Breast cancer relapse could be predicted with new blood test

by Jonathan Vernon

Atest that identifies genetic information in the blood picks up sensitive amounts of DNA that can be used to shape decisions about cancer treatment.

One of the challenges of modern medicine is to know if and when a cancer patient will relapse. A new study shows that months before tumors are visible on hospital scans, a “mutation-tracking” blood test can pick up valuable signs of a cancer’s return.

The study, undertaken by researchers at The Institute of Cancer Research (ICR) and The Royal Marsden NHS Foundation Trust – both in the UK – is an important step toward changing the way cancer is monitored in the clinic and informing treatment decisions.

The clue to identifying a return of cancer cells is to look at circulating tumor DNA present in the blood. These are cancer cells left behind that may seed new tumors even after treatment.

By monitoring patients with blood tests taken after surgery, the study says, and then every 6 months in follow-up, the researchers were able to predict very accurately who would experience a relapse.

The study involved 55 women who had been successfully treated for early-stage breast cancer.

It was found those who tested positive for circulating tumor DNA were at 12 times greater risk of relapse compared with those who tested negative. In addition, the blood test was able to detect cancer recurrence an average of 7.9 months before any visible signs appeared.

Explaining what the researchers are attempting to achieve with the blood test, Kat Arney, science information manager at Cancer Research UK, told BBC Radio:

“They are looking for ways to detect DNA that has been shed by tumor cells into the bloodstream and saying can we use this DNA as a way of monitoring if the cancer is coming back – how it is changing, how it is evolving in the body – and then could we use that to monitor cancer and pick up potentially when it has come back without having to give scans or biopsies.”

“There are still challenges in implementing this technology […] but the information that it provides could make a real difference to breast cancer patients, ” added Dr. Nicholas Turner, team leader in molecular oncology at ICR and consultant medical oncologist at The Royal Marsden.

FINDINGS COULD BE APPLIED TO ALL BREAST CANCER SUBTYPES

Because the researchers were searching for mutations common to various breast cancer types, they found the test could be applied to all subtypes of the disease.

“This test could help us stay a step ahead of cancer by monitoring the way it is changing and picking treatments that exploit the weakness of the particular tumor, ” says Prof. Paul Workman, chief executive at ICR.

The potential of this new test, Arney told BBC Radio, is to “separate those mutations that are driving the cancer from all the other genetic chaos that is going on in there, looking at how we can target these particular gene faults in this particular person, and those are the same faulty genes that are driving their relapse when the cancer comes back.”

Read More

First Malaria Vaccine Gets Approval from EMA

World’s first malaria vaccine has got approval from European Medicines Agency (EMA), addressing a major move toward prevention of a condition that kills more than 500,000 individuals globally every year, most of them being kids in Africa.

After evaluating the quality, safety and effectiveness of the vaccine known as RTS,S (brand name Mosquirix) EMA Committee for Medicinal Products for Human Use (CHMP) consider it should be used for immunization of kids in Africa aged 6 weeks to 17 months, together with other safety measures against malaria – like as insecticides and bed nets.

The CHMP recommendation is the initial move toward RTS,S becoming the initial approved vaccine for malaria. Next year, independent advisory teams from the World Health Organization (WHO) will evaluate evidence for the vaccine and make a decision whether to suggest its use.Malaria is a life-threatening condition triggered by Plasmodium parasites, passed on to humans through the bite of Anopheles mosquitoes.

Plasmodium falciparum is very dangerous malaria parasite, which the RTS,S vaccine targets. The vaccine works by causing an immune reaction in the body when P. falciparum initially goes into the bloodstream, protecting against the parasite from infecting and growing in the liver.

There were about 198 million cases of malaria all over the globe in 2013 and about 584,000 deaths from this deadly condition. About 90% of these deaths took place in Africa, mainly among kids under the age of 5 years.

Currently, the only effective protective measures towards malaria in Africa are the use of artemisinin-based combination therapies (ACTs) – which have to be given within one day of fever onset – and insecticides and bed nets to protect against mosquito bites. GSK’s RTS,S vaccine would be used together with present malaria-prevention approaches; in clinical studies, the vaccine has not proven effective enough to be used alone.

RTS,S would offer ‘significant contribution’ to managing malaria burden

Earlier this year, Clinical Research Society reported on the outcomes of a phase 3 clinical study for RTS,S, which were released in The Lancet.

The trial included 15,459 infants aged 6-12 weeks and kids aged 5-17 months from 11 sites throughout seven sub-Saharan nations, which includes Mozambique, Kenya, Malawi and Ghana.Initial trial outcomes showed that among individuals aged 5-17 months who obtained three doses of RTS,S, a 46 percent drop in malaria cases was noticed in the 18 months following, while babies aged 6-12 weeks saw a 27 percent decrease in malaria cases.

The investigators then followed individuals for an additional 20-30 months after providing a booster vaccine 18 months after the third dose. The 3-dose RTS,S regime plus the booster vaccine was identified to decrease the number of malaria instances by 39 percent among kids aged 5-17 months over an overall of 4 years of follow-up, although a 27 percent drop in malaria cases was identified over 3 years of follow-up among infants aged 6-12 weeks.

Significantly, the trial outcomes show that without a booster vaccine, the impact of RTS,S wanes over time. In inclusion, the absence of a booster jab hinders the vaccine’s capability to decrease cases of severe malaria. Because RTS,S does not provide complete protection for malaria, the CHMP say “It is essential that proven safety measures, for example, insecticide-treated bed nets, remain used in add-on to the vaccine.”

Read More

Simple Saliva Test May Identify Alzheimer’s Risk

An individual’s chance of getting  Alzheimer’s disease could be found out  through an easy saliva test, suggests a  new research. Lead author Shraddha Sapkota and colleagues recently reported their results at the 2015 Alzheimer’s Association International Conference (AAIC).

Alzheimer’s disease impacts about 5.3 million individuals in the US and is the 6th major cause of death in the US. It is estimated that by 2050, about 13.5 million People in America will have the problem. At the moment, there is no test to identify whether a person has Alzheimer’s or is at risk. An Alzheimer’s diagnosis needs thorough medical examination, such as physical and neurological diagnosis and mental status assessment. While there is presently no way to stop development of Alzheimer’s or to cure it, early examination can improve an individual’s chances of benefitting from medicines that deal with symptoms of the disease. What is more, early diagnosis of Alzheimer’s can increase the chances of involvement in clinical studies focused at discovering a cure for the condition. However, Sapkota and colleagues observe that a lot of diagnostic approaches for Alzheimer’s can be unpleasant and expensive, prompting the look for a easier, less expensive approach.

Saliva ‘is a promising body fluid’ for forecasting, and monitoring cognitive downfall

For their research, the study team applied liquid chromatography-mass spectrometry (LCMS) to evaluate the saliva samples of 22 individuals with Alzheimer’s, 25 individuals with mild cognitive impairment (MCI) – a possibility factor for Alzheimer’s – and 35 individuals with normal cognitive functioning. The scientists determined compounds that were more noticeable in the saliva of individuals with Alzheimer’s and MCI, differentiating them from healthy individuals. These results were verified in an additional sample such as seven individuals with Alzheimer’s, 10 with MCI and 10 cognitively normal individuals. Additional analysis brought to light that greater levels of specific substances in individuals’ saliva were related with poorer cognitive functioning. For instance, a greater level of a certain substance in the saliva of individuals with Alzheimer’s was related to slower information processing rate. The team considers their results hold promise for an affordable, simpler diagnostic method for Alzheimer’s, although they said a lot more work requires to be performed to identify just how effective such a examine could be.

Adding to above statement lead author Sapkota said,

“Saliva is simply obtained, safe and inexpensive, and has potential for forecasting and monitoring cognitive downfall, but we are in the quite early phases of this work and a lot more study is required. Equally crucial is the chance of using saliva to obtain targets for therapy to address the metabolic aspect of Alzheimer’s, which is even now not well recognized. This research gives us closer to fixing that mystery.”

Protein in cerebrospinal fluid may forecast drop from MCI to Alzheimer’s

Another research reported at the AAIC exposed that cerebrospinal fluid (CSF) has shown promise for forecasting the decline from MCI to Alzheimer’s. This research was carried out by Dr. Maartje Kester and colleagues, the research included 162 individuals with either MCI, Alzheimer’s or usual cognitive functioning. All individuals had two samples of CSF obtained during a 2-year period. The team identified that individuals with Alzheimer’s had greater baseline levels of neurogranin – a protein expressed in the brain – in their CSF samples than individuals with MCI and usual cognitive functioning. What is more, baseline neurogranin was higher among individuals whose MCI had developed to Alzheimer’s, showing that the protein may be a forecaster of cognitive downfall among people with MCI. The scientists also identified that neurogranin levels enhanced over time among individuals with normal cognitive functioning, but this was not the case for all those with MCI or Alzheimer’s. “This may suggest that neurogranin levels in CSF indicate very early synaptic loss in Alzheimer’s and may be helpful for early diagnosis,” notes Dr. Kester, adding:

“We identified that neurogranin is a most likely useful marker for the diagnosis, prognosis and tracking of Alzheimer’s.”

Read More

New Simple Blood test can Identify Whether Individual is Suffering from Asthma or Allergy

Getting an inhaler to get relief from the wheezing and coughing related with chronic asthma is very easy but understanding if it’s being applied to treat the right problem has not been as easy. Now, scientists from the University of Wisconsin have identified a biomarker that identifies whether a person is struggling from asthma or allergy. Their research was published recently in Proceedings of the National Academy of Sciences (PNAS). To identify the asthma-associated biomarker team of investigators viewed to the immune system and WBCs identified as neutrophils, which transferred more gradually over a chemotactic gradient in asthmatic sufferers than they did in nonasthmatic individuals. Chemotaxis is the motion of cells triggered by a chemical stimulant.

Study co-author Eric Sackmann stated the scientists were somewhat amazed that neutro
phil function was so distinct, even in mildly asthmatic sufferers. “Neutrophilic inflammation has mainly connected to sufferers with serious asthma, so it was exciting to notice this change in neutrophil chemotaxis velocity for sufferers with light asthma,”

Asthma is an inflammation related disease of the lungs that can cause to airway constriction and problems in breathing. Usually, asthma has been clinically diagnosed by identifying the volume of airway shrinking an individual has. Rather of seeking at the level of airway constriction, a neutophil chemotaxis check looks at the behavior of immune cells to distinguish among individuals who are suffering from asthma and those who are struggling from an allergic reaction like as rhinitis, which is an irritability of mucus membranes in the nose.

“Rather than analysing at the endpoint of this procedure, we go upstream and determine one of the primary inflammatory cells immediately to identify whether the cells’ functionality has been changed,” co-author stated. “This is a essentially different method in comparison to traditional evaluation.”

While neutrophil chemotaxis may sound challenging, the test is comparatively simply: A handheld gadget distinguishes neutrophils from a blood sample within 5 minutes. Then the system produces a chemoattractant (chemical) gradient throughout which the neutrophils shift. Gradually moving neutrophils suggest that an individual has asthma. The conventional blood draw and processing used in past techniques takes about an hour.

“Scientists have usually only measured the number of neutrophils or eosinophils in the blood sample but have not assessed functional readouts like as chemotaxis,” said Sackmann. “The chemotaxis analysis is easier to execute and offers, we would argue, more exciting readouts as we observe the cells over time. With our technological innovation we genuinely attempted to significantly simplify the whole process so the assessments can be conducted with restricted user operation time, and comparatively robustly.”

So instead of waiting for an asthma strike, or even extended cough, identifying asthma threat may be feasible with this simple test on a single drop of blood.

Read More

Researchers taking bold steps toward engineering new lungs

According to the World Health Organization, chronic obstructive pulmonary disease (COPD) currently affects more than 64 million people worldwide and is poised to become the third leading cause of mortality by 2030.

A hallmark of COPD is scarring of the lungs, a condition called pulmonary fibrosis, which impacts breathing. There is no cure for the condition or ability to repair the scarring that has occurred. Thus, in the late stages of lung disease, one remedy exists: organ transplantation.

Unfortunately, the combination of a severe shortage of donor organs and frequent rejection of the transplant by the recipient’s immune system has made even this method of last resort impractical for many.

In new research by Cheryl Nickerson and her team at Arizona State University’s Biodesign Institute and external collaborators, a radical approach to addressing the problems of transplantation potential and repairing scarred lungs is under investigation.

In work appearing in the advanced online edition of the journal PLOS ONE, the researchers describe an elegant method to improve aspects of lung engineering that may in the future contribute to providing a nearly limitless supply of donor organs, ideally matched to their recipients, or to repairing damaged lungs. Although years of work and further study remain before such research could be a reality in the clinic, the potential is there and the results in animal studies are promising.

The research team builds upon previous research that involves the removal of cells from the lung of a deceased individual and reseeding the resulting decellularized scaffold structure with stem cells from the lung recipient. The desired future outcome of such work would be a fully functioning lung built from the organ recipient’s own cells, therefore avoiding graft-host rejection. Although current research involves use of animal cells and scaffolds, the potential for translation to the clinic is an area of active research.

The new study, jointly funded by NIH, NASA, and a Mayo Clinic-ASU seed grant, demonstrates a number of critical advantages to conducting the cell re-population process in a dynamic suspension culture, in which the cells are allowed to gently tumble as they re-seed the decellularized lung.

“There is an urgent need for the development of lab-engineered lungs from patient stem cells that are suitable for both transplantation and as predictive models for biomedical research to probe the links between cell function and respiratory disease,” Nickerson said.

“This was an extraordinarily challenging but rewarding study that took years to complete, and we are excited that it will contribute to the current and growing body of knowledge in the field with potential downstream implications for regenerative medicine as well as identifying the underlying factors that may contribute to the transition of normal to fibrotic lung disease.”

Aurélie Crabbé, lead author of the new study (formerly with the Nickerson group and now at Ghent University, Belgium), highlights the tremendous potential for this pioneering strategy.

“Our study demonstrates that reseeding lung scaffolds under dynamic conditions could be beneficial for ex vivo lung engineering,” Crabbé said. “Dynamic culture conditions enhanced cell growth and viability, and stimulated stem cells to differentiate into matrix-producing cells as compared to static conditions – both findings might help rebuilding lungs from acellular scaffolds.

“Tremendous progress has recently been made on the use of cadaveric lungs as building blocks for the generation of new lungs, and we are hopeful that continued advancements in this field will one day provide a new source of much-needed organs.”

Nickerson and Crabbé were part of a multidisciplinary, multi-institute team, including researchers from the University of Vermont College of Medicine; Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona; and Arizona State University’s School of Life Sciences.

Pulmonary crisis

COPD is a lung disease characterized by increasing difficulty in breathing. The disease is progressive; the most common culprit is damage to the lungs caused by cigarette smoking.

The disease usually has two components, chronic bronchitis (an inflammation and partial blockage of the bronchial tubes supplying the lungs with air) and emphysema (loss of elasticity in the air sacs or alveoli of the lungs, causing shortness of breath). Cigarette smoking irritates the lung tissue and gradually destroys the malleable fibers of the lungs. Air pollution, chemical fumes, dust and secondhand smoke can also cause COPD.

Symptoms of the disease include shortness of breath, tightening of the chest and persistent cough accompanied by mucus. The underlying cause of these symptoms is scarring of the lungs (pulmonary fibrosis), which damages the lung tissue and cannot be repaired. Little is known regarding the cause of the scarring. Symptoms generally worsen with physical exercise. Flare-ups of severe symptoms, known as COPD exacerbation, become more frequent with disease progression and can be life-threatening.

COPD is usually diagnosed in middle age. The disease has no cure, and in severe cases, the only available medical intervention is organ transplantation. The clinical success of lung transplantation, however, requires lifelong immunosuppression, and chronic rejection of the new organ is common, with patients showing only 10-20 percent survival rate 10 years after transplantation.

Building designer lungs

To overcome the severe shortage of suitable donor organs and the issue of organ rejection by the recipient’s immune system, a daring new bioengineering strategy is being explored.

The idea is to remove the cells from a donor lung extracted from a cadaver, reseed the remaining decellularized scaffold with stem cells from the patient, allow the cells to adhere to the scaffold, grow and mature into the different cell types found in the functioning lung, and transplant the freshly developed, functioning organ in a living organism.

While not a reality for humans at this time, if successful in the future, this regenerative medicine approach holds the potential for a paradigm-shifting advance for sufferers of otherwise incurable lung disease.

Currently, the approach is being explored in animal models. The decellularization process is accomplished by sequentially treating lung tissues with specialized detergents, salts and enzymes. These act to remove the cellular material of the lung, leaving just the stripped-down extracellular matrix – a kind of scaffolding on which the new lung will be constructed using stem cells from the recipient.

To date, studies in which decellularized lungs from rodents were recellularized and transplanted showed marginal success in generating functioning pulmonary tissue. Experimental efforts have thus far demonstrated only partial recellularization of alveoli, airways and pulmonary vasculature. Though the fundamental approach appears sound, significant hurdles remain before the strategy can be applied to humans.

In the current study, researchers sought to improve the recellularization of the lung scaffold in a mouse model. Two cell types were used for the recellularization process, bone-marrow-derived mesenchymal stromal (stem) cells (MSCs) and alveolar type II cells, respectively.

Stem-cell challenge

Stem cells have the remarkable ability to differentiate into virtually any form of specialized cell in the body, when placed in the proper environment. Thus, the premise of the study is that stem cells exposed to the decellularized lung scaffold will take up residence and differentiate into all the specialized cell types necessary for a complete, functioning lung, much as the skeletal frame of a house is gradually dressed with walls, roof, windows and doors.

This is an audacious challenge, given the complexity of the lung, which contains more than 50 different cell types. Accordingly, optimizing the recellularization efficiency of lung scaffolds with stem cells under conditions that mimic the parental tissue environment is critical to coax the cells to multiply and mature into the different respiratory cell types, and to achieve the long-term goal of developing functional lungs in the lab that could one day be suitable for transplantation, as well as for building models of diseased or injured lungs to understand the underlying mechanisms of why damage is happening.

In an effort to improve lung recellularization, a dynamic rotating wall vessel (RWV) bioreactor was used. In previous research, this cell-culture technique has been shown to promote growth and differentiation of stem and epithelial cells. The apparatus provides a continuous suspension of the repopulating cells, which are contained in horizontally rotating cylinders, filled with a nutrient-rich media.

The motion of the RWV bioreactor offsets the natural sedimentation of cells, creating a gentle falling of cells along with their scaffolds contained in the culture medium. The activity mimics natural conditions of fluid shear – the motion of extracellular fluid over cell surfaces, which is believed to help direct proper growth and regeneration.

In the current study, comparisons were made between standard methods of recellularization using cells grown on lung scaffolds under static conditions, and those grown dynamically in a rotating bioreactor.

Cell fates

The results showed markedly different outcomes for cells grown under static and dynamic conditions. The decellularized lung scaffolds recellularized with mesenchymal stem cells for a total of 14 days displayed more abundant cells in the bioreactor, compared with static conditions. As a consequence, the quantity of RNA detected in recellularized lungs grown under bioreactor conditions was on average 3.8 times higher than for static recellularization.

Cells were more homogeneously distributed across the recellularized lungs raised in the bioreactor, compared with their static counterparts. In the case of C10 epithelial alveolar cells, static conditions yielded poor recellularization results, with abundant cell debris and low RNA compared with an abundance of intact cells cultured in the bioreactor. Both MSCs and C10 cells exhibited lower rates of cell death or apoptosis and higher cell proliferation in bioreactor vs. static recellularization conditions.

The authors speculate that biomechanical forces like fluid shear and accompanying changes in oxygenation, nutrient availability and waste dispersal, may contribute to the improved trajectories for cells grown in the dynamic suspension bioreactor system (RWV).

Also, when grown in the RWV, the stem cells expressed phenotypic markers of matrix-producing cells, or fibroblasts. This cell type normally contributes to fibrosis in the lungs of patients with COPD and other lung diseases, leading to the generation of afunctional scar tissue. However, in the context of ex vivo lung regeneration using acellular scaffolds, these fibroblast-like cells could help rebuild the matrix, which is normally deteriorated due to the chemical treatment. Therefore, the differentiation of stem cells into fibroblast-like cells under dynamic culture conditions in the RWV might generate a microenvironment that is beneficial for other cell typesto grow and differentiate into the desired functional lung tissue.

In addition to furthering the immediate goals of the project focused on transplantation, study of decellularized scaffolds also provides a novel means of studying cell-matrix interactions and other aspects of normal and diseased lung biology. Such studies will advance our understanding of how normal lung tissue becomes fibrotic, with potential for novel strategies to repair damaged lung tissue.

“Imagine, if we can one day create a fully functional normal or fibrotic lung in the lab, understand the reasons why it behaves the way that it does, learn the tipping points that cause it to transition either way, and test how preventative therapies work,” Nickerson said.

“The potential findings could have tremendous implications for diagnosis, treatment and prevention for a variety of respiratory disorders, including those due to infectious disease, cancer and environmental toxins.”

---

More information: “Recellularization of Decellularized Lung Scaffolds Is Enhanced by Dynamic Suspension Culture.” PLoS ONE 10(5): e0126846. DOI: 10.1371/journal.pone.0126846

Journal reference: PLoS ONE

Read More

The Innovative Genomics Initiative and the Future of Genomics Research

The Innovative Genomics Initiative at the Li Ka Shing Center for Genomic Engineering in Berkeley, CA, is defining the next-generation of genetic engineering and genomics research using CRISPR/Cas9 gene editing technology. CRISPR technology, discovered at UC Berkeley in 2012, enables scientists to learn about the specific functions of chromosomes by activating or inhibiting genes, and to change the functions of living cells and organisms by reprograming genetic information.

This introductory video provides an overview of CRISPR/Cas9 technology and describes some of the research applications the IGI and its collaborators will initially be investigating. Appearing in the video are Jennifer Doudna (IGI Executive Director; Professor, UC Berkeley; Investigator, HHMI), Mike Botchan (IGI Administrative Director and Professor, UC Berkeley), Jonathan Weissman (IGI Co-Director and Professor, UCSF; Investigator, HHMI), Jacob Corn (IGI Scientific Director, UC Berkeley), Jennifer Puck (Professor of Pediatrics, UCSF School of Medicine) and Janet Napolitano (President, University of California).

Read More