Body

Tokyo, Japan - The human liver is a vital organ involved in multiple functions. Because susceptibility to liver diseases is highly variable among patients, researchers from Tokyo Medical and Dental University (TMDU) and Cincinnati Children's Hospital Medical Center (CCHMC) have engineered a model liver system that can be personalized for disease modeling and drug discovery.

In a study that will be published in August in Cell Metabolism, an international team of researchers including TMDU developed a method for establishing multicellular human liver organoids (miniature livers) comprising different liver cell types that show liver tissue characteristics down to the gene and protein scale. They were able to create the livers within 20 days by combining different actively growing cell types established from pluripotent stem cells (PSCs), which can transform into almost any cell type.

Importantly, the researchers were able to trigger a liver disease known as steatohepatitis in these organoids, which was confirmed by the accumulation of fats and increased expression of inflammatory proteins. Additionally, these diseased organoids showed increased levels of fibrosis (tissue scaring) indicators.

"Using atomic force microscopy, we also measured the organoids' stiffness, which reflects the severity of liver fibrosis," says author Shodai Togo. "The ability to trigger disease symptoms in this organ-simulating model will improve our understanding of disease development and underlying causes, and will allow safe drug testing."

In another exciting achievement, the researchers also managed to establish sick liver organoids using PSCs from patients with Wolman disease.

"These patients are deficient in an enzyme involved in breaking down fatty material, resulting in fat accumulation in various organs including the liver," says co-author Rie Ouchi. "We then investigated ways to treat these sick organoids and succeeded in alleviating the disease symptoms using two different methods."

As the current treatment for Wolman disease is extremely expensive, this new research model is expected to facilitate the discovery of new and more affordable treatments. This experimental success also indicates that other diseases could be modeled using this approach.

As explained by lead author Takanori Takebe, "This novel and reproducible in-a-dish strategy paves the way to precise investigation of patient-specific disease mechanisms and the discovery of effective treatments using diseased human liver organoids."

The study describes the ability of a PI3-kinase inhibitor to combat Heterotopic Ossification and Fibrodysplasia Ossificans Progressiva in murine preclinical models

These results could have an impact on the treatment of patients with these diseases

Researchers from the Bellvitge Biomedical Research Institute (IDIBELL) and the University of Barcelona (UB) have described the ability of an inhibitor of the PI3Kα (BYL719) to block the ectopic bone formation in mice. This could lead to improve the treatment of two pathologies: heterotopic ossification and fibrodysplasia ossificans progressiva (FOP, a rare bone disease). The study was led by Dr. Francesc Ventura, head of the Cell Signaling and Bone Biology group.

Heterotopic ossification (OH) consists in the appearance of ossifications in inappropriate places (ectopic formation), such as tendons, muscles, and connective tissue. For this pathology there are risk factors such as prolonged immobility, spinal injuries, burns, hip operations, and muscle traumas. "Despite knowing this we still do not have a full understanding of the causes and the most appropriate treatment for the disease," says Dr. Francesc Ventura.

On the other hand, the FOP is a rare disease very similar to OH but has its origin in a genetic mutation. FOP patients have mutations in the gene encoding a bone growth factors receptor (BMPs), the ACVR1. The disease is gradually induced by episodes of inflammation that eventually result in the progressive formation of bone in muscles, tendons, and ligaments. These ossifications reduce drastically the mobility and life expectancy of those affected. There is currently no treatment for this disease.

"What we have observed in this study is that, in stem cells cultures and in preclinical models of the disease, the BYL719 inhibitor prevents the ectopic bone formation induced by mutations in ACVR1," explains Dr. Ventura. The BYL719 inhibitor was approved by the FDA last May for its use in patients with metastatic breast cancer. Therefore, there is a large amount of information about the use of BYL719 in humans. "In this study we have shown that it can also play an important role in the ossification and treatment of these bone diseases," adds Ventura.

(New York, NY - August 2, 2019) -- Mount Sinai researchers have developed a way to use immunotherapy drugs against treatment-resistant non-Hodgkin's lymphomas for the first time by combining them with stem cell transplantation, an approach that also dramatically increased the success of the drugs in melanoma and lung cancer, according to a study published in Cancer Discovery in August.

This type of immunotherapy, called "checkpoint blockade," ramps up the ability of immune cells called T cells to fight cancer by removing the "cloaking effect" that tumors use to hide from them. Checkpoint blockade therapy is effective in several tumor types, but generally ineffective in non-Hodgkin's lymphomas. However, the study found that when this immunotherapy is combined with a stem cell transplant, which the researchers call "immunotransplant," the process ramps up the T cells to increase the cancer-killing immune response tenfold, allowing it to be effective for non-Hodgkin's lymphoma and more successful for melanoma and lung cancer.

The transplant works by "making space" for re-infused immune cells (T cells) to proliferate by clearing out a patient's original immune system. While they are proliferating and building the immune system back up, they become activated, and the anti-tumor T cells' anticancer effect becomes stronger.

The findings have prompted the initiation of a clinical trial using the immunotransplant approach to treat patients with aggressive non-Hodgkin's lymphoma (clinicaltrials.gov/ct2/show/NCT03305445), which began enrolling patients in May. They also could eventually lead to effective therapies for other cancer types.

"Using immunotransplant to enhance the efficacy of checkpoint blockade therapy could be broadly significant as these immunotherapies are a standard therapy for melanoma, kidney cancer, lung cancer, and others," said the study's corresponding author Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at Mount Sinai. "Even for settings in which checkpoint blockade therapy proves ineffective, our data suggest that its efficacy may be 'rescued' by immunotransplant. This research also suggests that the addition of checkpoint blockade may improve other T cell therapies, such as CAR-T therapy."

Investigators based their findings in the study on their observation of how the immune system responded to bone marrow transplants, T cell therapy, immunotherapy, and immunotransplant in patients and mouse models.

Up to two decades before people develop the characteristic memory loss and confusion of Alzheimer's disease, damaging clumps of protein start to build up in their brains. Now, a blood test to detect such early brain changes has moved one step closer to clinical use.

Researchers from Washington University School of Medicine in St. Louis report that they can measure levels of the Alzheimer's protein amyloid beta in the blood and use such levels to predict whether the protein has accumulated in the brain. When blood amyloid levels are combined with two other major Alzheimer's risk factors - age and the presence of the genetic variant APOE4 - people with early Alzheimer's brain changes can be identified with 94% accuracy, the study found.

The findings, published Aug. 1 in the journal Neurology, represent another step toward a blood test to identify people on track to develop Alzheimer's before symptoms arise. Surprisingly, the test may be even more sensitive than the gold standard - a PET brain scan - at detecting the beginnings of amyloid deposition in the brain.

Such a test may become available at doctors' offices within a few years, but its benefits will be much greater once there are treatments to halt the disease process and forestall dementia. Clinical trials of preventive drug candidates have been hampered by the difficulty of identifying participants who have Alzheimer's brain changes but no cognitive problems. The blood test could provide a way to efficiently screen for people with early signs of disease so they can participate in clinical trials evaluating whether drugs can prevent Alzheimer's dementia.

"Right now we screen people for clinical trials with brain scans, which is time-consuming and expensive, and enrolling participants takes years," said senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology. "But with a blood test, we could potentially screen thousands of people a month. That means we can more efficiently enroll participants in clinical trials, which will help us find treatments faster, and could have an enormous impact on the cost of the disease as well as the human suffering that goes with it."

The test, an earlier version of which first was reported two years ago, uses a technique called mass spectrometry to precisely measure the amounts of two forms of amyloid beta in the blood: amyloid beta 42 and amyloid beta 40. The ratio of the two forms goes down as the amount of amyloid beta deposits in the brain goes up.

The current study involved 158 adults over age 50. All but 10 of the participants in the new study were cognitively normal, and each provided at least one blood sample and underwent one PET brain scan. The researchers classified each blood sample and PET scan as amyloid positive or negative, and found that the blood test from each participant agreed with his or her PET scan 88 percent of the time, which is promising but not accurate enough for a clinical diagnostic test.

In an effort to improve the test's accuracy, the researchers incorporated several major risk factors for Alzheimer's. Age is the largest known risk factor; after age 65, the chance of developing the disease doubles every five years. A genetic variant called APOE4 raises the risk of developing Alzheimer's three- to fivefold. And gender also plays a role: Two out of three Alzheimer's patients are women.

When the researchers included these risk factors in the analysis, they found that age and APOE4 status raised the accuracy of the blood test to 94%. Sex did not significantly affected the analysis.

"Sex did affect the amyloid beta ratio, but not enough to change whether people were classified as amyloid positive or amyloid negative, so including it didn't improve the accuracy of the analysis," said first author Suzanne Schindler, MD, PhD, an assistant professor of neurology.

Further, the results of some people's blood tests initially were considered false positives because the blood test was positive for amyloid beta but the brain scan came back negative. But some people with mismatched results tested positive on subsequent brain scans taken an average of four years later. The finding suggests that, far from being wrong, the initial blood tests had flagged early signs of disease missed by the gold-standard brain scan.

There is growing consensus among neurologists that Alzheimer's treatment needs to begin as early as possible, ideally before any cognitive symptoms arise. By the time people become forgetful, their brains are so severely damaged no therapy is likely to fully heal them. But testing preventive treatments requires screening thousands of healthy people to find a study population of people with amyloid build-up and no cognitive problems, a slow and expensive process.

As part of the study, the researchers analyzed the enrollment process for a prominent Alzheimer's prevention trial called the A4 study that used PET scans to confirm the presence of early Alzheimer's brain changes in potential participants. They concluded that prescreening with a blood test followed by a PET scan for confirmation would have reduced the number of PET scans needed by two thirds. Unlike blood tests, which cost a few hundred dollars, each PET scan costs upward of $4,000. A single site can only run a few dozen PET brain scans a month, because PET scanners are primarily reserved for patient care, not research studies.

"If you want to screen an asymptomatic population for a prevention trial, you would have to screen, say, 10,000 people just to get 1,500 or 2,000 that would qualify," Bateman said. "Reducing the number of PET scans could enable us to conduct twice as many clinical trials for the same amount of time and money. It's not the $4,000 per PET scan that we're worried about. It's the millions of patients that are suffering while we don't have a treatment. If we can run these trials faster, that will get us closer to ending this disease."

August 1, 2019--The American Thoracic Society has published an official clinical guideline on the evaluation and management of obesity hypoventilation syndrome in the Society's Aug. 1 American Journal of Respiratory and Critical Care Medicine.

Obesity hypoventilation syndrome (OHS) is a breathing disorder that affects some people who are obese, causing them to have too much carbon dioxide and too little oxygen in their blood. Medically, OHS is defined by the combination of obesity (body mass index ?30 kg/m2), sleep-disordered breathing and awake daytime hypercapnia (awake resting partial pressure of arterial CO2 or PaCO2 ?45 mmHg at sea level), after excluding other causes for hypoventilation.

Studies have estimated that 8-20 percent of obese patients with sleep apnea have this potentially life-threatening condition. According to the authors of the guideline, most patients with OHS are undiagnosed or misdiagnosed, jeopardizing their health and resulting in increased health care costs.

"The purpose of the guideline is to improve early recognition of OHS and advise clinicians concerning the management of OHS, with the goal of reducing variability in clinical practice and optimizing the evaluation and management of patients with OHS," said guideline panel chair Babak Mokhlesi, MD, MSc, a pulmonologist and a sleep specialist who is a professor of medicine and director of the Sleep Disorders Center and the Sleep Medicine Fellowship training program at the University of Chicago. "The panel believes that early recognition and effective treatment of OHS are important in improving morbidity and mortality."

The panel of 18 experts who produced the guideline included pulmonologists with expertise in sleep-disordered breathing, sleep specialists, a respiratory therapist, a critical care physician, a pulmonary hypertension specialist, an expert in weight reduction and a patient. The group reviewed the results of a systematic search of clinically relevant questions and focused on patient-centered outcomes, such as improving quality of life and quality of sleep, daytime sleepiness, gas exchange, need for supplemental oxygen, hospital resource utilization and death.

Using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework, the panel made five recommendations:

1) that clinicians use a serum bicarbonate level 2) that stable ambulatory patients with OHS receive positive airway pressure (PAP);

3) that continuous positive airway pressure (CPAP) rather than noninvasive ventilation (NIV) be offered as the first line treatment to stable ambulatory patients with OHS and co-existent severe obstructive sleep apnea;

4) that patients hospitalized with respiratory failure and suspected of having OHS be discharged with NIV until they undergo outpatient diagnostic procedures and PAP titration in the sleep laboratory (ideally within 2-3 months); and

5) that patients with OHS use weight-loss interventions that produce sustained weight loss of 25-30 percent of body weight (more likely to be obtained with bariatric surgery) to achieve resolution of OHS.

All the recommendations were deemed "conditional" by the panel because of the "very low level of certainty in the evidence."

The authors of the guideline noted several opportunities for research that they believe would benefit patients with OHS. Randomized trials, they wrote, are needed to determine which is better for screening obese patients with sleep-disordered breathing for OHS: measuring bicarbonate levels or oxygen saturation.

Studies are also needed to evaluate the impact of various PAP modes in OHS patients who do not have severe obstructive sleep apnea, whether patients suspected of OHS but discharged from the hospital without a diagnosis should continue on PAP treatment until an outpatient study confirms or rules out OHS and which bariatric weight-loss interventions are most effective in patients with OHS.

The panel emphasized that clinicians caring for these patients should consider severe obesity a major, modifiable factor in the development and severity of OHS. Clinicians need to educate their patients and engage in shared decision making about the best strategy for their patients to sustain weight loss of at least 25-30 percent, which the authors said is needed to resolve OHS.

In making its recommendations, the panel aimed for guidelines that could be used internationally. The authors recognize, however, that local resources may guide decisions within the framework on the panel's recommendation.

The authors emphasized that each patient is different, medically and personally. "No recommendation can take into account all of the variable and often compelling circumstances that might affect the potential benefits, harms and burdens of an intervention in specific cases and contexts," they wrote. Therefore, the guidelines should not be applied "in a blanket fashion."

PHILADELPHIA (August 1, 2019) - More than 1 million sepsis survivors are discharged annually from acute care hospitals in the United States. Although the majority of these patients receive post-acute care (PAC) services, with over a third coming to home health care (HHC), sepsis survivors account for a majority of readmissions nationwide. Effective interventions are needed to decrease these poor outcomes.

A national study from the Center for Home Care Policy & Research at the Visiting Nurse Service of New York, in collaboration with the University of Pennsylvania School of Nursing (Penn Nursing), shows that the combination of early home health nursing and at least one outpatient physician visit in the first week after hospital discharge reduced the risk of 30-day hospital readmission for sepsis patients by seven percentage points. The investigators concluded that the combination of home nursing visits and early physician follow-up facilitates a coordinated care plan and early surveillance for new or recurrent problems.

"Our findings support integrated care management, including scheduling physician follow-up before discharge rather than recommending that patients schedule their own follow-up, as well as a clear communication that this is a sepsis survivor so HHC can activate early attention," said Kathryn Bowles, PhD, FAAN, FACMI, van Ameringen Chair in Nursing Excellence, and the study's co-principal investigator. "If translated nationally, this operational strategy could complement national and state initiatives to improve the acute and PAC outcomes of sepsis survivors." "Our study revealed much room for improvement as only 28.1% of sepsis survivors transitioned to HHC received this intervention."

The researchers' findings have been published in the August issue of Medical Care in an article "Does Early Follow-Up Improve the Outcomes of Sepsis Survivors Discharged to Home Health Care?"

Allergies can be life-threatening when they cause anaphylaxis, an extreme reaction with constriction of the airways and a sudden drop in blood pressure. Scientists have identified a subtype of immune cell that drives the production of antibodies associated with anaphylaxis and other allergic reactions. The research was funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and reveals a potential target for new therapies to prevent severe allergic reactions. The findings are published online today in the journal Science.

Investigators at Yale University, New Haven, Connecticut, the Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, and their collaborators discovered a subtype of T cells--called T follicular helper cell 13, or Tfh13 cells--in laboratory mice bred to have a rare genetic immune disease called DOCK8 immunodeficiency syndrome. In humans, DOCK8 deficiency leads to recurrent viral infections of the skin and respiratory system and to severe allergies and asthma.

Allergies and anaphylaxis are linked to the production of high levels of high-affinity IgE antibodies, which bind strongly to allergens to spur allergic reactions. The investigators noted that mice with a DOCK8 deficiency had novel T follicular helper cells, not found in normal mice, that produced a unique combination of chemical messengers called cytokines.

They then took mice with normal immune systems and sensitized them with respiratory and food allergens to induce severe allergic reactions leading to anaphylaxis. While non-allergic mice lacked Tfh13 cells, allergic mice had both Tfh13 cells and high-affinity IgE. With genetic manipulation, the scientists prevented Tfh13 cell development in mice and found that the animals did not make anaphylactic IgE to allergens. To transfer this insight to humans, they then compared blood samples from people with peanut or respiratory allergies to those of non-allergic volunteers and found that individuals with allergies and the associated IgE had elevated levels of Tfh13 cells.

The study authors conclude that Tfh13 cells are responsible for directing antibody-producing B cells to create high-affinity IgE and that Tfh13 cells may be required for allergic disease, including anaphylaxis. They say targeting Tfh13 cells may represent a new strategy to prevent or treat allergic diseases. While such a strategy would likely not replace life-saving, emergency epinephrine when anaphylaxis occurs, therapies targeting Tfh13 cells might prevent the onset of anaphylaxis when an allergic person is exposed to an allergen.

(PHILADELPHIA) - A rare, short-lived population of immune cells in the bloodstream may serve as 'periscopes' to monitor immune status via lymph nodes deep inside the body, according to researchers in the Perelman School of Medicine at the University of Pennsylvania. Their findings are published this month in the Journal of Clinical Investigation (JCI).

"This finding paves the way for using blood samples to provide a snapshot of whole-body immunity," said the study's co-first author Laura Vella. MD, PhD, a physician-scientist who performed this work in the lab of senior author E. John Wherry, PhD, chair of the department of Systems Pharmacology and Translational Therapeutics. Vella is also a pediatric infectious diseases physician at Children's Hospital of Philadelphia (CHOP).

Researchers say this work could help better define and monitor the condition of the immune system in vulnerable groups, such as infants and small children, the elderly, patients taking immune-suppression drugs, and those with autoimmune-based disorders like inflammatory bowel disease (IBD).

"It's as if we're trying to find the toxins draining from a single pipe into the Great Lakes - how do we find and characterize what is originating from that one spot in the water of an entire glacial lake?" Wherry said. "The cells we're looking for in the bloodstream are 0.1 percent of all cell types circulating in the blood. But our 'periscope' allows us see what that rare cell type can tell us about immune system events that have happened in a distant part of the body."

The elusive cell population described in this study are T follicular helper cells (Tfh). These are a subset of immune T cells required for B cells in the germinal centers (GC) of lymph nodes to make antibodies that fight germs and other outside invaders. Some Tfh cells in lymph nodes uniquely express the surface receptor protein CXCR5 and the inhibitory molecule PD-1. Blood does contain some Tfh cells with theses markers; however, scientists have long debated whether Tfh cells exit lymph nodes and circulate in the blood with traces of their original markers.

To answer this question, the team assessed the cell surface markers of Tfhs collected from human thoracic ducts--the main, yet difficult to access, "drainpipe" carrying fluid from the lymph system to the blood stream.

To learn how characteristics of Tfh in blood connect to the lymph system, the team compared Tfhs from lymph node GCs to Tfh cells in lymph fluid and to those in the blood. The team consistently identified "CXCR5-bright PD-1-bright" Tfh cells in lymph fluid at the duct. These doubly labeled Tfhs shared many epigenetic features and expressed similar proteins with Tfh cells in the GC. This means that the Tfhs sampled in the lymphatic duct are cellular intermediates connecting the biology of Tfhs in lymph tissue to Tfhs in blood, ultimately putting to rest the doubt that Tfhs in the blood reflect what happened in the lymph in the immediate past.

The team sees their new-found ability to match more easily obtained samples in the blood with earlier immune events deep in the node as being clinically useful for a variety of applications. From assessing when patients are ready to receive vaccines after bone marrow transplants to measuring how first-line immune treatments for people with IBD or certain types of cancers affect the broader immune system, use of their new "periscope" approach opens the door for more personalized treatment plans.

Research led by King's College London has found that the currently recommended treatment for a common pregnancy liver disorder that can result in preterm birth and stillbirth, is ineffective and should be reconsidered.

In a paper published today in The Lancet, the team of scientists carried out a trial (called PITCHES) at 33 hospital maternity units in England and Wales between December 2015 and September 2018. 605 pregnant women with intrahepatic cholestasis of pregnancy (ICP) were recruited with half receiving ursodeoxycholic acid (known as 'urso'), the current drug used to treat the condition, and half a placebo. The researchers collected blood tests and samples, measured the women's level of itching and recorded birth information.

The authors found that urso did not have an impact on pregnancy outcomes including preterm birth, neonatal unit admission and stillbirth. They also found that it did not show any meaningful improvement in itch for most women, nor did it reduce the woman's bile acid levels.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder affecting approximately 5,500 pregnancies annually in the UK. The condition causes build-up of bile acids in the blood, and symptoms include itching, often severe. An increase in bile acid is associated with increased risk of stillbirth, preterm birth, and neonatal unit admission.

Before now, urso hasn't been tested in any large clinical trials to show whether it prevents premature birth and stillbirth.

Lead author Professor Lucy Chappell, Department of Women & Children's Health at King's College London said: "We want to find a safe and effective treatment for women with cholestasis of pregnancy, so that we can prevent stillbirths in this condition. This trial has shown that the widely used drug ursodeoxycholic acid is not the answer. It is essential that we share these findings with pregnant women and clinicians so that we can avoid unnecessary medication in pregnancy. We now need to focus on finding a treatment that does work."

The research was funded by the Efficacy and Mechanism Evaluation (EME) Programme - a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. It builds on an earlier study which identified a simple bile acid blood test that could tell risk of stillbirth.

Jenny Chambers, CEO of ICP Support said: "As a charity we witness the anxiety that many women with ICP experience because the fear of stillbirth is uppermost in their minds; effective drug treatments are therefore vital to help reduce this fear. The trial clearly demonstrates that for most women urso is not the drug to do this and while the outcome is likely to be hugely disappointing for women, it is also vital that they are not being falsely reassured. What we now urgently need is a drug treatment that can reduce both the itch and the risk of stillbirth that is associated with the condition and ICP Support will continue to work with researchers in their fight to do this."

Scientists are now looking to identify other potential treatments for women with ICP. A clinical drug trial will be starting in early 2020 using rifampicin, an antibiotic that is also an effective treatment for itch outside pregnancy and improves removal of bile acids from the blood stream.

"It is now clear that urso should not be used routinely to treat all women with ICP. Our future research focus will be to try to establish whether there is a subgroup of women who may still benefit from this drug, and also to focus on new drugs to improve outcomes for mothers and babies of ICP pregnancies," added Professor Catherine Williamson, Department of Women & Children's Health at King's College London and co-investigator of the PITCHES trial.

PITTSBURGH--A team of researchers from Carnegie Mellon University has published a paper in Science that details a new technique allowing anyone to 3D bioprint tissue scaffolds out of collagen, the major structural protein in the human body. This first-of-its-kind method brings the field of tissue engineering one step closer to being able to 3D print a full-sized, adult human heart.

The technique, known as Freeform Reversible Embedding of Suspended Hydrogels (FRESH), has allowed the researchers to overcome many challenges associated with existing 3D bioprinting methods, and to achieve unprecedented resolution and fidelity using soft and living materials.

Each of the organs in the human body, such as the heart, is built from specialized cells that are held together by a biological scaffold called the extracellular matrix (ECM). This network of ECM proteins provides the structure and biochemical signals that cells need to carry out their normal function. However, until now it has not been possible to rebuild this complex ECM architecture using traditional biofabrication methods.

"What we've shown is that we can print pieces of the heart out of cells and collagen into parts that truly function, like a heart valve or a small beating ventricle," says Adam Feinberg, a professor of biomedical engineering (BME) and materials science & engineering at Carnegie Mellon, whose lab performed this work. "By using MRI data of a human heart, we were able to accurately reproduce patient-specific anatomical structure and 3D bioprint collagen and human heart cells."

Over 4000 patients in the United States are waiting for a heart transplant, while millions of others worldwide need hearts but are ineligible for the waitlist. The need for replacement organs is immense, and new approaches are needed to engineer artificial organs that are capable of repairing, supplementing, or replacing long-term organ function. Feinberg, who is a member of Carnegie Mellon's Bioengineered Organs Initiative, is working to solve these challenges with a new generation of bioengineered organs that more closely replicate natural organ structures.

"Collagen is an extremely desirable biomaterial to 3D print with because it makes up literally every single tissue in your body," explains Andrew Hudson, a BME Ph.D. student in Feinberg's lab and co-first author on the paper. "What makes it so hard to 3D print, however, is that it starts out as a fluid--so if you try to print this in air it just forms a puddle on your build platform. So we've developed a technique that prevents it from deforming."

The FRESH 3D bioprinting method developed in Feinberg's lab allows collagen to be deposited layer-by-layer within a support bath of gel, giving the collagen a chance to solidify in place before it is removed from the support bath. With FRESH, the support gel can be easily melted away by heating the gel from room temperature to body temperature after the print is complete. This way, the researchers can remove the support gel without damaging the printed structure made of collagen or cells.

This method is truly exciting for the field of 3D bioprinting because it allows collagen scaffolds to be printed at the large scale of human organs. And it is not limited to collagen, as a wide range of other soft gels including fibrin, alginate, and hyaluronic acid can be 3D bioprinted using the FRESH technique, providing a robust and adaptable tissue engineering platform. Importantly, the researchers also developed open-source designs so that nearly anyone, from medical labs to high school science classes, can build and have access to low-cost, high-performance 3D bioprinters.

Looking forward, FRESH has applications in many aspects of regenerative medicine, from wound repair to organ bioengineering, but it is just one piece of a growing biofabrication field. "Really what we're talking about is the convergence of technologies," says Feinberg. "Not just what my lab does in bioprinting, but also from other labs and small companies in the areas of stem cell science, machine learning, and computer simulation, as well as new 3D bioprinting hardware and software."

"It is important to understand that there are many years of research yet to be done," adds Feinberg, "but there should still be excitement that we're making real progress towards engineering functional human tissues and organs, and this paper is one step along that path."

An experimental vaccine against respiratory syncytial virus (RSV), one of the leading causes of infectious disease deaths in infants, has shown early promise in a Phase 1 human clinical trial. A team of researchers, including The University of Texas at Austin's Jason McLellan, report today in the journal Science that one dose of their vaccine candidate elicited large increases in RSV-neutralizing antibodies that were sustained for several months.

People contract RSV in all stages of life, but it's most dangerous in the very young and the very old. The virus causes pneumonia, bronchiolitis and other lower respiratory tract diseases. Every year, millions of people become sickened by RSV, and more than 100,000 die, mostly in areas that lack access to modern medical care. For infants under 1 year of age, RSV is second only to malaria for infectious disease deaths.

Barney Graham and Peter Kwong of the National Institute of Allergy and Infectious Diseases' Vaccine Research Center (VRC), along with McLellan, a former postdoctoral researcher at VRC and now an associate professor at UT Austin, spearheaded the development of the vaccine candidate DS-Cav1.

Scientists have tried to create an RSV vaccine using traditional methods for more than 50 years -- and so far, none has worked. Instead, McLellan and his colleagues took a new approach, called structure-based vaccine design.

It was already known that a certain part of RSV, called the F protein, triggers the human immune system to produce antibodies. But the F protein is a shape shifter -- before it infects a cell, it takes one shape and then during infection, it shifts to a second shape. If the immune system encounters an RSV virus with the F protein in the first shape, it makes potent antibodies. But if the protein is in the second shape, fewer antibodies are elicited, and they are not very effective. Producing RSV vaccines using traditional methods usually leads to F proteins in the second shape and a poor antibody response.

This is where the structure-based approach comes in. First, the researchers used a technique called X-ray crystallography to determine the atomic-level structure of the F protein in the first shape. Next, they re-engineered the F protein to take away its shape-shifting ability, locking it in the shape that elicits the best antibodies.

In 2013 they tested several versions as a vaccine in both mice and nonhuman primates. These protein variants elicited high levels of neutralizing antibodies and protected the animals against RSV infection.

"Our first time testing these stabilized molecules in animals, the response was 10-fold higher than anything anyone had ever seen before," McLellan said. "And at that point, we're thinking, 'This is it. We've got it.' That was exciting."

The most promising of these vaccine candidates, DS-Cav1, was selected for clinical evaluation and subsequently manufactured by the VRC.

The Science report is an interim analysis of data from the first 40 healthy adult volunteers enrolled in the trial, which began in the National Institutes of Health Clinical Center in 2017. Researchers found that the vaccine candidate elicits a greater than 10-fold increase in RSV-neutralizing antibodies, compared with the number of antibodies a person produces naturally from RSV exposure earlier in life.

The results are promising, but McLellan is careful to put them in perspective.

"The Phase 1 just asks: Is it safe and is it eliciting the types of antibodies and response that we were hoping to see?" he said. "It still needs to go through Phase 2 and Phase 3, looking at efficacy such as, is it reducing the severity of disease, or is it reducing hospitalizations?"

Many drugs fail to make it all the way through clinical trials. But if this one does, or another based on the same F protein structure that he helped discover, McLellan says it could be a game changer.

"If it works reasonably well and we prevent 70 to 80 percent of all deaths, just think of all the little infants and toddlers we'd save," McLellan said. "There aren't that many vaccines in the world, and so if we're able to actually participate in making one that works and saves lives, that would be awesome."

JACKSONVILLE, Fla. -- Known for its poor prognosis, lung adenocarcinoma is the most common type of lung cancer, responsible for about 4 of 10 diagnoses, according to the National Cancer Institute. Researchers on Mayo Clinic's Florida campus can now distinguish between two pathways where this deadly cancer can develop. They say their discovery could help future patients. The findings appear in Cancer Cell.

"The ability to identify the specific pathway by which a patient's lung adenocarcinoma came about increases our ability to predict which patients are likely -- or unlikely -- to benefit from a particular treatment, and hopefully offer alternative options to patients whose cancer subtype is unlikely to respond," says Alan Fields, Ph.D., a cancer biologist and the study's senior author. Dr. Fields is the Monica Flynn Jacoby Professor of Cancer Research at Mayo Clinic.

He and his team studied the molecular features of lung adenocarcinoma in mice and found two ways that this cancer can develop. The first way depends on the cancer-causing gene known as "protein kinase C iota (PKCiota)." The second pathway, identified as the "Wnt/Beta-catenin signaling pathway," was found to operate independently of PKCiota. Lung adenocarcinomas that stem from the two different pathways were also found to form in different regions of the lung and through different cells of origin.

Once these two pathways were revealed in mice, Dr. Fields and colleagues considered how their discovery may apply to people. To begin, they compared the pathways in the mouse model to the six known molecular subtypes of this cancer in humans. The scientists found a match: a molecular marker that allowed them to predict which human lung adenocarcinoma cells originated from the PKCiota-independent pathway that they'd discovered in mice.

To test whether the tumors arising from the PKCiota-dependent and independent pathways might be sensitive to specific cancer therapies, Dr. Fields' team then conducted an experiment on human cells and the mouse model. As hypothesized, they found that two drugs affected the adenocarcinoma subtypes differently, depending on their underlying pathway. These results suggested to the investigators that they can predict how these cancer subtypes will respond to targeted therapies.

As a next step, the team will work to determine whether they can effectively and specifically identify PKCiota-dependent versus independent lung adenocarcinoma in human patients and confirm whether experimental drugs can predictably inhibit the growth of lung cancer in the PKCiota-dependent and independent patients.

Because the PKCiota pathway is also important to other cancers, the researchers think that their findings may apply beyond lung cancer.

This work builds on previous efforts by Dr. Fields and colleagues, who were the first to discover the connection between PKCiota, and the initiation, promotion and spread of lung cancers.

August 1, 2019 -- From risks of violence and abuse to disrupting their development, humanitarian crises present major threats to the wellbeing of children, and for more than two decades Child Friendly Spaces have been considered one of the best ways to respond.

A recent study by World Vision and Columbia University Mailman School of Public Health looked at the impact of Child Friendly Spaces in five countries affected by humanitarian emergencies and found major differences across settings. This is the first study to evaluate whether existing interventions successfully provide a safe environment and opportunities for children to engage in activities. The findings are published in the journal BioMed Central Public Health.

"Now more than ever children living in dangerous places, and those affected by disasters, are extremely vulnerable to violence, exploitation, abuse, and neglect. We know Child Friendly Spaces have been seen as a key intervention to protect them and promote their well-being, but there has previously been little robust evidence related to their impact," says Kevin Savage, World Vision's Humanitarian Research Director.

World Vision and Columbia Mailman School worked with partners from the Global Alliance for Child Protection to carry out a multi-country evaluation of CFS in humanitarian emergencies over four years. The study, which covered 23 Child Friendly Spaces and included Somali refugees in Ethiopia, South Sudanese refugees in Uganda, Syrian refugees in Iraq and Jordan, and children affected by an earthquake in Nepal, found both encouraging and challenging results. The researchers compared children who attended for several months with children who had not attended at all. They also considered parents' views of the experience of younger children and interviewed older children themselves.

Perceptions of risk, well-being and knowledge of resources were measured before children began attending the Child Friendly Spaces, and measured again once they had been operating for several months.

The findings showed younger children who attended consistently showed greater improvements in psychosocial well-being than those who did not attend. When activities were implemented with quality, and well suited to the local context, Child Friendly Spaces were effective in reducing protection concerns and promoting development.

Professor Alastair Ager at Columbia Mailman School's Heilbrunn Department of Population and Family Health, the study's lead researcher, noted: "Younger children who attended Child Friendly Spaces consistently showed major improvements in well-being compared to those not attending." However, there was little evidence that the spaces had a positive impact on older children. "Engaging youth is recognised as challenging in humanitarian contexts given pressures on livelihoods, so future interventions need to be more explicitly shaped to their interests and circumstances," noted Ager.

The research is a timely reminder for all those involved, from aid agencies to government donors, to ensure consistent quality regardless of where the spaces are set up, said World Vision.

"It is clear children benefit from Child Friendly Spaces, but this research reminds us how important it is to ensure this intervention always meet quality standards, and that we must continually strive to better meet the needs of vulnerable children and young people," said Savage.

“Beyond Child Friendly Spaces, this work highlights the value rigorous evaluation techniques - implemented through multidisciplinary teams – can have on guiding programming and consequently improving the lives of children and families in humanitarian contexts,” said Sabrina Hermosilla, PhD, first author, Department of Population and Family Health at Columbia Mailman School.

Organizations are already implementing some of the lessons the research highlighted, with a recent rewrite of guidelines. "But more needs to be done to ensure a sector-wide rethink to ensure children of all ages get the support they need," said Ager.

Co-authors are Janna Metzler and Miriam Musa, Columbia Mailman School.

What The Study Did: The financial and environmental costs of unused portions of drugs from cataract surgery at four surgical sites in the U.S was investigated in this study.

Authors: Cassandra L. Thiel, Ph.D., of the New York University School of Medicine in New York, is the corresponding author

(doi:10.1001/jamaophthalmol.2019.2901)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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Biomedical researchers at KU Leuven have found a new way to study endometrial diseases such as endometriosis and cancer. They were able to grow three-dimensional cell structures from diseased tissue of patients. The biobank can be used to unravel the disorders and test drugs.

Diseases of the endometrium are an important cause of infertility. One example is endometriosis, which is characterised by growth of endometrial-like tissue outside the uterine cavity, resulting in chronic abdominal pain and painful sexual intercourse. Up to half of the patients are subfertile or infertile. Treatment usually requires surgery and permanent hormonal therapy, which is incompatible with pregnancy.

Although endometriosis affects one in ten women worldwide in their fertile years, the illness remains taboo. Public figures like actress Lena Dunham and, recently, fashion designer Alexa Chung, who both suffer from endometriosis, are trying to raise awareness about the disease.

Another important disorder is endometrial cancer, the most common gynecological cancer, with tumours growing in and from the endometrium. We need a better understanding of, and more effective treatments for both diseases. But in order to make progress, researchers have to be able to grow and study the endometrium in the lab.

In 2017, Professor Hugo Vankelecom and his team at Department of Development and Regeneration at KU Leuven developed 'organoids' from a healthy endometrium. These three-dimensional cell structures are grown in a petri dish from tissue fragments and cells of clinical biopsies. The organoids accurately replicate the original endometrial tissue.

With this new study, the team have gone even further, developing organoids from a broad spectrum of endometrial diseases, including endometriosis and endometrial cancer. "The organoids form 'avatars', as it were, of the diseased tissue and can also be used to test the effect of drugs and new drug candidates," senior author Hugo Vankelecom (KU Leuven) explains. "Our study shows that endometrial cancer organoids of different patients are each in a specific way sensitive to chemotherapeutic drugs. Further research will show whether such tests can be of help in the clinical treatment of individual patients. This is an example of what we call personalised medicine."

"We now have a biobank of organoids from endometrium in healthy and diseased conditions. This can help us discover how an aberrantly functioning endometrium causes infertility and then look for treatments. Our new research model offers the potential to better understand and eventually treat uterine diseases such as endometriosis," concludes Vankelecom.