Category Archives: Cell Medicine

February 22, 2017 Micrograph showing a lymph node invaded by ductal breast carcinoma, with extension of the tumour beyond the lymph node. Credit: Nephron/Wikipedia

Working with human breast cancer cells and mice, researchers at Johns Hopkins say they have identified a biochemical pathway that triggers the regrowth of breast cancer stem cells after chemotherapy.

The regrowth of cancer stem cells is responsible for the drug resistance that develops in many breast tumors and the reason that for many patients, the benefits of chemo are short-lived. Cancer recurrence after chemotherapy is frequently fatal.

"Breast cancer stem cells pose a serious problem for therapy," says lead study investigator Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine, director of the Vascular Biology Program at the Johns Hopkins Institute for Cell Engineering and a member of the Johns Hopkins Kimmel Cancer Center. "These are the cells that can break away from a tumor and metastasize; these are the cells you most want to kill with chemotherapy. Paradoxically, though, cancer stem cells are quite resistant to chemotherapy."

Semenza says previous studies have shown that resistance to chemotherapy arises from the hardy nature of cancer stem cells, which are often found in the centers of tumors, where oxygen levels are quite low. Their survival is made possible through proteins known as hypoxia-inducible factors (HIFs), which turn on genes that help the cells survive in a low-oxygen environment.

In this new study, described Feb. 21 in Cell Reports, Semenza and his colleagues conducted gene expression analysis of multiple human breast cancer cell lines grown in the laboratory after exposure to chemotherapy drugs, like carboplatin, which stops tumor growth by damaging cancer cell DNA. The team found that the cancer cells that survived tended to have higher levels of a protein known as glutathione-S-transferase O1, or GSTO1. Experiments showed that HIFs controlled the production of GSTO1 in breast cancer cells when they were exposed to chemotherapy; if HIF activity was blocked in these lab-grown cells, GSTO1 was not produced.

Semenza notes that GSTO1 and related GST proteins are antioxidant enzymes, but GSTO1's role in chemotherapy resistance did not require its antioxidant activity. Instead, following exposure to chemotherapy, GSTO1 binds to a protein called the ryanodine receptor 1, or RYR1, that triggers the release of calcium, which causes a chain reaction that transforms ordinary breast cancer cells into cancer stem cells.

To more directly assess the role of GSTO1 and RYR1 in the breast tumor response to chemotherapy, the researchers injected human breast cancer cells into the mammary gland of mice and then treated the mice with carboplatin after tumors had formed. In addition to using normal breast cancer cells in the experiments, the team also used cancer cells that had been genetically engineered to lack either GSTO1 or RYR1. Loss of either GSTO1 or RYR1, the researchers report, decreased the number of cancer stem cells in the primary tumor, blocked metastasis of cancer cells from the primary tumor to the lungs, decreased the duration of chemotherapy required to induce remission and increased the duration of time after chemotherapy was stopped that the mice remained tumor-free.

Although the study showed that blocking the production of GSTO1 may improve the efficacy of chemotherapy drugs, such as carboplatin, GSTO1 is only one of many proteins that are produced under the control of HIFs in breast cancer cells that have been exposed to chemotherapy. The Semenza lab is working to develop drugs that can block the action of HIFs, with the hope that HIF inhibitors will make chemotherapy more effective.

Explore further: Toughest breast cancer may have met its match

More information: Haiquan Lu et al. Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment, Cell Reports (2017). DOI: 10.1016/j.celrep.2017.02.001

Triple-negative breast cancer is as bad as it sounds. The cells that form these tumors lack three proteins that would make the cancer respond to powerful, customized treatments. Instead, doctors are left with treating these ...

Working with mice, Johns Hopkins researchers report they have identified chemical signals that certain breast cancers use to recruit two types of normal cells needed for the cancers' spread. A description of the findings ...

Working with human breast cancer cells and mice, scientists at The Johns Hopkins University say new experiments explain how certain cancer stem cells thrive in low oxygen conditions. Proliferation of such cells, which tend ...

Chemotherapy is a key part of the standard treatment regimen for triple-negative breast cancer patients whose cancer lacks expression of estrogen and progesterone receptors and the human epidermal growth factor receptor 2 ...

Existing chemotherapy approaches treat cancer by targeting cells that are actively multiplying and have a high metabolic rate. However, cancer stem cells can escape this targeting, leading to chemotherapy-resistant cancer ...

Conventional, high-dose chemotherapy treatments can cause the fibroblast cells surrounding tumors to secrete proteins that promote the tumors' recurrence in more aggressive forms, researchers at Taipei Medical University ...

Chemotherapy has long been standard treatment for many cancers, but its clinical benefits can also come with well-documented side effects. Doctors say the challenge is knowing which patients will experience these side effects, ...

Working with human breast cancer cells and mice, researchers at Johns Hopkins say they have identified a biochemical pathway that triggers the regrowth of breast cancer stem cells after chemotherapy.

In order for cancer to spread, malignant cells must break away from a tumor and through the tough netting of extracellular matrix, or ECM, that surrounds it. To fit through the holes in this net, those cancerous cells must ...

How we think and fall in love are controlled by lightning-fast electrochemical signals across synapses, the dynamic spaces between nerve cells. Until now, nobody knew that cancer cells can repurpose tools of neuronal communication ...

Researchers at the University of Pittsburgh School of Medicine have uncovered a novel genetic mechanism of thyroid cancer, as well as a marker that may predict response to a particular class of drugs, not just in patients ...

Treating multiple myeloma (MM) with myxoma virus (MYXV) eliminated a majority of malignant cells in preclinical studies, report investigators at the Medical University of South Carolina (MUSC) and elsewhere in an article ...

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Scientists identify chain reaction that shields breast cancer stem cells from chemotherapy - Medical Xpress

Scientists have coaxed sound-sensing cells in the ear, called "hair cells," to grow from stem cells. This technique, if perfected with human cells, could help halt or reverse the most common form of hearing loss, according to a new study.

These delicate hair cells can be damaged by excessive noise, ear infections, certain medicines or the natural process of aging. Human hair cells do not naturally regenerate; so as they die, hearing declines.

More than 20 million Americans have significant hearing loss resulting from the death or injury of these sensory hair cells, accounting for about 90 percent of hearing loss in the United States, according to the Centers for Disease Control and Prevention.

In the new study, scientists at Harvard University and the Massachusetts Institute of Technology reported that they isolated stem cells from a mouse ear, discovered how to get them to multiply in a laboratory setting, and then converted them into hair cells. Their previous efforts, in 2013, produced only 200 hair cells. With a new technique, however, the research team has increased this number to 11,500 hair cells that were grown from one mouse ear. [Inside Life Science: Once Upon a Stem Cell]

Their paper describing the stem cell advance appears today (Feb. 21) in the journal Cell Reports.

Jeffrey Corwin, an expert on hair-cell regeneration and a professor of neuroscience at the University of Virginia School of Medicine, who was not part of this new research, called it "a very impressive studyby a dream team of scientists" and "a big advance" in the pursuit of regenerating these sensory hearing cells in humans.

Hair cells grow in bundles in the inner ear, and are so named because they look like hairs. Many hair cells within the ear are involved in balance, not hearing. But in the cochlea, the hearing organ deep in the ear canal, there are two kinds of specialized hair cells: outer hair cells, which amplify pitch and enable humans to discern subtle differences in sound; and inner hair cells, which convert sound into electrical signals sent to the brain. Humans have two cochleae (one in each ear), and each has only about 16,000 hair cells.

In fish, birds, lizards and amphibians, cochlear hair cells that die can be regenerated in as fast as a few days. However, in mammals, for the most part, the cells cannot regenerate except for mice and other small mammals when they are newly born. But since so many species can naturally regenerate hair cells from a stem cell precursor, including some newborn mammals, many researchers have been motivated to find a way to rekindle hair-cell regeneration in adult mammals and, of course, in humans, Corwin said.

The new research was done by a team led by Albert Edge, director of the Tillotson Cell Biology Unit at the Massachusetts Eye and Ear Infirmary and professor of otolaryngology at Harvard Medical School in Boston.

In 2012, Edge's group discovered stem cells in the ear called Lgr5+ cells. These cells are also found in the gut, where they actively regenerate the entire lining of human intestines every eight days. The research team soon found a way to coax the Lgr5+ cells to differentiate into hair cells, instead of intestinal cells. But the process was slow, and the yield was low.

Now, the researchers have increased the yield dramatically by inserting a new step. After removing Lgr5+ cells from mice, the researchers first get them to divide in a special growth medium. This step produced a two-thousandfold increase in Lgr5+ cells, Edge told Live Science. Then, the researchers moved these stem cells into a different kind of growth culture and added certain chemicals to turn the Lgr5+ cells into hair cells. [7 Ways the Mind and Body Change With Age]

These laboratory-grown hair cells appear to have many of the characteristics of actual inner and outer hair cells, although they might not be fully functional, Edge said. The most immediate use for this new technique will be to create a large set of the cells to test drugs and to identify compounds that can heal damaged hair cells or regrow them and restore hearing, Edge said.

Scientists have had difficulty testing drugs on large batches of actual hair cells because there are so few in mammalian ears and they are deep in the cochlea, hard to extract, Edge said.

The researchers have reason to believe the technique to regenerate fully functional hair cells in humans could someday work. As reported in their paper, the team tested the technique on a sample of healthy ear tissue from a 40-year-old patient who underwent a labyrinthectomy (removal of parts of the inner ear) to access a brain tumor. The adult human stem cells isolated from this tissue also multiplied and differentiated into hair cells, although not as robustly as the mouse cells did.

But as Corwin noted about Edge's research, "You can see in their paper that they are perfecting their technique as they go along."

Follow Christopher Wanjek @wanjekfor daily tweets on health and science with a humorous edge. Wanjek is the author of "Food at Work" and "Bad Medicine." His column, Bad Medicine, appears regularly on Live Science.

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Hear This: Scientists Regrow Sound-Sensing Cells - Live Science

If we cut off the tail of a lizard, it grows back. If we cut off the hand of a human being, it does not grow back. Why not? This question has perplexed scientists for a long time. Recently scientists at the Translational Genomics Research Institute (TGen) and Arizona State University (ASU) in the US identified three tiny RNA switches (known as microRNAs) which turn genes on and off and are responsible for the regeneration of tails in the green lizard. Now researchers are hoping that using the next generation genomic DNA and computer analysis will lead to discoveries of new therapeutic approaches to switch on similar regenerative genes in human beings.

Micro RNAs are able to control many genes at the same time. They have been compared to an orchestra conductor controlling and directing many musicians. Hundreds of genes (musicians playing the orchestra of life), controlled by a few micro RNA switches, have been identified that are responsible in the regenerative process. This may well mark the beginning of a new era in which it may be possible to regenerate cartilage in knees, repair spinal cords and amputated limbs.

Tissue regeneration has become an attractive field of science, triggered by exciting advances in stem cell technologies. Stem cells are undifferentiated biological cells that are then converted into various types of cells such as heart, kidney or skin through a process known as differentiation. They can divide into more stem cells and provide a very effective mechanism for repair of damaged tissues in the body. The developing embryo contains stem cells which are then transformed into specialised cells as the embryo develops. They can be obtained by extraction from the bone marrow, adipose tissue or blood, particularly the blood from the umblical cord after birth.

Stem cells are now finding use in a growing number of therapies. For instance leukaemia is a cancer of the white blood cells. To treat leukaemia, one approach is to get rid of the diseased white blood cells and replace them with healthy cells. This may be done by a bone marrow transplant through which the patients bone marrow stem cells are replaced with those from a healthy, matching donor. If the transplant is successful, the stem cells migrate into the patients bone marrow resulting in the production of new, healthy white blood cells that replace the abnormal cells. Stem cells can now be artificially grown and then transformed (differentiated) into the heart, kidney, nerve or other typed of cells.

The field of regenerative medicine is developing at a fast pace. It involves the replacement, engineering or regeneration of human tissues and organs so that their normal function can be restored. Tissues and organs can also be grown in the laboratory if the body cannot heal itself. If the cells of the organ being grown are derived from the patients own cells, the possibility of rejection of the transplanted organ is minimised. Stem cells may also be used to regenerate organs.

Each year about 130,000 organs, mostly kidneys, are transplanted from one human being to another. The process of growing organs artificially has been greatly accelerated by the advent of 3D bioprinting. This involves the use of 3D printing technologies through which a human organ, liver or kidney, is produced by printing it with cells, layer-by-layer. This became possible when it was discovered that human cells can be sprayed through the nozzles of an inkjet printer without destroying or damaging them. Tissues and organs can thus be produced and transplanted into humans. Joints, jaw bones and ligaments can also be produced in this manner.

Initially, the work was confined to animals when ears, bones and muscle tissues were produced by bioprinting and then successfully transplanted into animals. Even prosthetic ovaries of mice were produced and transplanted so that the recipient mice could conceive and give birth later. While gonads have not been produced by bioprinting in humans, blood vessels have already been produced by the printing process and successfully transplanted into monkeys. Considerable work is also going on in the production of human knee cartilage pads through the bioprinting process. Wear and tear of the cartilage results in difficulties in walking, particular in older age groups, and often requires knee replacement through surgeries. The development of technologies to replace the damaged cartilages with new cartilages made by bioprinting could prove to be invaluable.

Another area of active research in this field is the production of human skin by bioprinting which may be used for treating burns and ulcers. Technologies have been developed to spray stem cells derived from the patient directly on the areas of the body where the skin is needed. In this way, stem cells help skin cells regrow under suitable conditions. Similar progress is being made in generating liver, kidney and heart tissues so that the long waiting time for donors can be circumvented.

When will we be able to print entire human organs? It has been estimated that complete human kidneys and livers should become commercially available through the bioprinting process within five to seven years. Hearts will probably take longer because of their more complex internal structure. However, one thing is clear: a huge revolution is now taking place in the field of regenerative medicine, triggered by spectacular advances in stem cell research. This presents a wonderful opportunity for learning and developing expertise in this field for us in our country.

In Pakistan a number of important steps have been taken in this fast evolving field. One of them is the establishment of a first rate facility for stem cell research in the Dr Panjwani Centre for Molecular Medicine and Drug Research (PCMD) in the University of Karachi. This institution has already earned an international reputation because of its outstanding publications in this field.

A second important development is that plans to set up an Institute for Translational Regenerative Medicine at PCMD so that Pakistan remains at the cutting edge in this fast emerging field are now under way.

Such initiatives can however only contribute to the process of socio-economic development if they operate under an ecosystem that is designed to promote the establishment of a strong knowledge economy.

Pakistan spends only about 0.3 percent of its GDP on science and about two percent of its GDP on education, bringing the nations ranking to the lowest 10 countries in the world. This is largely due to the stranglehold of the feudal system over our democracy. It is only by tapping into our real wealth our children that Pakistan can emerge from the quagmire of illiteracy and poverty and stand with dignity in the comity of nations.

The writer is chairman of UN ESCAP Committee on Science Technology & Innovation and former chairman of the HEC. Email: [emailprotected]

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Amazing medicine - The News International

February 21, 2017 by Katherine Unger Baillie Long-lived plasma cells (yellow) dwell in the bone marrow. Credit: University of Pennsylvania

If you've ever wondered how a vaccine given decades ago can still protect against infection, you have your plasma cells to thank. Plasma cells are long-lived B cells that reside in the bone marrow and churn out antibodies against previously encountered vaccines or pathogens.

While plasma cells are vital components of the immune system, they can also be a contributor to disease, as is the case in autoimmune diseases, such as lupus and rheumatoid arthritis, and in certain cancers, such as multiple myeloma.

Now, a group led by researchers at the University of Pennsylvania School of Veterinary Medicine, has come to a better understanding of how these cells are maintained. Using a specialized type of microscope that captures the movement and interaction of cells in living organisms, the scientists observed that, in the bone marrow, immune cells called regulatory T cells closely interact with plasma cells and support them. When the T cells aren't there, plasma cells vanish.

"This interaction was completely unanticipated," said senior author Christopher A. Hunter, Mindy Halikman Heyer Distinguished Professor of Pathobiology and chair of the Department of Pathobiology at Penn Vet. "If we can understand what controls these long-lived plasma cells, then maybe we can augment that interaction, making more plasma cells to, for example, enhance vaccine efficiency. Or, if you want to limit autoimmunity or cancer, maybe there is an opportunity to disrupt this niche to mitigate some of those conditions."

The research, published in the journal Cell Reports, was led by two trainees in Hunter's laboratory, Arielle Glatman Zaretsky and Christoph Konradt, along with a team of researchers from Penn Vet, Penn's Perelman School of Medicine, Harvard Medical School, Osaka University, Medimmune, the University of California, San Diego, and The Wistar Institute.

Hunter's laboratory has long investigated how the immune system responds to infection with the parasite Toxoplasma gondii. They have used high-tech microscopy to visualize the dynamics of immune cells and other structures in living organisms.

This specialized imaging was able to turn up a surprising finding. A video of the bone marrow in a mouse exposed to T. gondii revealed that the animal's plasma cells disappeared, later returning as the infection was controlled.

A few other groups had seen plasma cells behave similarly in response to systemic inflammation or infection, but the reason for the drop in plasma cells remained unclear.

"We don't know whether these cells leave the bone marrow or die there during infection, but, either way, they are gone," said Glatman Zaretzky. "And that set up a great system to understand what kinds of cellular interactions normally create the hospitable environment and allow the plasma cells to remain there."

The research team had noticed that regulatory T cells, which Hunter calls "the health and safety inspectors" of the immune system because they keep immune responses at the appropriate level, were located in a similar region of the bone marrow as the plasma cells, next to the blood vessels. And, when mice were exposed to an infection, these "T regs" declined precipitously, just as the plasma cells had.

Together, these observations called to mind an earlier finding by another group of scientists that showed that T regs play a key role in protecting the bone marrow from inflammation. In other words, it suggested that T regs make the bone marrow an immune-privileged site, shielding its vital components from the potentially damaging effects of infection or immune response.

Curious whether these T regs interacted with plasma cells, the researchers examined both cell types in mice that have T regs labeled with a green fluorescent marker and plasma cells labeled with a yellow one. They found that T regs appeared to be closely interacting with plasma cells for extended periods of time.

"No one had put these two cell types together before," Hunter said. "Yet, when we looked, we saw that these interactions were not rare but were frequent and sustained."

Further studies found that both of these cell types also interact with dendritic cells, which are thought to promote plasma-cell survival. The researchers also demonstrated that T regs were necessary to maintain plasma cells, showing that enhancing T reg survival in mice during infection increased plasma-cell numbers and that experimentally depleting T regs led to reductions in plasma cells.

The work gives insight into how the body is able to sustain plasma cells for so long, ensuring that they will jump into action even years after a vaccine was administered or an earlier infection was conquered. They also lay the foundation for targeting this cell populationa feat that has thus far escaped scientiststo ameliorate autoimmune diseases that arise due to inappropriate antibody production or to treat cancers that form from plasma cells.

Explore further: Shp1 protein helps immune system develop its long-term memory

More information: Cell Reports, DOI: 10.1016/j.celrep.2017.01.067 , http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30137-7

A protein called Shp1 is vital to the immune system's ability to remember infections and fight them off when they reappear, researchers at A*STAR have found.

Antibody-secreting plasma cells arise from B cell precursors and are essential for adaptive immune responses against invading pathogens. Plasma cell dysfunction is associated with autoimmune and neoplastic disorders, including ...

Melbourne researchers have identified a protein responsible for preserving the antibody-producing cells that lead to long-term immunity after infection or vaccination.

Multiple myeloma is a cancer of the plasma cells that reside inside bone marrow. Plasma cells produce certain proteins that build up the immune system. In abnormal quantities, these proteins damage the body and compromise ...

Scientists have identified the gene essential for survival of antibody-producing cells, a finding that could lead to better treatments for diseases where these cells are out of control, such as myeloma and chronic immune ...

Scientists from A*STAR's Bioprocessing Technology Institute (BTI) have uncovered the crucial role of two signalling molecules, DOK3 and SHP1, in the development and production of plasma cells. These discoveries, published ...

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T cells support long-lived antibody-producing cells - Medical Xpress - Medical Xpress

New research provides further evidence of autologous hematopoietic stem cell transplantation as an effective treatment for multiple sclerosis, after finding the procedure halted disease progression for 5 years in almost half of patients.

Lead study author Dr. Paolo Muraro, of the Department of Medicine at Imperial College London in the United Kingdom, and colleagues recently reported their findings in JAMA Neurology.

The results come just a fortnight after another study revealed the success of a similar treatment in a small group of patients with relapsing-remitting multiple sclerosis (RRMS).

However, Dr. Muraro and team warn that further trials are needed to determine the efficacy and safety of autologous hematopoietic stem cell transplantation (AHSCT), after a small number of patients died within 100 days of treatment.

In AHSCT, a patient's own stem cells are harvested. The patient is then subject to high-dose chemotherapy to eliminate any diseased cells.

Next, the harvested stem cells are returned to the patient's bloodstream, with the aim of restarting normal blood cell production. In simple terms, AHSCT "resets" the immune system.

"We previously knew this treatment reboots or resets the immune system - and that it carried risks - but we didn't know how long the benefits lasted," notes Dr. Muraro.

For their study, the researchers assessed data from 25 treatment centers across 13 countries, identifying 281 patients with multiple sclerosis (MS) who underwent AHSCT between 1995-2006. Of these patients, 78 percent had a progressive form of MS.

Using the Expanded Disability Status Scale (EDSS), the team evaluated patients' progression-free survival at 5 years after treatment and any improvements in MS symptoms.

An EDSS score of zero represents no disability, seven represents the use of a wheelchair, while 10 represents death from MS. At the beginning of the study, patients had an average EDSS score of 6.5.

Overall, the researchers found that 46 percent of patients experienced no disease progression in the 5 years after treatment.

Patients with RRMS - characterized by inflammatory attacks, or "flare-ups," followed by periods of remission - had the best outcomes, with 73 percent experiencing no worsening of symptoms in the 5 years after AHSCT.

Additionally, patients experienced small improvements in MS symptoms after AHSCT. Patients with progressive MS saw their EDSS score rise by 0.14 a year after treatment, while patients with RRMS experienced a 0.76 increase in their EDSS score.

Patients with a younger age, few immunotherapies prior to AHSCT, and a lower EDSS score at study baseline also showed better outcomes with AHSCT.

While these findings show promise for the use of AHSCT for patients with MS, the team notes that there were eight deaths in the 100 days after AHSCT, which were thought to have been treatment related.

AHSCT involves aggressive chemotherapy, which can severely weaken the immune system and increase susceptibility to infection.

"In this study, which is the largest long-term follow-up study of this procedure, we've shown we can 'freeze' a patient's disease - and stop it from becoming worse, for up to 5 years.

However, we must take into account that the treatment carries a small risk of death, and this is a disease that is not immediately life-threatening."

Dr. Paolo Muraro

Dr. Muraro notes that, importantly, this study did not include a group of MS patients who did not receive treatment, further highlighting the need for more studies assessing the safety and efficacy of AHSCT.

"We urgently need more effective treatments for this devastating condition, and so a large randomized controlled trial of this treatment should be the next step," he adds.

Read about a study that links vitamin D level at birth to the risk of MS.

See more here:
Multiple sclerosis: Stem cell transplantation may halt disease progression - Medical News Today

This article was originally published on The Conversation. Read the original article.

Most of the research behind new medical advances is carried out using either animal tissues or cancer cells. Both tools have their problems: results from animals and humans do not always match up and cancer cells grown for years in laboratories often do not mimic the tissues they originally came from very well. Bridging the gap between whole animals and simple cells can be a challenge during the development of new treatments, but this is beginning to change since scientists have learned how to grow organoids.

Organoids are clusters of cells that organize themselves into mini versions of our organs. They are grown from stem cells, and their use has only become possible with the discovery of the precise conditions needed to keep stem cells alive outside the body. Organoids were first made from intestines but have since been made using many other tissues, including liver, breast and even brain cells. This will allow scientists to better study the development and diseases of these organs.

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An engineer from CNRS (French Reseach Institut Center) introduces embryonic stem cells in a mouse embryo to set a genetically modified line, Marseille, France, February 9, 2012. Organoidslab-grown miniature versions of organsare proving to be a game changer in the field of medical research. Anne-Christine Poujoulat/AFP/Getty Images

They are grown in a gel that allows them to develop three-dimensionally, so they mimic the architecture of our organs much more realistically than a simple layer of cells. Stem cells from the intestine multiply to form a ball, in which the hollow centeris like the space inside the intestine. The surface of these balls then buds outwardat various points to form pocket-like extensions. This is similar to the intensely folded surface of the gut wall.

Organoids have several advantages over existing approaches. Stem cells are taken from animals or patients and continually multiply so the organoids can be maintained for months. They provide an unlimited supply of material for study, meaning fewer animal studies are required. Making organoids from patients also raises intriguing possibilities for personalized medicine.

In traditional cell cultures every cell is identical but stem cells can form many different cell types, so organoids contain a much more realistic mixture of cells. For example, M cells are specialized cells in the gut wall that act as surveillance posts, capturing bacteria from the gut and showing them to the immune system so it can monitor for danger. Some harmful bacteria exploit this to invade the gut wall. It was previously tricky to grow M cells in the lab for study, but they can be grown in organoids. When added to organoids, Salmonella, a bacterium that causes food poisoning, infected M cells more often than other cell types, suggesting this may be a route of infection in humans.

Some common disease-causing bacteria are surprisingly difficult to grow in the lab, making them hard to study. Clostridium difficile causes numerous cases of diarrhoea every year, a serious condition in frail patients. It has been difficult to grow C. difficile because it requires conditions without oxygen, but researchers in the U.S. have shown that the bug can survive inside intestinal organoids. Bacteria were injected into the centerof intestinal organoids and produced a toxin that made the organoid wall leakier, damaging its ability to act as a barrier.

Organoids made from patient biopsies are allowing us to investigate differences between individuals. Patients with cystic fibrosis show varied responses to treatments. One group of researchers grew organoids from patient biopsies and tested their response to different combinations of drugs. In the future this may be used to quickly find the best treatment for each individual.

Tumors also vary hugely between individuals. Dutch researchers grew organoids from patients with colorectal tumors and identified genetic changes that had occurred in the tumour cells compared to the patients healthy tissue. They were then able to see how these altered the way the cells behaved. They tested anti-cancer drugs on the organoids and could tell which drugs did and did not kill the tumor cells.

Imagine if organoids were routinely made from tumor biopsies and used to identify the best chemotherapy combination for each patient. This is certainly plausible, but the process will first need to be made quicker and cheaper.

All this makes organoids an exciting new tool for researchers. Most work currently focuses on the stomach and intestine, but the technique is quickly expanding to other tissues, such as liver, breast and brain. Organoids will transform the way we conduct medical research, from basic understanding to drug development and personalized therapies. Expect to hear much more about them in the future.

Louise ThompsonisPhD candidate in Molecular and Cellular Physiology at theUniversity of Liverpool.

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Here's Why Organoids Are a Game Changer in Medical Research - Newsweek

1. Combining tumor-specific T cells and pathogen-based immune stimulation, reenergized adoptive cell transfer (ReACT) targeted and eradicated tumor cells in mice.

2. ReACT led to increased migration of activated T cells to the tumors, a metric that correlated with decreased tumor size.

Evidence Rating Level: 2 (Good)

Study Rundown: Because cancer cells can evade being targeted by the bodys immune system, therapies have been developed to alter the tumors immune microenvironment. One therapy, adoptive cell transfer (ACT), involves engineering T cells to target cells that express tumor-associated antigens (TAAs). Although this therapy has potential, the tumor microenvironment causes inhibition of T cell function, preventing the therapys long-term efficacy. Another approach has been to use pathogens that express TAAs to stimulate the immune system. However, since some tumor cells have altered TAAs, they evade being targeted. In this study, these two approaches were combined into a therapy named ReACT: T cells were engineered to target a TAA as well as a bacterial antigen, and the cells were administered along with a bacterial adjuvant.

When treated with ReACT, a majority of mice with implanted melanoma cells experienced tumor eradication. An increased frequency of T cells in the tumor environment correlated with decreased tumor size. In addition, biomarker levels indicated effective T cell migration and activation. A polyclonal form of ReACT was also tested in a mouse model of melanoma; following tumor eradication in these mice, more tumor cells were introduced but failed to survive, demonstrating an immunological memory response induced by this therapy.

This study demonstrated a new approach for a safer and more efficacious cancer immunotherapy. Future studies will need to more closely mimic a clinical model and provide specific data describing the mechanism of T cell function in this therapy.

Click to read the study in PNAS

Relevant Reading: Cancer Immunotherapy: Strategies for Personalization and Combinatorial Approaches

In-Depth [animal study]: The researchers obtained CD8 T cells that expressed a T cell receptor (TCR) that recognizes a TAA specific to murine melanoma cells. These T cells were then engineered to express a TCR that recognizes the antigen ovalbumin (OVA). In mice with melanoma tumors, this treatment was only effective when the T cells were administered in conjunction with OVA conjugated to Listeria (LM-OVA), a model organism used for pathogen-based cancer vaccines. Seven out of 10 mice experienced complete tumor cell eradication (p<0.001). Neither the engineered T cells alone nor the LM-OVA alone was sufficient to produce significant tumor regression.

Next, the properties and functions of the ReACT T cells were analyzed. The CD8 T cells were present at a higher frequency in the ReACT-treated mice and this value negatively correlated to tumor size, with an r-value of -0.699. These T cells had an activated phenotype, with an increased expression of CD44 and other transcription factors as well as a decreased expression of inhibitory receptors such as CTLA-4. These T cells also had a high expression of CXCR3, a chemokine receptor involved in migration to tumor cells.

Finally, polyclonal ReACT was tested in mice with melanoma tumors. Tumor-specific CD8 T cells were generated by stimulating them with dendritic cells presenting a pool of TAAs; the cells were additionally engineered to express the OVA TCR, and administered to mice along with LM-OVA. Eleven out of 16 mice experienced complete tumor eradication. These mice were then reintroduced to the same melanoma cell line and were resistant to tumor relapse, demonstrating the establishment of an immunological memory response.

Image: PD

2017 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.

2 Minute Medicines The Classics in Medicine: Summaries of the Landmark Trials is available now in paperback and e-book editions.

This text summarizes the key trials in:General Medicine and Chronic Disease, Cardiology, Critical and Emergent Care, Endocrinology, Gastroenterology, Hematology and Oncology, Imaging, Infectious Disease, Nephrology, Neurology, Pediatrics, Psychiatry, Pulmonology, and Surgery.

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Augmented adoptive cell transfer eradicates solid tumors [PreClinical] - 2 Minute Medicine

February 20, 2017 by Dov Smith

Non-Hodgkin lymphomas (NHL), tumors which may originate from B or T lymphocytes, account for approximately 3% of the worldwide cancer burden. Most epidemiological studies of NHL have been carried out in North American and European populations, with a few focusing on East Asian populations. Very few epidemiological studies have been conducted on B-cell non-Hodgkin lymphoma (B-NHL) in Middle Eastern populations.

Since Israelis and Palestinians represent genetically and culturally diverse populations living in geographic proximity, research analyzing their risk factors can enrich our understanding of genes and environment in the causation of lymphoma. Despite sharing the same ecosystem, the populations differ in terms of lifestyle, health behaviors and medical systems. Yet both populations report high incidences of NHL, which represents the fifth most common malignancy in Israel and the eighth most common malignancy among West Bank Palestinians. (As of 2012, Israel also ranked first in the world in NHL incidence rates.)

Now, Israeli and Palestinian researchers, led by Prof. Ora Paltiel, Director of the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, and a Senior Physician in Hadassah's Hematology Department, have conducted a large scale epidemiological study examining risk factors for B-NHL and its subtypes in these two populations.

Recruiting from both the Palestinian Arab and Israeli Jewish populations, the researchers looked at medical history, environmental and lifestyle factors among 823 people with B-cell non-Hodgkin lymphoma (B-NHL) and 808 healthy controls. Using data from questionnaires, pathology review, serology and genotyping, they uncovered some risk factors common to both populations and other factors unique to each population.

The data, reported in the peer-reviewed journal PLOS ONE, showed that in both populations, overall B-NHL was associated with recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a blood cancer. An inverse association was noted with alcohol use. Some exposures, including smoking and greater-than-monthly indoor pesticide use, were associated with specific subtypes of B-NHL.

The data also pointed to differences between the populations. Among Palestinian Arabs only, risk factors included gardening and a history of herpes, mononucleosis, rubella, or blood transfusion, while these factors were not identified in the Israeli Jewish population. In contrast, risk factors that applied to Israeli Jews only included growing fruits and vegetables, and self-reported autoimmune diseases.

The researchers concluded that differences in the observed risk factors by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by lymphoma subtypes infer specific causal factors for different types of the disease. These findings require further investigation as to their mechanisms.

The fact that risk factors operate differently in different ethnic groups raises the possibility of gene-environment interactions, that is, that environmental exposures act differently in individuals of different genetic backgrounds. But this divergence may reflect differences in diet, cultural habits, socioeconomic, environmental and housing conditions, medical services, exposure to infections in early life or other factors.

This study reflects a unique joint scientific effort involving Israeli and Palestinian investigators, and demonstrates the importance of cooperative research even in politically uncertain climates. Cancer epidemiology will be enriched through the broadening of analytic research to include under-studied populations from a variety of ethnicities and geographic regions.

"Apart from the scientific contribution that this research provides in terms of understanding risk factors for NHL, the study entails an important research cooperation among many institutions. The study provided opportunities for training Palestinian and Israeli researchers, and will provide for intellectual interaction for years to come. The data collected will also provide a research platform for the future study of lymphoma. Epidemiologic research has the potential to improve and preserve human health, and it can also serve as a bridge to dialogue among nations," said Prof. Ora Paltiel, Director of the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, and a Senior Physician in Hadassah's Hematology Department.

Explore further: Israeli lifestyle and environment may pose exceptional risks for Hodgkin's lymphoma

More information: Geffen Kleinstern et al. Ethnic variation in medical and lifestyle risk factors for B cell non-Hodgkin lymphoma: A case-control study among Israelis and Palestinians, PLOS ONE (2017). DOI: 10.1371/journal.pone.0171709

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Researchers cooperate to find risk factors for B cell non-Hodgkin lymphoma - Medical Xpress

JACKSONVILLE, Fla. As a boy growing up in Kano, Nigeria, Dr. Abba Zubair dreamed of going to space.

On Sunday, his work hitched a ride with a private rocket blasting off from NASA's Kennedy Space Center in Cape Canaveral, Fla., on a trip to the International Space Station.

Dr. Zubair, an associate professor of laboratory medicine and pathology at the Mayo Clinic's Florida campus, prepared a science package involving stem cells as part of a resupply mission to the ISS aboard a SpaceX Falcon 9 rocket.

"It was my first rocket launch view," said Dr. Zubair, who was on hand to watch and listen to the deafening sound as his experiment rode into space. "It was incredible."

The stem cells -- specialized cells derived from bone marrow come from Dr. Zubair's lab. Dr. Zubair, according to a report from the Mayo Clinic, specializes in cellular treatments for disease and regenerative medicine. He hopes to find out how the stem cells hold up in space and if they can be more quickly produced in microgravity.

More specifically, Zubair said, he is hoping the research can help in treatment of patients who have suffered a stroke-related brain injury.

"Stem cells are known to reduce inflammation," he said in a press release. "We've shown that an infusion of stem cells at the site of stroke improves the inflammation and also secretes factors for the regeneration of neurons and blood vessels."

The problem with such a treatment and studying the treatment is generating enough stem cells for the job. Based on current regenerative medicine studies, patients need at least 100 million stem cells for an effective dose. However, reproducing stem cells can be time consuming since the cells naturally limit their numbers.

"Scalability is a big issue," Dr. Zubair said. "I've been interested in a faster way to make them divide."

And on earth, everything is impacted by gravity, from how high we grow to our bone size and other physiological traits. "So, how can we use the effect of gravity to impact how the cells divide?" he asked.

Experiments that simulate stem cell growth in microgravity, thus far, have shown cells do grow more quickly than experimental controls, he said. So he began working toward getting an experiment into space. The experiment needed to be designed so the crew onboard the space station could run the experiment with some simple training, and Dr. Zubair will be able to watch the experiment in real time via a video connection. "We'll get some data as early as next week," he said.

If all goes well, growing stem cells in space something Dr. Zubair admits sounds like a dream of the distant future might become a reality more quickly than many people think.

"There are some companies interested in floating labs," he said. "I think the future is bright. There are a lot of possibilities in the area of regenerative medicine."

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Mayo doc's stem cell experiment blasts into space - Post-Bulletin

Posted February 20, 2017 Atlanta, GA

The Georgia Institute of Technology will play a key role in a new public-private partnership to help establish best practices and eventual industry-wide standards for the production of therapies using living cells to treat a range of conditions.

The new partnership aims to advance techniques to process, measure and analyze cell, gene, tissue-engineered, and regenerative medicine products, as well as cell-based drug discovery products.

We are poised to make a significant impact in how cells and regenerative medicine products are manufactured across the world through this new strategic partnership, said Krishnendu Roy, Robert A. Milton Chair and professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

Roy will serve as one of the Charter Board Members for the new International Standards Coordinating Body (SCB), which was recently established in coordination with National Institute of Standards and Technology (NIST) and Alliance for Regenerative Medicine (ARM).

Georgia Tech has already taken a leadership role in development of best practices and analytical standards that will impact biomanufacturing and innovation through the national roadmap on cell manufacturing developed by the National Cell Manufacturing Consortium (NCMC) and the newly established Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3M), Roy said.

Compared to traditional pharmaceuticals, which are made primarily through chemical processes, biological medicines, also known as biopharmaceuticals, are much more challenging to produce. With medicines like cell-therapies, gene therapies and engineered tissues, finding ways to produce larger quantities at a time while ensuring high-quality and safety is a key challenge.

The SCBs long-term mission is to efficiently and effectively support sector standards development to accelerate product development and scalability, and streamline regulatory submission review and approval, said Robert A. Preti, chairman of ARM and president of cell manufacturing industry partner PCT, a Caladrius Company.

The new standards initiative comes on the heels of the establishment of two National Manufacturing Innovation Institutes announced last December. One, the Institutes for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), which the U.S. Department of Commerce is supporting with a five-year, $70 million grant is a consortium of more than 150 companies, academic institutions and other organizations focused towards working on improving the way biopharmaceuticals are produced, with a goal of bringing down costs and finding ways to get the drugs into the hands of clinicians and patients faster. The second, Advanced Regenerative Manufacturing Institute (ARMI) is funded by the Department of Defense and focuses on biofabrication of engineered tissues as replacement of damaged and diseases organs as well as for therapeutics development. Georgia Tech is poised to play key roles in these initiatives as well.

These synergistic national and international activities further establish Georgia Tech as a leading academic institution in the biopharmaceutical area, Roy said. In January 2016, Georgia Tech announced the Marcus Center as a research center devoted to developing processes and techniques to manufacture living cells. The center was made possible by a $15.7 million grant from the Atlanta-based Marcus Foundation. This center intends to work closely with NIIMBL and ARMI to further leverage these unique private-public partnerships and develop transformative technologies to bring cell-based therapies and regenerative medicines to clinic faster and at a lower cost.

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New Partnership to Advance Production Standards in Biomanufacturing - Research Horizons