnosed very late."

AMPK acts as a fuel gauge for the cell, overseeing energy input and output to keep the cell running smoothly. Similar to a car sensor flashing a low-gas signal or turning off a vehicle's AC to save energy, AMPK slows down cell growth and changes the cell's metabolism if the cell's fuel (nutrients) is low. Previously, Shaw discovered that AMPK could halt tumors' revved-up metabolism, as well as restore normal function to the liver and other tissues in diabetics.

"We found that tumors grew much more slowly when AMPK was not present," says Research Associate Lillian Eichner."That means that AMPK is not always functioning as a tumor suppressor, as we originally thought."

The team analyzed which genes in tumor cells from the same mouse models were being activated under various conditions. One gene that was particularly active was Tfe3, which is known to activate cellular recycling. It turned out that when tumors became large enough that cells in the middle were too far from easy access to nutrients, AMPK signaled Tfe3 to initiate recycling of cellular materials as nutrients--effectively cannibalizing pieces of the cell--for the tumor to use.

"Previously we were focused on how we could activate AMPK," says Eichner. "Now that we've identified this mechanism, we can shift to how to inhibit it in certain cancers."

Shaw, who holds the William R. Brody Chair, adds, "We're excited because more advanced tumors seem to rely on AMPK to survive, and understanding this mechanism means we may be able to treat them."

We welcome researchers from different part of the to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatmentand many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . 

You can submit your abstract on Session or Track : 16.Anti-Aging Medicine

Realizing the potential of gene therapy for neurological disorders

Promising findings from preclinical animal studies show the potential of gene therapy for treating incurable neurological disorders. In new research presented today, scientists successfully used gene therapy to slow the progression and improve symptoms of disorders such as amyotrophic lateral sclerosis and Parkinson's disease.

Gene therapy typically employs an inactivated virus to carry new genetic cargo into cells, altering specific genes to treat or prevent a disease. Researchers might replace a mutated gene with a healthy copy of the gene, turn off a disease-causing gene, or add a new gene to the body to help fight a disease.

Although gene therapy is a promising treatment option for a limited number of conditions, including certain cancers, the technique is still experimental for most diseases, with ongoing research to ensure they will be safe and effective in human patients. Animal studies are a key part of the process by which an experimental gene therapy treatment goes to clinical trial.

Research new findings show that:

• A new technique allows gene therapy to be delivered to the entire spinal cord in mice (M. Bravo Hernandez, abstract 208.10).
• Gene therapy safely and effectively extends life and improves motor function in a mouse model of ALS (Gretchen Thomsen, abstract 208.16).
• Gene therapy slows the progression of neuronal loss in a mouse model of inherited Parkinson's disease (Jose L. Lanciego, abstract 292.01).
• Gene therapy shows promise in a mouse model of Batten disease, a childhood neurodegenerative disease (Shibi Likhite, abstract 355.01).

"Gene therapy holds the promise to transform the lives of patients with incurable neurological diseases," said Fredric Manfredsson, PhD, of Michigan State University. "The research presented today represents important and exciting steps toward being able to prevent and treat disorders that currently have no cure, such as Parkinson's disease and Alzheimer's disease."

We welcome researchers from different part of the to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatmentand many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . 

You can submit your abstract on Session or Track :2.Cellular and Gene Therapy

New immunotherapy technique can specifically target tumor cells

A new immunotherapy screening prototype developed by University of California, Researchers can quickly create individualized cancer treatments that will allow physicians to effectively target tumors without the side effects of standard cancer drugs.

UCI's Weian Zhao and Nobel laureate David Baltimore with Caltech led the research team that developed a tracking and screening system that identifies T cell receptors with 100-percent specificity for individual tumors within just a few days. Research findings appear in Lab on a Chip.

In the human immune system, T cells have molecules on their surfaces that bind to antigens on the surface of foreign or cancer cells. To treat a tumor with T cell therapy, researchers must identify exactly which receptor molecules work against a specific tumor's antigens. UCI researchers have sped up that identification process.

"This technology is particularly exciting because it dismantles major challenges in cancer treatments," said Zhao, Chao Family Comprehensive Center and the Sue & Bill Gross Stem Cell Research Center. "This use of droplet microfluidics screening significantly reduces the cost of making new cancer immunotherapies that are associated with less systemic side effects than standard chemotherapy drugs, and vastly speeds up the timeframe for treatment."

Zhao added that traditional cancer treatments have offered a one-size-fits-all disease response, such as chemotherapy drugs which can involve systemic and serious side effects.

T cell receptor (TCR)-engineered T cell therapy, a newer technology, harnesses the patient's own immune system to attack tumors. On the surface of cancer cells are antigens, protruding molecules that are recognized by the body's immune system T cells. This new therapy places engineered molecules on the patient's T cells which will bind to their cancer cell antigens, allowing the T cell to destroy the cancer cell. TCR therapy can be individualized, so each patient can have T cells designed specifically for their tumor cells.

This antigen-TCR recognition system is very specific -- there can be hundreds of millions of different types of TCR molecules. A big challenge for TCR-T cell therapy development remains in identifying particular TCR molecules out of a pool of millions of possibilities. Finding a match can take up to a year (time many cancer patients don't have) and can cost half a million dollars or more per treatment.

By using miniscule oil-water droplets, Zhao's team designed a device that allows for individual T cells to join with cancer cells in microscopic fluid containers. The TCRs that bind with the cancer cells' antigens can be sorted and identified within days, considerably faster than the months or year that previous technologies required. The technology also significantly reduces the cost of making individualized TCRs and accelerates the pipeline of TCR-T cell therapy to clinic.

Through a partnership with Amberstone Biosciences, a UCI start-up, this entire platform and screening process will be available to pharmaceutical companies for drug development within just a few months. Not only can this technology help revolutionize TCR-T cell therapies for cancer, but it will also be a powerful tool for discovering other immunological agents, including antibodies and CAR-T cells, and for elucidating new immunology and cancer biology at a depth not possible before

We welcome researchers from different part of the world to submit your latest research at our upcoming conference “12th World Congress on Cell & Tissue Science” scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

Advance stem cell therapy with biodegradable scaffold

Rutgers scientists have created a tiny, biodegradable scaffold to transplant stem cells and deliver drugs, which may help treat Alzheimer's and Parkinson's diseases, aging brain degeneration, spinal cord injuries and traumatic brain injuries.

A biodegradable inorganic nano-scaffold, consisting of stem cells, proteins and drugs, for advanced stem cell therapy and drug delivery.

Credit: KiBum Lee, Letao Yang and Sy-Tsong Dean Chueng

Stem cell transplantation, which shows promise as a treatment for central nervous system diseases, has been hampered by low cell survival rates, incomplete differentiation of cells and limited growth of neural connections.

So, Rutgers scientists designed bio-scaffolds that mimic natural tissue and got good results in test tubes and mice, according to a study in Nature Communications. These nano-size scaffolds hold promise for advanced stem cell transplantation and neural tissue engineering. Stem cell therapy leads to stem cells becoming neurons and can restore neural circuits.

"It's been a major challenge to develop a reliable therapeutic method for treating central nervous system diseases and injuries," said study senior author KiBum Lee, Department of Chemistry and Chemical Biology at Rutgers University-New Brunswick. "Our enhanced stem cell transplantation approach is an innovative potential solution."

The researchers, in cooperation with neuroscientists and clinicians, plan to test the nano-scaffolds in larger animals and eventually move to clinical trials for treating spinal cord injury. The scaffold-based technology also shows promise for regenerative medicine.

We welcome researchers from different part of the world to submit your latest research at our upcoming conference “12th World Congress on Cell & Tissue Science” scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

Novel method to block immunosuppression in cancer

Belgian research groups from the UCLouvain and WELBIO, VIB and Ghent University, and the biotechnology company Aargenx elucidated the three-dimensional structure of an assembly of proteins operating on cells that dampen immune responses. They also discovered how an antibody can block this assembly and the immunosuppression it induces downstream. Such an antibody could serve to stimulate immunity against tumor cells in cancer patients, triggering the destruction of their tumors by immune cells. The study is published in the authoritative Journal Science.

Immunosuppression through a cascade of interactions

Tregs (regulatory T lymphocytes) are immunosuppressive cells that normally counterbalance excessive immune reactions to prevent autoimmune diseases. But in cancer patients, they play deleterious roles by tempering immune reactions against tumor cells. Tregs induce their effects by producing a protein messenger called TGF-beta. This messenger transmits inhibitory signals to immune cells in the immediate vicinity, notably those that are supposed to destroy tumors in cancer patients.

The way Tregs produce TGF-beta is complex and finely regulated, because TGF-beta is very potent and must be kept under tight control. Three years ago, Prof. Sophie Lucas and her team at the de Duve Institute of the UCLouvain discovered that TGF-beta is released by Tregs from a protein called GARP, present on the Treg surface.

In collaboration with argenx, her team also discovered that it was possible to block the release of TGF-beta from GARP with specific antibodies, which were rare and difficult to obtain. The next thing to find out was how GARP regulates the production of the TGF-beta messenger and how antibodies actually block its release.

The molecular mechanisms elucidated

Sophie Lucas and argenx initiated a collaboration with the team of Prof. Savvas Savvides at the VIB-UGent Center for Inflammation Research, to resolve the three-dimensional structure of the protein assembly made of GARP and TGF-beta.

The researchers used X-ray crystallography, a method that has been used to study the structure of molecules for more than a century and that is still being developed for the study of biological macromolecules at atomic resolution. However, they were confronted with the practical problem that they could not readily obtain crystals of the GARP and TGF-beta complex.

Via a highly collaborative effort spearheaded by Dr. Stéphanie Lienart (UCLouvain) and Dr. Romain Merceron (VIB -- Ghent University), the two teams decided to use a blocking antibody to stabilize the structure -- a successful approach that not only helped to generate suitable crystals for structure determination, but also provided details about how a therapeutic antibody might function.

Prof. Savvas Savvides (VIB-UGent): "We discovered that GARP resembles a horseshoe that is straddled by TGF-beta. The two molecules are so intricately assembled that TGF-beta itself contributes to the structure of the GARP horseshoe. The antibody fragment sticks to both GARP and TGF-beta in the assembly. It appears to glue the two molecules to one another, ensuring that when other molecules pull on one part of the assembly, the small, active part of TGF-beta is not released, and is thus prevented from conveying its inhibitory message." 

Prof. Sophie Lucas (de Duve Institute at the UCLouvain): "Visualization of this large molecular assembly illustrates the feasibility of blocking TGF-beta activity emanating from a precisely defined and restricted cellular source, such as the surface of Tregs. This can lead to the design of exquisitely specific approaches to treat various diseases associated with altered TGF-beta or Treg activity, most notably for the immunotherapy of cancer." 

We welcome researchers from different part of the world to submit your latest research at our upcoming conference “12th World Congress on Cell & Tissue Science” scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

Normal function of ALS and dementia linked gene determined for the first time

The normal function of a gene associated with the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has been determined for the first time by University of Bath scientists.

Both ALS, the most common form of motor neurone disease, and FTD progressively develop in adults and have been shown to be closely linked, with overlapping genetic origins and similar effects on some nervous system cells. There is no cure for either disease.

One gene, called C9orf72, is strongly suspected to be the cause of inherited ALS and FTD when a short sequence of DNA repeats hundreds or even thousands of times within the gene, causing problems in its transcription and expression. However, until now scientists were uncertain as to what normal role or roles the C9orf72 gene played in cells.

A University of Bath team from the Department of Biology and Biochemistry have now biochemically characterised the protein produced by the C9orf72 gene and have shown that it is a guanine nucleotide exchange factor (GEF).

GEFs are a type of protein which regulate molecules called RABs which control key processes inside cells. They respond to signals received by a cell in normal as well as diseased states. Recent evidence suggests that some GEF proteins may be potential therapeutic targets for developing drugs to treat various diseases, including cancer.

Dr Vasanta Subramanian said: "It is vital that we know as much as we can about the causes and triggers for ALS and FTD, so we have a better chance of developing treatments, and even one day a cure for these devastating diseases.Understanding the function of C9orf72, which is linked to both diseases, is a crucial step in that process."

 "These findings are very timely, as new gene therapy approaches are being developed to specifically target the C9orf72 gene. Understanding what the healthy gene is doing within cells will be important in ensuring that the toxic and not the beneficial effects of the gene are targeted"said Dr Brian Dickie, Director of Research, Motor Neurone Disease Association 

We welcome researchers from different part of the world to submit your latest research at our upcoming conference “12th World Congress on Cell & Tissue Science” scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

New epigenetic drug strategy to treat cancer

Researchers have discovered that inhibiting CDK9, a DNA transcription regulator, reactivates genes that have been epigenetically silenced by cancer. Reactivation leads to restored tumor suppressor gene expression and enhanced anti-cancer immunity. It is the first time this particular kinase has been linked to gene silencing in mammals.

It has been established that epigenetic mediators of gene silencing present new targets for cancer drugs. Hanghang Zhang, PhD, Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine at Temple University (LKSOM), performed a live cell drug screen with genetic confirmation to identify CDK9 as a target and to develop and test an effective inhibitor -- MC180295.

The new drug is highly selective, potentially avoiding the side effects associated with inhibiting the cell cycle. In the study it showed broad effectiveness against cancer both in vitro and in vivo. The drug was discovered in collaboration with investigators at the Moulder Center for Drug Discovery at the Temple University School of Pharmacy.

"In addition to reactivating tumor suppressor genes, CDK9 inhibition induces sensitivity to the immune checkpoint inhibitor ?-PD-1 in vivo," said Issa. "It is an excellent target for epigenetic cancer therapy."

 

We welcome researchers from different part of the world to submit your latest research at our upcoming conference “12th World Congress on Cell & Tissue Science” scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

'Cellular dust' provides new hope for regenerative medicine

While stem cells have the most therapeutic potential, the benefits of regenerative medicine may best be mobilised using extracellular vesicles (EVs), also known in the past as "cellular dust." A team of researchers from CNRS, AP-HP, INSERM and Paris Descartes and Paris Diderot Universities have tested these vesicles for the first time in a porcine model for the treatment of post-operative digestive fistulas. Their results, which yielded a 100% success rate and open the door to testing in humans and broader possibilities for applications.

Extracellular vesicles are matter that is released by cells. Seen for many years as not having any value, this 'cellular dust' has been studied and presents therapeutic properties similar to their mother cells, without their disadvantages: These vesicles do not divide, limiting the risk of cancer, and do not differentiate either, thus preventing the development of poor function. Furthermore, it appears that they can be produced by a single donor for several patients, and have already demonstrated their therapeutic potential in animals in repairing heart, liver and kidney lesions.

In the case of digestive fistula, in which there is abnormal communication between organs in the digestive tract or with the skin, regenerative medicine is an important therapeutic avenue to explore. Fistulas of this kind respond poorly to current treatments; they can develop following post-operative complications or an auto-immune disorders such as Crohn's disease, which causes digestive tract dysfunction.

For the first time, scientists at the Matières et systèmes complexes Lab (CNRS/Université Paris Diderot), the Gastroenterology and Endoscopy Department at the Hôpital Européen Georges Pompidou (HEGP) AP-HP and the Laboratoire Imagerie de l'angiogénèse, plateforme d'imagerie du petit animal (INSERM/Université Paris Descartes/HEGP), used extracellular vesicles from stem cells to treat digestive fistula in a swine model. The study reveals that local injections into the fistula of a gel containing these vesicles results in the complete closure of post-operative digestive fistula.

Researchers intend to test the new approach in a perineal fistula model found in Crohn's disease, with the hope of replacing the vvv. The vesicle gel could be administered locally and easily and become a simpler, safer and more effective treatment.

We welcome researchers from different part of the world to submit your latest research at our upcoming conference “12th World Congress on Cell & Tissue Science” scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

3-D bioprinting of living structures with built-in chemical sensors

An international team of researchers led by Professor Michael Kühl at the Department of Biology, University of Copenhagen has just published a breakthrough in 3D bioprinting. Together with German colleagues at the Technical University of Dresden (Centre for Translational Bone, Joint and Soft Tissue Research), Professor Kühls group implemented oxygen sensitive nanoparticles into a gel material that can be used for 3D printing of complex, biofilm and tissue like structures harboring living cells as well as built-in chemical sensors.

3-D-bioprinted structure containing green algae (Chlamydomonas) in a hydrogel. Credit: Anja Lode, TU Dresden

Kühl explains: "3D printing is a wide spread techniques for producing object in plastic, metal, and other abiotic materials. Likewise, living cells can be 3D printed in biocompatible gel materials (bioinks) and such 3D bioprinting is a rapidly developing field, e.g. in biomedical studies, where stem cells are cultivated in 3D printed constructs mimicking the complex structure of tissue and bones. Such attempts lack on line monitoring of the metabolic activity of cells growing in bioprinted constructs; currently, such measurements largely rely on destructive sampling. We have developed a patent pending solution to this problem."

The group developed a functionalized bioink by implementing luminescent oxygen sensitive nanoparticles into the print matrix. When blue light excites the nanoparticles, they emit red luminescent light in proportion to the local oxygen concentration -- the more oxygen the less red luminescence. The distribution of red luminescence and thus oxygen across bioprinted living structures can be imaged with a camera system. This allows for on-line, non-invasive monitoring of oxygen distribution and dynamics that can be mapped to the growth and distribution of cells in the 3D bioprinted constructs without the need for destructive sampling.

Kühl continues: "It is important that the addition of nanoparticles doesn't change the mechanical properties of the bioink, e.g. to avoid cell stress and death during the printing process. Furthermore, the nanoparticles should not inhibit or interfere with the cells. We have solved these challenges, as our method shows good biocompatibility and can be used with microalgae as well as sensitive human cell lines."

 

"This is a breakthrough in 3D bioprinting. It is now possible to monitor the oxygen metabolism and microenvironment of cells on line, and non-invasively in intact 3D printed living structures" says Prof. Kühl. "A key challenge in growing stem cells in larger tissue- or bone-like structures is to ensure a sufficient oxygen supply for the cells. With our development, it is now possible to visualize the oxygen conditions in 3D bioprinted structures, which e.g. enables rapid testing and optimization of stem cell growth in differently designed constructs."

 

Kühl ends: "3D bioprinting with functionalized bioinks is a new powerful technology that can be applied in many other research fields than biomedicine. It is e.g. extremely inspiring to combine such advanced materials science and sensor technology with my research in microbiology and biophotonics, where we currently employ 3D bioprinting to study microbial interactions and photobiology."

 

We welcome researchers from different part of the to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . For more info visit :Cell Tissue Science 2019

New tool gives deeper understanding of glioblastoma

Researchers  from Baker Institute for Animal Health have developed a new tool to study genetic "switches" active in glioblastoma tumors that drive growth of the cancer. In a new paper in Nature Genetics, they identified key switches in different types of tumors, including switches linked to how long a patient survives.

Glioblastoma is an aggressive cancer that forms in the brain or spinal cord. "It's a devastating disease, and there are no good treatment options," said lead author Tinyi Chu, Graduate Fellow, Danko's lab. Even when patients undergo treatment, most survive just 15 months post-diagnosis.

In the new study, Danko's group partnered with colleagues at the State University of New York Upstate Medical University to analyze 20 glioblastoma samples from its tissue bank.

"A lot of diseases, including cancer, fundamentally are defects in how our genes are used, not necessarily in the genes themselves," said Danko, Assistant Professor of Biomedical Sciences. Genes make up only two percent of our genome. Switches called transcription factors bind to the genome to turn those genes on and off, which trigger the cellular changes that cause disease.

To analyze the tumors, the researchers used a technique called ChRO-seq that creates a map of which switches are active and which genes they turn on.

Using ChRO-seq data, the team was able to classify the glioblastomas into subtypes, based on which particular switches were active in the different tumors compared to healthy brain tissues. They also identified three switches that will be tested in larger studies to determine their ability to predict which patients will survive longer with the disease, including two switches whose connections were previously unknown.

Chu is now analyzing an even larger group of glioblastomas to link patient survival and treatment outcomes with the active switches in each tumor. He hopes the results could inform personalized treatment plans for patients or help to develop new therapies in the future.

The new technique studies not only cancer, but many other diseases caused by malfunctions in gene regulation, such as certain types of heart or autoimmune diseases. "ChRO-seq gives you a lot of information about what switch is turning on a tumor or a diseased cell," said Danko. "It gives you a starting point to think about how you can shut that switch off."

 

We welcome researchers from different part of the to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . For more info visit :Cell Tissue Science 2019

Cancer stem cells use normal genes in abnormal ways

CDK1 is a "normal" protein -- its presence drives cells through the cycle of replication. And MHC Class I molecules are "normal" as well -- they present bits of proteins on the surfaces of cells for examination by the immune system. 

But a University of Colorado Cancer Center study published in the Journal Cancer Research shows that a population of cancer cells marked by MHC Class I molecules and high CDK1 is anything but normal. In fact, these MHC Class I-high, CDK1 high molecules may be at the heart of conditions including melanoma, pancreatic and colon cancers. These cells may, in fact, be the long-sought cancer stem cells that often resist treatments like chemotherapy to reseed these cancers once treatment ends.

From the outset, the goal of this study was different than most. Often, cancer researchers will grow tumors and then ask what kinds of drugs or genetic changes make tumors grow or shrink. However, the current study wondered not what makes tumors change size, but what factors in these cells initiate tumor growth in the first place. To answer this question, the study used patient samples, mouse models and publicly available genetic data to search for the genetic/genomic commonalities in cells capable of initiating melanoma, pancreatic and colon cancers.

The findings start with a molecule called MHC Class I, a common molecule that coats the outside of human cells and functions a bit like a hand waving a flag. When MHC Class I molecules wave "flags" (actually bits of proteins), that are not from host tissue, the immune system recognizes the cell as foreign and attacks it. For this reason, most cancer cells downregulate MHC as a way of evading the immune system.

But the current study shows that the population of cancer cells able to initiate the formation of new tumors does not downregulate MHC Class I molecules. In fact, if anything this special population of cancer cells upregulates MHC Class I molecules.

"Probably, these cells have another way to evade the immune system," says Mayumi Fujita, MD, PhD, Investigator at CU Cancer Center and Professor in the CU School of Medicine Departments of Dermatology and Immunology/Microbiology.

Oddly, this population of cancer cells that retains MHC Class I molecules also retains another feature of healthy cells, namely the presence of a protein called CDK1. CDK1 is a master regulator of the cell cycle -- with CDK1, cells progress through the cycle of replication; without CDK1, they do not. In this case, the more CDK1, the more able melanoma cells were to initiate new tumors.

"Our next question was why," Fujita says. "Why would CDK1 control not just the cell cycle, but also stem-ness?"

Finally, the answer includes something that is not "normal." Sox2 is a transcription factor that helps embryonic and neural stem cells keep their stem-ness. It is also a known marker of cancer stem cells, implicated in the development of more than 25 forms of the disease. Despite its identification as a driver of cancer, Sox2 remains a difficult target.

"It's very difficult to control a transcription factor like Sox2. We can show Sox2 is very important for tumorigenesis, but it's difficult to have a Sox2 inhibitor," Fujita says.

However, the current study found that CDK1 directly interacted with Sox2 to keep these cancer cells "stemmy." And here is the important part: "If CDK1 controls Sox2 function through this interaction, probably we can someday inhibit it, maybe through some way of targeting CDK1 or perhaps some way to interfere with the interaction of CDK1 with Sox2," Fujita says.

Importantly, this signature of MHC Class 1, CDK1 and Sox2 was common across melanoma, colon and pancreatic cancers, implying that cancer stem cells across cancer types may share common features.

"We can't say that all tumor types have this signature, but it's prevalent. We think probably this phenotype is very common in melanoma, pancreatic and colon cancer," Fujita says.

Moving forward, the Fujita group hopes to further define the mechanism of Sox2 regulation via CDK1 in hopes of finding essential links that might be targets for new drugs aimed, eventually, at stopping the action of Sox2.

We welcome researchers from different part of the world to submit your latest research at our upcoming conference "12th World Congress on Cell & Tissue Science" scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

Combining genetic and sun exposure data improves skin cancer risk estimates

By combining data on individuals' lifetime sun exposure and their genetics, researchers can generate improved predictions of their risk of skin cancer.

Pierre Fontanillas, PhD, and colleagues at 23andMe, Inc., collected genetic and survey data from over 210,000 consented research participants of European descent. They analyzed the data to identify correlations between previously known and potentially novel skin cancer risk factors and the occurrence of three forms of skin cancer: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Past studies had found that exposure to ultraviolet (UV) light increases skin cancer risk, as do other environmental factors such as living in a sunnier climate or at a higher altitude, and personal factors such as lighter skin pigmentation, higher numbers of moles on the skin, and family history of skin cancer.

"We aimed to validate previously known skin cancer risk factors in a large cohort, add detail to these and explore potential new ones, and find out whether and how these factors might interact with genetic risk," said Dr. Fontanillas.

They found that while each single factor was not particularly significant on its own, multiple factors could be combined into statistical models that were more informative. The best-performing models incorporated a genetic risk score composed of data on up to 50 genetic variants, along with survey data on family history, skin pigmentation and sensitivity, number of moles, estimated current sun exposure, sunbathing frequency before the age of 30, and body mass index (BMI).

The new models achieved a high predictive accuracy (area under the curve [AUC], between 0.81 and 0.85). Genetic factors alone accounted for 8.3 to 15.2 percent of the variance explained in skin cancer risk. Although the three skin cancers have different physiology, models did not find fundamental differences between the three cancer types, nor did they show strong interaction between genetic and environmental risk factors. While the self-reported nature of the survey data permitted researchers to collect a large dataset, it also presented some challenges, Dr. Fontanillas noted.

"Measuring lifetime exposure is generally challenging. It is particularly hard to capture sun exposure and when in life it happened, and it may be that some of the other correlates we found, like higher BMI, reflect a lack of outdoor activity rather than being directly correlated with risk of skin cancer," he said.

Moving forward, the researchers plan to expand their sample to groups with non-European ancestry and are exploring additional methods of calculating genetic risk score and measuring sun exposure. They hope to eventually obtain risk estimates accurate enough to be used by individuals and clinicians.

We welcome researchers from different part of the world to submit your latest research at our upcoming conference "12th World Congress on Cell & Tissue Science" scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019