Rhythm of cells: Daily changes in human cells

Life is subject to natural rhythms, such as the light and dark cycle or seasonal variation in temperature. A recent study shows that the composition of human cell membranes varies depending on the time of day. These cyclical changes in cell membranes could have a significant impact on health and disease, scientists say.

The analysis of cell membranes revealed significant daily rhythms in eleven fatty acids.

Credit: © magann / Fotolia

Life is subject to natural rhythms, such as the light and dark cycle or seasonal variation in temperature. A recent study by researchers at the Vetmeduni Vienna, shows that the composition of human cell membranes varies depending on the time of day. These cyclical changes in cell membranes could have a significant impact on health and disease. The results were published in the Journal of Biological Rhythms.

Fatty acids are important components of cell membranes. They have signalling functions within the cells and play a role in controlling metabolic processes in the entire body. Thomas Ruf and Walter Arnold of the Research Institute of Wildlife Ecology at the University of Veterinary Medicine, Vienna, investigated these cyclic fluctuations in human cells.

"Nearly all physiological processes in humans and animals, such as body temperature or heart rate, undergo daily rhythms, and many even exhibit annual fluctuations. We wanted to find out if these rhythms are related to changes in cell membranes," explains first author Thomas Ruf.

The researchers investigated buccal mucosa cells in 20 subjects over a period of one year. Study participants collected their cells on a predetermined day every month at three hour intervals by intensively rinsing their mouths with water and then freezing the samples in special flasks.

The composition of fatty acids changes during the course of the day

The analysis of the cell membranes revealed significant daily rhythms in eleven fatty acids. Several fatty acids were present in higher concentrations at night, others during the daytime. "The cellular changes have one thing in common: they always occurred at about the same time in all participants. This shows that a clear rhythm is present," Ruf explains.

"From animal physiology, we know that the fatty acid composition in cell membranes can be remodelled in response to environmental conditions. Fatty acid composition is especially subject to seasonal fluctuations. However, while the participants of our study all showed daily fluctuations, seasonal changes occurred only in individual cases."

In contrast to wildlife, no clear annual rhythm could be seen in the fatty acid patterns of the study participants. Around one half of the subjects showed yearly rhythms, but these were not synchronous. Some participants exhibited a peak in spring or in summer, while in others the same fatty acid had higher concentrations in autumn or in the winter. "In western countries, seasons are having an increasingly smaller impact on the body. This is due to the prevalence of artificial light, which makes for longer days, and the long heating season, which minimises temperature fluctuations. Annual rhythms still exist, but these are no longer synchronised with the seasons," says Ruf.

Certain diseases occur in seasonal rhythms

This remodelling of human cell membranes could be of medical importance. It is known that certain fatty acids such as omega-3 fatty acids offer protection against certain diseases, while others, if taken up in excess, can have negative effects. The composition of the fatty acids in cell membranes may therefore have a variety of different health consequences.

"This may also explain why certain diseases and even death occur at specific times of day. Statistically speaking, heart attacks occur more often in the morning than in the evening. Blood pressure usually rises before noon. We currently do not know exactly what causes the changes in the composition of the cell membranes. The type of food eaten and the time of food intake may also play a role. These questions must still be researched," Ruf points out.

In addition to consuming sufficient quantities of important healthy fatty acids such as omega-3 fatty acids in fish oil or oleic acids in olive oil, it may also be important to choose the right time for intake.

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The above post is reprinted from materials provided by University of Veterinary Medicine Vienna.

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Cell structure discovery advances understanding of cancer development

A cell structure has been discovered that could help scientists understand why some cancers develop. For the first time, a structure called 'the mesh' has been identified which helps to hold together cells. This discovery changes our understanding of the cell's internal scaffolding.

A 3-D view of the mesh: microtubules (green tubes) of the mitotic spindle are held together by a yellow network, the mesh.

Credit: Warwick Medical School

University of Warwick researchers have discovered a cell structure which could help scientists understand why some cancers develop.

For the first time a structure called 'the mesh' has been identified which helps to hold together cells. This discovery, which has been published in the online journal eLife, changes our understanding of the cell's internal scaffolding.

This also has implications for researchers' understanding of cancer cells as the mesh is partly made of a protein which is found to change in certain cancers, such as those of the breast and bladder.

The finding was made by a team led by Dr Stephen Royle, associate professor and senior Cancer Research UK Fellow at the division of biomedical cell biology at Warwick Medical School. Dr Royle said: "As a cell biologist you dream of finding a new structure in cells but it's so unlikely. Scientists have been looking at cells since the 17th Century and so to find something that no-one has seen before is amazing."

Researchers at the University's Warwick Medical School made the discovery by accident while looking at gaps between microtubules which are part of the cells' 'internal skeleton'. In dividing cells, these gaps are incredibly small at just 25 nanometres wide -- 3,000 times thinner than a human hair.

One of Dr Royle's PhD students was examining structures called mitotic spindles in dividing cells using a technique called tomography which is like a hospital CAT scan but on a much smaller scale. This meant that they could see the structure which they later named the mesh.

Mitotic spindles are the cell's way of making sure that when they divide each new cell has a complete genome. Mitotic spindles are made of microtubules and the mesh holds the microtubules together, providing support. While "inter-microtubule bridges" in the mitotic spindle had been seen before, the researchers were the first to view the mesh.

The study received funding and support from Cancer Research UK and North West Cancer Research.

Dr Royle said: "We had been looking in 2D and this gave the impression that 'bridges' linked microtubules together. This had been known since the 1970s. All of a sudden, tilting the fibre in 3D showed us that the bridges were not single struts at all but a web-like structure linking all the microtubules together."

The discovery impacts on the research into cancerous cells. A cell needs to share chromosomes accurately when it divides otherwise the two new cells can end up with the wrong number of chromosomes. This is called aneuploidy and this has been linked to a range of tumours in different body organs.

The mitotic spindle is responsible for sharing the chromosomes and the researchers at the University believe that the mesh is needed to give structural support. Too little support from the mesh and the spindle will be too weak to work properly, however too much support will result in it being unable to correct mistakes. It was found that one of the proteins that make up the mesh, TACC3, is over-produced in certain cancers. When this situation was mimicked in the lab, the mesh and microtubules were altered and cells had trouble sharing chromosomes during division.

Dr Emma Smith, senior science communications officer at Cancer Research UK, said: "Problems in cell division are common in cancer -- cells frequently end up with the wrong number of chromosomes. This early research provides the first glimpse of a structure that helps share out a cell's chromosomes correctly when it divides, and it might be a crucial insight into why this process becomes faulty in cancer and whether drugs could be developed to stop it from happening."

North West Cancer Research (NWCR) has funded the research as part of a collaborative project between the University of Warwick and the University of Liverpool, where part of the research is being carried out.

Anne Jackson, CEO at NWCR, said: "Dr Royle and Professor Ian Prior at the University of Liverpool have made significant inroads into our understanding of the way in which cancer cells behave, which could potentially better inform future cancer therapies.

"As a charity we fund only the highest standard of research, as evidenced by Dr Royle's work.

"All our funded projects undergo a thorough peer review process, before they are considered by our scientific committee. Our specially selected scientific committee includes some of the UK's leading professors, award-winning scientists and pioneering professionals."

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The above post is reprinted from materials provided by University of Warwick

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Melanoma: Two Drug Combo Halves Death Risk

Progression, tumor growth slowed, side effects considerable but manageable

CHICAGO -- An immunotherapy combination for untreated melanoma reduced the risk of death or progression by more than half as compared with a drug currently used as a standard of care, a large randomized trial showed.

Patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) had a median progression-free survival (PFS) of 11.5 months compared with 2.9 months for ipilimumab alone and 6.9 months with nivolumab monotherapy. Median PFS with the combination and with nivolumab alone increased to 14 months -- more than four times greater than the PFS of patients who received only ipilimumab -- among patients whose tumors tested positive for programmed death receptor ligand 1 (PD-L1), the target of nivolumab.

The PFS improvement came at a price of increased toxicity, as grade 3/4 adverse events occurred twice as often with the combination as with ipilimumab monotherapy, but even patients who discontinued treatment because of side effects did better with the combination, as reported here at the American Society of Clinical Oncology meeting."The majority of adverse events were managed and resolved with established algorithms, so based upon the available evidence, the combination represents a means to improve outcomes, particularly for patients whose tumors have less than 5% PD-L1 expression," Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, said during a press briefing.

The rationale for combining the two drugs comes from recognition that cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD-1 represent distinct but complementary pathways involved in the negative regulation of anti-tumor immunity. Ipilimumab targets CTLA-4 and nivolumab targets PD-L1. Preclinical and phase I and II clinical studies have consistently shown greater activity (including response, complete response, and survival) with the combination than with ipilimumab alone.

Wolchok reported findings from the first phase III trial to compare nivolumab alone or in combination with ipilimumab versus ipilimumab alone. Investigators in the multicenter trial enrolled almost 1,000 patients with untreated, unresectable, or metastatic melanoma. Patients were randomized to ipilimumab, nivolumab, or the combination. Treatment continued until disease progression or development of unacceptable toxicity.

Data were stratified by PD-L1 expression, BRAF expression, and melanoma stage (byAmerican Joint Commission on Cancer criteria). The trial had co-primary endpoints of PFS and overall survival, and Wolchok reported data for PFS. Secondary endpoints included objective response rate, correlation between PD-L1 expression and efficacy, and safety.

The primary comparison was nivolumab monotherapy and the combination versus ipilimumab alone, which is a current standard of care for the patient population enrolled in the study. The results showed that the combination reduced the hazard for death or progression by 58% versus ipilimumab alone (P<0.00001). Nivolumab alone reduced the hazard by 43% versus ipilimumab (P<0.00001).

An exploratory analysis showed that the combination significantly reduced the hazard for death or progression by 26% versus nivolumab monotherapy (HR 0.74, 95% CI 0.60-0.98).

The level of PD-L1 expression had a major influence on efficacy. Patients whose tumors had expression levels of at least 5% had median PFS of 14.0 months with the combination or nivolumab alone versus 3.9 months with ipilimumab. For tumors with PD-L1 expression <5%, the combination was the clear winner with a median PFS of 11.2 months compared with 5.3 months with nivolumab alone and 2.8 months with ipilimumab monotherapy.

Secondary analyses favored the combination and nivolumab over ipilimumab, including overall response rate (57.6% with the combination, 43.7% with nivolumab alone, and 19.0% with ipilimumab, P<0.001), complete response, and partial response. Median duration of response had yet to be reached in any of the treatment groups but favored the combination (13.1 months) and nivolumab (11.7) over ipilimumab (6.9).

Median reduction in tumor size was 51.9% with the combination, 34.5% with nivolumab, and 5.9% with ipilimumab.

On the basis of the efficacy analysis, the results appeared to be a slam-dunk for the combination. The safety data added a new consideration to the evaluation process.

In the combination arm, 55% of patients had grade 3/4 adverse events, most often diarrhea, elevated liver enzymes, colitis, rash, and fatigue. However, Wolchok emphasized that the rate was in line with earlier studies of the combination. Grade 3/4 adverse events occurred in 16.3% in the nivolumab arm and 27.3% of those treated with ipilimumab alone.

A similar difference existed across treatment groups with respect to the proportion of patients who discontinued because of grade 3/4 adverse events: 29.4% with the combination, 5.1% with nivolumab alone, and 13.2% with ipilimumab alone. However, patients who discontinued the combination had an overall response rate of 68%, and half of the responses occurred after patients stopped treatment, Wolchok said.

The trial had established guidelines for managing adverse effects and stopping treatment, and "clearly, they worked." Overall survival data, which continue to mature, should help inform discussions with patients about choosing between the combination and monotherapy, he added.

"This study highlights just how much progress we've made in the treatment of melanoma," said press briefing moderator Jyoti D. Patel, MD, of Northwestern University's Feinberg School of Medicine in Chicago. "Certainly, this is a powerful combination, and it comes with some toxicity, but it is clearly manageable in a global setting.

"The most important thing this study shows is that we are beginning to define which patients may benefit from one drug and those that may benefit from both drugs. That will only inform conversations about toxicity for patients and physicians as they decide the treatment course."

The study was supported by Bristol-Myers Squibb.

Wolchok disclosed relevant relationships with Bristol-Myers Squibb, Merck, Medimmune, ZIOPHARM Oncology, Polynoma, Polaris, Jounce Therapeutics, GlaxoSmithKline, Potenza Therapeutics, VesuviusPharmaceuticals, EMD Serono, Janssen Oncology, and Merck.

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Six-month-old conjoined twin sisters separated in Haiti

On Friday, May 22, physicians and nurses separated a pair of six-month-old conjoined Haitian twins, the first such operation ever performed on Haitian soil.

Henri Ford, Md, chief of Surgery, Children's Hospital Los Angeles, holds formerly conjoined twins Michelle and Marian three days after their separation surgery in Haiti.

Credit: Image courtesy of Childrens Hospital Los Angeles

On Friday, May 22, an 18-member team of physicians and nurses from Children's Hospital Los Angeles (CHLA) and Keck Medicine of the University of Southern California (USC) led an international collaboration to separate a pair of six-month-old conjoined Haitian twins, the first such operation ever performed on Haitian soil.

Marian Dave-Nouche Bernard and Michelle Dave-Nouche Bernard, born as one on Nov. 24, 2014, were separated after a seven-hour surgery at University Hospital of Mirebalais (HUM), in Mirebalais Haiti, a poor rural community in the country's Central Plateau, about 36 miles northeast of the capital city of Port-au-Prince.

"The girls are doing fantastic," said surgical team leader Henri Ford, MD, MHA, the Haitian-born surgeon in chief at Children's Hospital Los Angeles and vice dean for Medical Education, professor and vice chair for Clinical affairs, Department of Surgery, Keck School of Medicine of USC. "It was an extremely exhilarating day; not only did our preparations pay off and the surgery succeed in spectacular fashion, but this was also a time to put politics aside and celebrate our national pride."

Marian and Michelle -- "omphalopagus" twins since they are connected at the abdomen -- are actually triplets (sister Tamar is healthy and normal). The two sisters had faced each other since birth, but recuperated in separate beds in HUM's neonatal intensive care unit. They were ready to be discharged 12 days after surgery. "We anticipate Marian and Michelle will recover fully and go on to lead healthy and happy lives," Ford says.

Conjoined twins occur in roughly 1 in 200,000 births and omphalopagus twins represent about 30 percent of all conjoined twin births. As triplets, these girls are considered even rarer, occurring 1 in an estimated 1 million births. Fused together by the breastbone (or xiphoid bone) in the lower portion of the sternum, Marian and Michelle also had attached livers that would be separated during the procedure.

It took the international surgical team almost seven hours to separate the conjoined twins.

The mother, Manoucheca Ketan, 35, gave birth to all three of her daughters at HUM after carrying them for 36 weeks. The twins shared a crib until 10 a.m. on May 22, when Ketan and her husband, David Bernard, 31, watched as their infant daughters were wheeled into surgery as one. Ten hours later, after the surgery, the parents wept when they next saw the twins -- resting in separate cribs.

By then, the girls were already feeding on formula and breast milk. "It was an extraordinary moment," Ketan said, describing her reaction when she first laid eyes on her separated daughters. "When I first met Dr. Ford, he told me he was confident we could separate my children, but I didn't know how it would turn out when the day started. Now I am feeling a lot of joy and want to recognize and thank the hospital for everything."

The complex surgical procedure got underway within 24 hours of the arrival of the 18-member surgical team of surgeons, anesthesiologists and nurses from Children's Hospital Los Angeles. The Los Angeles team was joined by 12 medical staff from Centres GHESKIO, Hospital Bernard Mevs-Project Medishare and Hopital Universitaire de Mirebalais (HUM), led by Dr. Maclee Jean-Louis, director of Surgery at HUM. The group comprised what Ford described as an international medical "Dream Team."

The family received free treatment from HUM, which is supported by the Haitian Ministry of Health and Partners in Health, an international health organization. Keck Medicine and CHLA covered the travel expenses of the medical team and donated supplies to ensure the success of the operation.

Anticipating a six- to eight-hour procedure, doctors made the first incision along the abdominal wall that connected Marian and Michelle at 1:14 p.m. At 2:50 p.m., the girls were surgically separated to a burst of applause from the team and Marian was moved to an adjacent table. Donning red caps, Marian's team of six doctors and nurses hovered over her to close her incision, while Michelle's team worked in yellow caps -- ironically reflecting the colors of USC. "The mom gave them red and yellow bands months ago to identify them," Ford explains. "They were destined to be separated by Trojan surgeons."

Michelle was wheeled out of the surgery suite at 4:45 p.m., followed by Marian at 4:58 p.m.

"This surgery took less time than previous conjoined twin separations we have performed at CHLA, since there was no pelvic attachment," explains James Stein, lead surgeon during the separation and associate chief of surgery at Children's Hospital. Stein, an associate professor of surgery at Keck School of Medicine, has now separated six pairs of conjoined twins. "There are surgeries that require the expanded expertise of a place like CHLA, but the twins' anatomy and our team's expertise allowed us to undertake the surgery in Haiti, and compile the appropriate resources to do the surgery there safely."

Ford said that by doing the operation in Haiti, the children would benefit emotionally from the proximity of their parents and the surgery could be done more cost-effectively than if it were done in Los Angeles.

After completing the first ever surgery in Haiti to separate conjoined twins, part the international team takes a break in the surgery suite at University Hospital in Mirebalais.

During the seven-hour operation, the girls underwent 11 separate procedures, with only a few minor complications. Early on, surgeons and anesthesiologists encountered a "cross circulation" -- when fluids, blood and medication pass through one twin's liver to the other without benefiting the first.

Michelle's heart rate elevated, but the surgeons -- Stein, Ford and Aaron Jensen, MD, along with CHLA anesthesiologists Duc Nguyen, MD, and Joanna E. Green, MD -- remedied the situation by expeditiously separating the livers and individually hydrating the girls intravenously.

Doctors also removed an ovarian cyst in Michelle and surgically inserted patch material in both girls to reconstruct their abdominal walls after separation. They also formed new belly buttons for the twins, whose midline vertical scars should nearly disappear over time, Stein says.

One moment during the operation seemed to sum up the enormity of the procedure for Ford. "Their lower chests were connected so we had to remove a piece of the sternum, the breastbone, and then you could see their lungs and their hearts beating," he recalled.

Once the girls were moved to intensive care, a team of intensivists led by a graduate of CHLA's pediatric residency program, Peggy Han, MD, now an attending intensivist at Weill-Cornell, and neonatal intensive care unit nurses worked with HUM staff to oversee the twins' recovery. Volunteers from two other U.S. hospitals would fly in later to join the team and help oversee care after the CHLA team departed. Forty-eight hours after surgery, the girls were breathing independently, and after 72 hours they were being fed with a combination of breast milk and formula, Ford says.

Ford started recruiting his team back in September after his first conversation with the twins' doctors at HUM. Ford and team members would make almost monthly trips to Haiti between the November births and the May 22 surgery, checking up on the health of the girls and making sure that the proper human and material resources or equipment were available to safely do the surgery at HUM. By March, the team was set and the girls, strong and healthy, were scheduled for the May procedure.

Hours after the surgery, the Haitian media reported on the milestone operation and, three days postoperatively, the famous twins were paid a visit by Haitian First Lady Sophia Martelly and Minister of Health Florence Guillaume.

In the coming weeks, the girls will recover from their incisions and undergo physical therapy to help strengthen neck muscles weakened due to facing in a single direction for such a long time. "The girls look great; we don't expect any more surgeries," Stein says. "This was all about planning and organization. The amazing part for all of us is conducting seven hours of surgery, and then seeing two kids side by side, when they used to be just one. It's just awe-inspiring."

"I liken the entire international team of surgeons, anesthesiologists, intensivists, respiratory therapists and nurses to a symphony orchestra," says team leader Ford, who no doubt would make Gustavo Dudamel proud.

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The above story is based on materials provided by Childrens Hospital Los Angeles. Note: Materials may be edited for content and length.

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Crows count on 'number neurons'

Neurobiologists have discovered cells in the crow brain that respond to a specific number of items. The study provides valuable insights into the biological roots of counting capabilities. What makes this finding even more interesting is that a long evolutionary history separates us from birds; as a consequence, the brains of crows and humans are designed very differently.

Crows recognized the number of dots shown in computer displays. Tübingen researchers discovered ‘number neurons’ in the crow’s end-brain that responded to a specific number of items.

Credit: Andreas Nieder

An old story says that crows have the ability to count. Three hunters go into a blind situated near a field where watchful crows roam. They wait, but the crows refuse to move into shooting range. One hunter leaves the blind, but the crows won't appear. The second hunter leaves the blind, but the crows still won't budge. Only when the third hunter leaves, the crows realize that the coast is clear and resume their normal feeding activity.

Helen Ditz and Professor Andreas Nieder of the University of Tübingen found the neuronal basis of this numerical ability in crows. They trained crows to discriminate groups of dots. During performance, the team recorded the responses of individual neurons in an integrative area of the crow endbrain. This area also receives inputs from the visual system. The neurons ignore the dots' size, shape and arrangement and only extract their number. Each cell's response peaks at its respective preferred number.

The study published in PNAS provides valuable insights into the biological roots of counting capabilities. "When a crow looks at three dots, grains or hunters, single neurons recognize the groups' 'threeness' ," says Helen Ditz. "This discovery shows that the ability to deal with abstract numerical concepts can be traced back to individual nerve cells in corvids."

What makes this finding even more interesting is that a long evolutionary history separates us from birds. As a consequence, the brains of crows and humans are designed very differently.

"Surprisingly, we find the very same representation for numbers as we have previously discovered in the primate cortex," Prof. Andreas Nieder says. "It seems as if corvids and primates with independently und distinctively developed endbrains have found the same solution to process numbers." Even abstract behavior which we think of as sophisticated mental feats ultimately has biological roots.

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The above story is based on materials provided by Universitaet Tübingen.Note: Materials may be edited for content and length.

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New drug triggers tissue regeneration: Faster regrowth and healing of damaged tissues

Research focuses on select tissues injured through disease, surgery and transplants, but early findings indicate potential for broad applications

The concept sounds like the stuff of science fiction: take a pill, and new tissues grow to replace damaged ones. Researchers have now announced steps toward turning this idea into reality. They have detailed how a new drug repaired damage to the colon, liver and bone marrow in animal models -- even saving mice who would have died in a bone marrow transplantation model.

Scientist holding white laboratory mouse. (stock image)

Credit: © efmukel / Fotolia

The concept sounds like the stuff of science fiction: take a pill, and suddenly new tissues grow to replace damaged ones.

Researchers at Case Western Reserve and UT Southwestern Medical Center this week announced that they have taken significant steps toward turning this once-improbable idea into a vivid reality. In a study published in the June 12 edition of Science, they detail how a new drug repaired damage to the colon, liver and bone marrow in animal models -- even going so far as to save the lives of mice who otherwise would have died in a bone marrow transplantation model.

"We are very excited," said Sanford Markowitz, MD, PhD, the Ingalls Professor of Cancer Genetics at the university's School of Medicine and a medical oncologist at University Hospitals Case Medical Center's Seidman Cancer Center. "We have developed a drug that acts like a vitamin for tissue stem cells, stimulating their ability to repair tissues more quickly. The drug heals damage in multiple tissues, which suggests to us that it may have applications in treating many diseases."

The institutions collaborating on this work next hope to develop the drug -- now known as "SW033291" -- for use in human patients. Because of the areas of initial success, they first would focus on individuals who are receiving bone marrow transplants, individuals with ulcerative colitis, and individuals having liver surgery. The goal for each is the same: to increase dramatically the chances of a more rapid and successful recovery.

The key to the drug's potential involves a molecule the body produces that is known as prostaglandin E2, or PGE2. It is well established that PGE2 supports proliferation of many types of tissue stem cells. Markowitz and University of Kentucky Professor Hsin-Hsiung Tai earlier had demonstrated that a gene product found in all humans, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), degrades and reduces the amount of PGE2 in the body.

Markowitz, also a Harrington Discovery Institute Scholar-Innovator, and James K.V. Willson, MD, a former Case Western Reserve colleague now at UT-Southwestern, hypothesized that inhibiting 15-PGDH would increase PGE2 in tissues. In so doing, it would promote and speed tissue healing. When experiments on mice genetically engineered to lack 15-PGDH proved them correct, the pair began searching for a way to inactivate 15-PGDH on a short-term basis.

The preliminary work began in test tubes. Yongyou Zhang, PhD, a Case Western Reserve research associate in Markowitz's lab and a lead author on the study, developed a test where cells glowed when 15-PGDH levels changed. Zhang then traveled to UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, where Willson serves as director. Zhang and UT Southwestern researchers Bruce Posner, PhD, and Joseph Ready, PhD, collaborated to comb through the center's library of 230,000 different chemicals. Ultimately they identified one chemical that they found inactivated 15-PGDH.

"The chemical, SW033291, acts in an incredibly potent way," Markowitz said. "It can inactivate 15-PGDH when added at one part in 10 billion into a reaction mixture, which means it has promise to work as a drug."

A series of experiments showed that SW033291 could inactivate 15-PGDH in a test tube and inside a cell, and, most importantly, when injected into animal models. The third finding came through collaboration between Markowitz and Stanton L. Gerson, MD, director of the Case Comprehensive Cancer Center, UH Seidman Cancer Center, and the National Center for Regenerative Medicine, as well as the Asa and Patricia Shiverick-Jane Shiverick (Tripp) Professor of Hematological Oncology.

Case Western Reserve research associate Amar Desai, PhD, worked between the Markowitz and Gerson laboratories to determine the effect of SW033291 on mice that had received lethal doses of radiation and then received a partial bone marrow transplant. Without SW033291, the animals died. With it, they recovered.

From there, more detailed studies showed that mice given SW033291 recovered normal blood counts six days faster than mice that were transplanted without receiving SW033291. In addition, SW033291-treated mice showed faster recovery of neutrophils, platelets and red blood cells. Neutrophils battle infection, platelets prevent bleeding, and red blood cells deliver oxygen throughout the body.

In addition, Desai's work showed that when SW033291 increases PGE2 in bone marrow, the body also begins to produce other materials that bone marrow stem cells need to survive. Finally, these benefits emerged without any adverse side effects, even at SW033291 doses much higher than would be required for 15-PGDH inhibition.

When investigators treated mice with other diseases, the SW033291 drug again accelerated tissue recovery. For example, the investigators teamed with Fabio Cominelli, MD, PhD, a Case Western Reserve Professor and Chief of the Division of Gastroenterology and Liver Disease, to study a mouse model of ulcerative colitis. SW033291 healed virtually all the ulcers in the animals' colons and prevented colitis symptoms. In mice where two-thirds of their livers had been removed surgically, SW033291 accelerated regrowth of new liver nearly twice as fast as normally happens without medication.

Because bone marrow, colon, and liver are significantly different tissues, the investigators believe the pathway by which SW033291 speeds tissue regeneration is likely to work as well for treating diseases of many other tissues of the body. However, the next stages of the research will concentrate on three diseases where SW033291 already shows promise to provide dramatic improvement.

In bone marrow transplants, for example, effects of SW033291 in accelerating tissue growth would provide the body the cells required to fight off the two most common and sometimes fatal complications, infection and bleeding. For those suffering the debilitating impact of colitis, accelerating tissue growth could heal colon ulcers more quickly, which in turn could allow patients to take lower dosages of other medications that treat colitis -- some of which have serious side effects. Finally, the promise of tissue growth could increase survival rates for patients with liver cancer; in some cases today, physicians are unable to perform surgery because the amount of the liver to be removed would be so great as to pose severe risk to the patient. But having a drug to accelerate the liver's regrowth could make surgery a viable option.

The team's next step will be to complete studies showing safety of SW033291-related compounds in larger animals, a required part of the pathway to secure approval from the U.S. Food and Drug Administration for trials in humans. If the drugs prove safe and effective in those clinical trials, they could then become available for general use by physicians. Investigators hope to partner with pharmaceutical companies to be able to start human trials within three years.

"These are thrilling times for us as researchers, and it is also an exciting time for Case Western Reserve," Markowitz said. "In Cleveland, there has been a major effort in the last two to three years to figure out how all our institutions can together work to develop drugs. This discovery is really something we should celebrate. It helps put us on the map as a place where new drugs get invented."

Markowitz added that this research received crucial financial assistance from Case Western Reserve University School of Medicine's Council to Advance Human Health (CAHH), from the Harrington Discovery Institute at University Hospitals, and from multiple National Institutes of Health grants that included the Case GI SPORE, led by Markowitz, and the National Center for Accelerating Innovation at the Cleveland Clinic. Additional support was received from the Marguerite Wilson Foundation; the Welch Foundation; the Cancer Prevention & Research Institute of Texas; Inje University; and the Korean National Research Foundation. Generous major gifts also came from the Leonard and Joan Horvitz Foundation and the Richard Horvitz and Erica Hartman-Horvitz Foundation.

Markowitz said the authors' contributions to this research are truly a tribute to the powers of collaboration. Senior authors Hsin-Hsiung Tai, Stanton L. Gerson, Joseph M. Ready, Bruce Posner, James K.V. Willson and Markowitz provided substantial leadership. Markowitz and Willson, former director of the Case Comprehensive Cancer Center and now director of the Simmons Cancer Center at UT Southwestern, initiated the project to study the potential of inhibiting 15-PGDH as a tissue-healing treatment strategy. Tai, at the University of Kentucky, Lexington, originally discovered 15-PGDH and tested SW033291 as a 15-PGDH inhibitor. Gerson and Markowitz partnered to show the SW033291 drug is effective for regenerating bone marrow in mice. Ready, a UT Southwestern chemist, synthesized SW033291 for the studies and has made multiple other highly promising derivatives of the compound. Posner, also a chemist from UT Southwestern, oversaw the search through the 230,000 compounds in the UT Southwestern chemical library.

Lead authors Yongyou Zhang, Amar Desai, Sung Yeun Yang, Ki Beom Bae, Monika I. Antczak, Stephen P. Fink and Shruiti Tiwari contributed equally to the scientific investigation. Zhang, Case Western Reserve, led the experiments that identified the drug. Desai, Case Western Reserve, performed experiments that showed that SW033291 works in bone marrow transplantation in mice. Yang and Bae, now at Inje University in Korea, worked in the Markowitz laboratory on studies of colitis (Yang) and on liver regrowth after surgery (Bae). Antczak worked in the Ready lab at UT Southwestern on the chemical synthesis of SW033291. Fink and Tiwari, both of Case Western Reserve, completed the work on the colitis mouse model.

Markowitz also cited important collaboration of two Case Western Reserve participating authors -- gastroenterologist Fabio Cominelli, who played a role in the success of the colitis experiments in mice, and Mark Chance, who contributed proteomics expertise for studies that showed how SW033291 works. Other participating investigators also contributed substantially: Joseph E. Willis, Dawn M. Dawson, David Wald, Wei-Dong Chen, Zhenghe Wang, Lakshmi Kasturi, Gretchen A. Larusch, Lucy He, Luca Di Martino, Juan Sanabria, Chris Dealwis, and Debra Mikkola, all of Case Western Reserve; Zora Djuric, University of Michigan, Ann Arbor; Ginger L. Milne, Vanderbilt University, Nashville; and Noelle S. Williams, Jacinth Naidoo, and Shuguang Wei, all at UT-Southwestern, Dallas.

"An impressive number of individuals contributed to the discovery of this 15-PGDH inhibitor drug," Markowitz said. "Each one of them has done something absolutely remarkable and indispensable to the success of the study."

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Story Source:

The above story is based on materials provided by Case Western Reserve University. Note: Materials may be edited for content and length.

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Wired Health: how are innovative technologies disrupting health care?

Last Friday, April 24th, marked the second annual Wired Health conference in London, UK, where members of the health care industry and curious spectators came together to discuss and explore how technology is shaping medicine today.

Health care aficionados, technological innovators and curious spectators met in London for a 1-day summit investigating the latest advances in the medical sector.

human behavior, Sutherland cited the rise in unnecessary visits to the UK's emergency departments coinciding with a shift in what it was called. Though it was once widely known as "Accidents and Emergencies," it is now referred to as merely "A&E," taking away the inherently bloody connotations and making it sound more like the initials of two people in love.

Rory Sutherland, of Ogilvy & Mather, addresses a packed audience at Wired Health 2015.

Referring to the emergency department by its full name on signs and in official literature could encourage patients to direct themselves to their GPs instead, decreasing the number of patients who unnecessarily use the emergency service and saving the UK's National Health Service (NHS) precious money.

"If you create a name for something," Sutherland added, "we automatically assume it's a norm."

He also explained that the way choices are presented can affect outcomes, particularly in the health care setting.

For example, when the NHS implemented the use of delayed prescriptions for antibiotics - when a prescription goes into effect a few days after an appointment, in a "wait-and-see approach" - unnecessary use of antibiotics decreased significantly.

In effect, changing the choice structure of things can alter behavior.

Removing the 'wrong' choice

Another man who recognizes that manipulating how choices are made can have positive effects in the field of medicine is Marc Koska, founder of the LifeSaver program. He noted that around the world, 1.3 million people die every year from infected needles that are reused.

After years of researching this problem, Koska came up with a simple solution to disrupt it: a syringe that is impossible to reuse. His K1 syringe is made on the same machinery and from the same materials as existing syringes, but it has an auto-disable mechanism that prevents reuse by employing a plunger that automatically locks in place and breaks if forced.

Koska showed conference-goers heartbreaking undercover footage of small children receiving injections with needles that had previously been used on HIV-positive patients, demonstrating the problem the global health care community faces.

The issue is so great that the World Health Organization (WHO) announced their third ever global policy, aiming to reduce unnecessary injections and ensure that only auto-disable syringes are used. This mandate will come into effect in 2020.

Koska noted that for every $1 spent on proper syringe disposal, over $14 could be saved on health care costs resulting from HIV, HBV and HCV. His charity SafePoint is working to improve this basic level of health care around the world. By taking the option of making the wrong decision out of the equation, Koska and colleagues are disrupting the unsafe practices that put patients at risk.

Bringing the element of choice to alternative limbs

For those who have lost limbs, there has been relatively little choice when it comes to what kind of prosthetic will become their new arm or leg. Though there have been advancements in so-called bionic reconstructions, the ability for a patient to take ownership over the design of their new limb has not really been an option - until now, that is.

The Alternative Limb Project, led by Sophie de Oliveira Barata, brings this choice to the patient, creating bespoke prosthetics for those who have lost their limbs. Each client can plan the design, and the company then works with product designers to create beautiful works of art that are also functional arms, hands, legs or feet.

Some of the designs featured by The Alternative Limb Project included a crystal leg, a limb with a speaker and mp3 dock, and a Japanese-inspired leg with pullout compartments for storage.

Some of the beautiful creations on display at Wired Health even included secret compartments in which the wearer can store things.

Speaking to a packed crowd, de Oliveira Barata explained that one of her clients recently had the idea to add a drone to an artificial arm that can "fly off the arm like a hawk" and take aerial photos.

Her unique approach empowers her clients to take ownership of their limbs, making them stand out as works of art, rather than as something to be hidden away.

Work from the company was recently thrust into the spotlight when the UK's Channel 4 introduced singer and performance artist Viktoria Modesta as "the world's first amputee pop artist."

In the video below, Modesta wears several creations from The Alternative Limb Project, including the "Spike," the "Crystal" and the "Light."

Writing on the company's website, Modesta explains how, after a voluntary operation to remove her leg - which was damaged from birth - she did not want to hide her altered body:

"Initially, after my voluntary operation, I mostly wanted to get a leg that provided balance to my body in its shape. Three years after the amputation, I then saw it as an opportunity to regard the leg as a fashion item and an art project which seemed rather fun and exciting."

Disrupting the aging process

Another speaker who took the stage at Wired Health was Brad Perkins, of Human Longevity, Inc. (HLI) - a company that focuses on genomics and cell therapy. They are tackling diseases caused by age-related decline by building a comprehensive database on human genotypes and phenotypes.

Perkins began his career at the Centers for Disease Control and Prevention (CDC), eventually spearheading investigations into the anthrax attacks in the US in 2001.

He explained that over the past 30 years, there has been a genomic revolution in bacteriology, in terms of how we study it, adding that "we humans are next" to go under the microscope.

HLI are currently working on building their database on human genotypes and phenotypes, and Perkins noted that "health care systems will be disrupted by this technology."

Interestingly, the integrated health records, along with clinical data that they are using to build their database, will become cloud-based and subjected to machine learning. HLI's 5-year goal is to achieve 1 million integrated health records so that they can fully interpret the meaning of the human genome.

"There is a potential to generate as many insights into health and disease as there has been in the last 100 years in the next 10 years," Perkins said, thus contributing to extended life spans.

Notable technological innovations

Between the Bupa Startup Stage - a platform for new companies to present their products and innovations - and the Wired Health Clinic - an exhibition where conference-goers were able to interact with new technologies - there was no shortage of interesting gadgets and gizmos.

Starstim cap

Ana Maiques models the Starstim cap from Neuroelectrics for MNT at Wired Health.

One of the most striking gadgets was a noninvasive wireless cap, which acts as a neurostimulator. Named Starstim, the cap was created by Neuroelectrics, a company led by Ana Maiques.

The cap works by delivering a low current directly to the brain through small electrodes, and it acts as an electroencephalography (EEG) and accelerometry recording system.

Because the cap is portable, it can be used both in a clinical setting and at home, where patients can employ neurofeedback to balance their EEG.

Potential applications include treatment for ADHD, chronic pain,stroke rehabilitation, cognitive enhancement, addiction and depression.

Lumo graphic reader

When dealing with innovation, there are naturally challenges to overcome, and one of the biggest is funding. Anna Wojdecka, creator of the Lumo, spoke to Medical News Today about her search to find adequate funding to take her design from prototype to finished product. She described her product as such:

"Lumo is a low-cost graphic reader for the blind and visually impaired. It translates colors into sound and black lines into tactile feedback, enabling the user to read shapes, graphs and diagrams directly from a page and draw in color."

She added that the aim of her product is to "make learning environments more inclusive and enrich interaction between blind and sighted people." When the finished product is available, Wojdecka told MNT it will sell for between $150-200. She can be contacted via Twitter @helloLUMO.

Tao WellShell

The Tao WellShell fits in the palm of the hand, acting as a gym on the go.
Image credit: Tao Wellness

Another notable gadget was the Tao WellShell, which is a handheld device that fits in the palm of the hand and works in tandem with an app to give the user a resistance workout anywhere. It can be used at home, sitting at a desk or even on a bus, train or plane.

Insulin Angel

In the realm of tiny handheld devices sits the Insulin Angel, which tracks a medication's temperature to help the user monitor and maintain effectiveness. In addition to warning the user in the event the medication has been forgotten, the Insulin Angel also tracks medication usage and waste, and displays results through a smartphone app.

Cupris Health smartphone otoscope

Given that smartphones have become our constant companions these days, innovations that incorporate these devices make other technologies easily accessible. Cupris Health is a company that is doing just that; they have turned smartphones into medical devices by employing clip-on attachments.

They displayed their smartphone-connected otoscope at the conference, explaining that parents can now take pictures of their children's ears and send the images and symptoms directly to the doctor, who can remotely advise on treatment.

How can these disruptions work together?

If conference-goers were hoping to be spoiled for choice, Wired Health 2015 certainly did not disappoint. The vast amount of startups, gadgets and solutions on display was staggering. Though the main theme of disruption was reinforced throughout the speakers' presentations and in the innovations shown in the main hall, there was a sense of disjointedness this year.

Whereas last year's conference was overwhelmingly focused on how to harness data, this year's focus felt a bit forced, as if there was no clear way to sew everything together. But perhaps this is indicative of just how quickly and in how many different directions the health care industry is moving.

Indeed, how data, research and innovation can be unified and harnessed to result in positive health outcomes is the challenge the medical community faces today. Perhaps Wired Health 2016 will focus on this issue.

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