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Blood Test for Early Detection of Pancreatic Cancer Headed to Clinic

A newly identified biomarker panel could pave the way to earlier detection and better treatment for pancreatic cancer, according to new research from the Perelman School of Medicine at University of Pennsylvania. Currently over 53,000 people in the United States are diagnosed with pancreatic cancer — the fourth leading cause of cancer death — every year. The blood biomarkers, detailed today in Science Translational Medicine, correctly detected pancreatic cancer in blood samples from patients at different stages of their disease.

The majority of pancreatic cancer patients are not diagnosed until an advanced stage, beyond the point at which their tumors can be surgically removed.

A team led by Ken Zaret, PhD, director of the Penn Institute for Regenerative Medicine and the Joseph Leidy Professor of Cell and Developmental Biology, and Gloria Petersen, PhD, from the Mayo Clinic, identified a pair of biomarkers that physicians could soon use to discover the disease earlier.

“Starting with our cell model that mimics human pancreatic cancer progression, we identified released proteins, then tested and validated a subset of these proteins as potential plasma biomarkers of this cancer,” Zaret said. The authors anticipate that health care providers will use the early-detection biomarkers to test for their presence and levels in blood from pancreatic cancer patients and blood drawn from individuals with a high risk of developing pancreatic cancer, including those who have a first-degree relative with pancreatic cancer, are genetically predisposed to the disease, or who had a sudden onset of diabetes after the age of 50.

“Early detection of cancer has had a critical influence on lessening the impact of many types of cancer, including breast, colon, and cervical cancer. A long standing concern has been that patients with pancreatic cancer are often not diagnosed until it is too late for the best chance at effective treatment,” said Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center (ACC) at the University of Pennsylvania. “Having a biomarker test for this disease could dramatically alter the outlook for these patients.”

The biomarker panel, enabled by discovery work of first author Jungsun Kim, PhD, a postdoctoral fellow in Zaret’s lab, builds on a first-of-its-kind human-cell model of pancreatic cancer progression the lab described in 2013. They used stem-cell technology to create a cell line from a patient with advanced pancreatic ductal adenocarcinoma. Genetically reprogramming late-stage human cancer cells to a stem-cell state enabled them to force the reprogrammed cells to progress to an early cancerous state, revealing secreted blood biomarkers of early-stage disease along the way.

The best candidate biomarker, plasma thrombospondin-2 (THBS2), was screened against 746 cancer and control plasma samples using an inexpensive, commercially available protein-detection assay. The team found that blood levels of THBS2, combined with levels of a known later-stage biomarker called CA19-9, was reliable at detecting the presence of pancreatic cancer in patients.

The team refined the assay with independent investigations of plasma samples from patients with different stages of cancer, from individuals with benign pancreatic disease, and from healthy controls, all obtained from Petersen, who directs the biospecimen resource program for pancreas research at the Mayo Clinic.

“Positive results for THBS2 or CA19-9 concentrations in the blood consistently and correctly identified all stages of the cancer,” Zaret said. “Notably, THBS2 concentrations combined with CA19-9 identified early stages better than any other known method.” The combination panel also improved the ability to distinguish cases of cancer from pancreatitis. The panel will next be validated in a set of samples from pancreatic cancer patients who provided a research blood sample prior to their diagnosis.

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Clinical Trial Results Marks a Significant Accomplishment for Medicortex Finland

Medicortex Finland Oy, a biotechnology company developing a diagnostic kit for brain injury detection based on a medical breakthrough biomarker, recently completed analyzing the results from the first clinical trial. Medicortex is working towards the validation of a Traumatic Brain Injury (TBI) biomarker and incorporating it into a quick and reliable diagnostic kit that can be easily used by the first responders and healthcare professionals, and by people with no medical profession.

The trial consisted of patients that were hospitalized due to a head injury.  Medicortex collected body fluid samples of 12 patients who had sustained a head injury, and analyzed the presence of the novel biomarker between the patients and healthy control subjects.

“The biodegradation product we are targeting has never been used for TBI indication. The fact that we can readily find it in easily accessible body fluids such as urine and saliva enables us to develop a user-friendly diagnostic kit for TBI detection”, says Dr. Adrian Harel, Chief Executive Officer of Medicortex Finland.

“Collecting and testing human samples in a clinical trial is a significant accomplishment for us, and represents a meaningful step forward in the development of a fast and inexpensive diagnostic kit for head injuries,” added Dr. Harel. “Brain injuries are devastating, leading to mortality if not diagnosed. The opportunity to develop the first portable non-invasive kit to detect head injuries and concussion is so desperately needed,” added Harel.

Dr. Marten Kvist, Medical Director of Medicortex, says “We are excited of the clinical results which confirm the diagnostic potential of the unique biomarker, it will be further developed into a diagnostic aid for first responders and paramedics, it will help prioritize evacuation and reframe from administration of contraindicated medications.”

The clinical trial was supported and funded in part by Tekes (the Finnish Funding Agency for Innovation). Medicortex is currently raising money for the next step clinical development of the brain injury test. The planned multicenter clinical study including up to 160 study subjects will prove the validity of the new biomarker test for TBI diagnostics.

The general public can help contribute in the development of MediCortex’s diagnostic kit via a crowdfunding campaign at www.invesdor.com/medicortex  Medicortex is issuing shares with the goal of raising capital to match funds the firm has already applied via Tekes.

Medicortex Finland Oy (http://www.medicortex.fi) is a biotechnology company dedicated to improving the diagnostics and treatment of Traumatic Brain Injury (TBI). Its current focus is to develop biomarker diagnostics that evaluate the extent and severity of TBI. Once the company completes this test its next goal will be to develop an innovative drug to halt the progression of brain injury.

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New Avenue for Anti-Depressant Therapy Discovered

Researchers have made a ground-breaking discovery revealing new molecular information on how the brain regulates depression and anxiety. In so doing, they identified a new molecule that alleviates anxiety and depressive behaviour in rodents. The research, led by Eleanor Coffey, Research Director at Åbo Akademi University in Finland is a collaborative effort between scientists in Finland and the US.

The researchers found that a protein called JNK when active, represses the generation of new neurons in the hippocampus, a part of the brain that controls emotions and learning. By inhibiting JNK solely in newly generated nerve cells in the hippocampus, the researchers were able to alleviate anxiety and depressive behaviour in mice. This previously unknown mechanism brings fresh insight on how the brain works to regulate mood and indicates that inhibitors of JNK, such as the one used here, can provide a new avenue for anti-depressant and anxiolytic drug development.

Depression and anxiety are highly prevalent disorders and represent one of the largest causes of disability worldwide. These results are important as many patients do not respond to current treatments and it has long been recognised that new mechanistic understanding of these disorders would be necessary to in order to identify drugs for treatment resistant depression.

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New Non-Invasive Assay May Improve Surveillance Of Heart And Other Solid-Organ Transplants

Patients who have received a solid organ transplant require lifelong immunosuppressive therapy. The threat of transplant rejection due to insufficient drug therapy must be balanced against increased risks of infections and cancer from excessive immunosuppression. A significant unmet need exists for non-invasive diagnostic tools to monitor transplant recipients, especially for early detection of active injury and rejection. A report in The Journal of Molecular Diagnostics describes a new non-invasive test that measures donor-derived cell-free DNA (dd-cfDNA) in plasma that has the potential to reduce complications and rejection, improving outcomes in transplant recipients.

“dd-cfDNA is an emerging biomarker of transplanted organ injury, and the availability of a clinical-grade, analytically validated assay is critical for advancement of this biomarker toward improving the outcomes of transplant patients,” explained lead investigator Marica Grskovic, PhD, Associate Director, R&D, CareDx, Inc. (Brisbane, CA).

Plasma cfDNA has been proposed as a biomarker for prenatal testing, cancer, and organ transplantation. Taking advantage of genetic differences between a transplant donor and recipient, techniques have been developed to measure levels of a donor’s DNA in the recipient’s plasma, serum, or urine as a way to monitor the health of transplanted tissue, whether from the heart, lungs, liver, or other organs.

Although dd-cfDNA assays for research have been described previously, this is the first time a clinical-grade assay has been reported. The new assay detects plasma dd-cfDNA within the range of levels evident from transplant patient samples.

An advantage of the new next-generation sequencing (NGS)-based amplification assay is that it does not require determination of the donor’s and recipient’s genotype, a process which requires significant time, cost, and tissue availability. Although tissue biopsy is another way to monitor a transplanted organ, it is invasive, time consuming, costly, and risky. The new assay can be completed within three days, which can be important for clinical decision-making.

In the current report, data are presented from a multi-center heart transplantation study showing that dd-cfDNA was, on average, three-fold higher in patients experiencing acute rejection than in stable transplant recipients without acute rejection. A decrease in dd-cfDNA levels upon successful anti-rejection treatment was also observed.

Hannah Valantine, MD, Senior Investigator NHLBI, and NIH Chief Officer for Scientific Workforce Diversity, stated, “In collaboration with colleagues Drs. Stephen Quake, Kiran Khush, and Iwijn De Vlaminck at Stanford, we performed the pioneering research studies using NGS for heart and lung transplant. I am delighted to see this technology translating into a clinical-grade assay to which patients will have access to improve the precision of patient management.”

The researchers expect the assay to be useful for monitoring other types of transplanted organs. Additional multi-centered observational studies for heart and kidney transplant patients are underway to further evaluate the assay’s clinical validity and utility. The assay is currently validated only for single organ donor/recipient pairs.

“These results show promise in using cfDNA not only to detect rejection, but also to monitor response to treatment. The ongoing measurement of cfDNA may allow clinicians to better personalize care, adjust immunosuppression regimens, and improve the long-term outcomes of transplant recipients,” noted Dr. Grskovic.

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New Clinical Trial Marks a Significant Accomplishment for Medicortex

Medicortex Finland Oy (www.medicortex.fi), a biotechnology company developing a diagnostic kit for brain injury based on a medical breakthrough biomarker, recently was granted clearance to begin a clinical trial. The trial will consist of patients that are hospitalized due to a head injury.

“Collecting and testing human samples in a clinical trial is a significant accomplishment for Medicortex, and represents a meaningful step forward in the development of a fast inexpensive diagnostic kit for head injury,” said Dr. Adrian Harel, Chairman and Chief Executive Officer of Medicortex Finland. “Brain injury is a devastating condition with mortality if not diagnosed. The opportunity to develop the first portable non-invasive kit for head injury and concussion to help the patients and families that so desperately need it is remarkable.”

Samples of body fluids: blood, urine, plasma and Cerebrospinal fluid will be taken from these subjects and will be analyzed for a novel biomarker using a biochemical assay from Medicortex.

In this clinical trial. Medicortex intends to collect body fluid samples of 12 patients who have sustained a head injury, and analyze for the existence of a biomarker between the patients and healthy control subjects. Based on our earlier laboratory animal tests we can expect promising result from the study.

https://clinicaltrials.gov/ct2/sho/NCT02836951?term=medicortex&rank=1

“We are excited to begin a clinical test, confirming the presence of this unique biomarker, it will be further developed into a diagnostic aid for first responders and paramedics, it will help prioritize evacuation and reframe from administration of contraindicated medications, ” said Dr. Marten Kvist,  a TBI expert.

Medicortex is working towards the identification of a Traumatic Brain Injury (TBI) biomarker and incorporating it into a quick and reliable diagnostic kit that can be easily used by the first responders and healthcare professionals, and also by people with no medical profession.

This clinical trial is supported and funded in part by Tekes (the Finnish Funding Agency for Innovation).

Medicortex Finland Oy is a biotechnology company dedicated to developing diagnostics and treatments for acute neurodegenerative conditions, including brain injury and concussion. One of the company’s missions is to identify a new biomarker in order to reliably assess the severity and extent of brain injury. Medicortex was founded by Dr. Adrian Harel in Turku, Finland, in 2014 and it operates as a privately owned company. Dr. Harel has a track record in the business management and leadership of early-stage biotechnology companies.

 

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Study Finds Potential New Biomarker for Cancer Patient Prognosis

To treat or not to treat? That is the question researchers at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) hope to answer with a new advance that could help doctors and their cancer patients decide if a particular therapy would be worth pursuing.

Berkeley Lab researchers identified 14 genes regulating genome integrity that were consistently over-expressed in a wide variety of cancers. They then created a scoring system based upon the degree of gene over-expression. For several major types of cancer, including breast and lung cancers, the higher the score, the worse the prognosis. Perhaps more importantly, scores could accurately predict patient response to specific cancer treatments.

The researchers said the findings, to be published Aug. 31 in the journal Nature Communications, could lead to a new biomarker for the early stages of tumor development. The information obtained could help reduce the use of cancer treatments that have a low probability of helping.

Overtreating Cancer

“The history of cancer treatment is filled with overreaction,” said the study’s principal investigator, Gary Karpen, a senior scientist in Berkeley Lab’s Division of Biological Systems and Engineering with a joint appointment at UC Berkeley’s Department of Molecular and Cell Biology. “It is part of the ethics of cancer treatment to err on the side of overtreatment, but these treatments have serious side effects associated with them. For some people, it may be causing more trouble than if the growth was left untreated.”

One of the challenges is that there has been no reliable way to determine at an early stage if patients will respond to chemotherapy and radiation therapy, said study lead author Weiguo Zhang, a project scientist at Berkeley Lab.

“Even for early stage cancer patients, such as lung cancers, adjuvant chemotherapy and radiotherapy are routinely used in treatment, but overtreatment is a major challenge,” said Zhang. “For certain types of early stage lung cancer patients, there are estimates that adjuvant chemotherapy improves five-year survival only about 10 percent, on average, which is not great considering the collateral damage caused by this treatment.”

The researchers noted that there are many factors a doctor and patient must consider in treatment decisions, but this biomarker could become a valuable tool when deciding whether to use a particular therapy or not.

Study co-author Anshu Jain, an oncologist at the Ashland Bellefonte Cancer Center in Kentucky and a clinical instructor at the Yale School of Medicine, added that the real value of this work may be in helping doctors and patients consider alternatives to the typical course of treatment.

“These findings are very exciting,” said Jain. “The biomarker score provides predictive and prognostic information separate from and independent of clinical and pathologic tumor characteristics that oncologists have available today and which often provide only limited clinical value.”

Hunting for New Biomarkers

The study authors focused on genes regulating the function of centromeres and kinetochores – the essential sites on chromosomes that spindle fibers attach to during cell division – based upon results from earlier research by the Karpen group and other labs in the field. In normal cell division, microtubule spindles latch on to the kinetochores, pulling the chromosome’s two chromatids apart.

What the Karpen team previously found in fruit flies is that the overexpression of a specific centromere protein resulted in extra spindle attachment sites on the chromosomes.

“This essentially makes new centromeres functional at more than one place on the chromosome, and this is a huge problem because the spindle tries to connect to all the sites,” said Karpen. “If you have two or more of these sites on the chromosome, the spindles are pulling in too many directions, and you end up breaking the chromosome during cell division. So overexpression of these genes may be a major contributing factor to chromosomal instability, which is a hallmark of all cancers.”

This chromosomal instability has long been recognized as a characteristic of cancer, but its cause has remained unclear.

To determine if centromeres play a role in chromosome instability in human cancers, the researchers analyzed many public datasets from the National Center for Biotechnology Information, the Broad Institute and other organizations that together contained thousands of human clinical tumor samples from at least a dozen types of cancers. The researchers screened 31 genes involved in regulating centromere and kinetochore function to find the 14 that were consistently overexpressed in cancer tissue.

The extensive records included information on DNA mutations and chromosome rearrangements, the presence and levels of specific proteins, the stage of tumor growth at the time the patient was diagnosed, treatments given, and patient status in the years following diagnosis and treatment. This allowed the researchers to correlate the centromere and kinetochore gene expression score (CES) with patient outcomes either with or without treatments.

Genome Instability and Cancer Therapy

“We were surprised to find such a strong correlation between CES and things like whether the patient survived five years later,” said Karpen. “Another finding – one that is counterintuitive – is that high expression of these centromere genes is also related to more effective chemotherapy and radiation therapy.”

The researchers hypothesized that the degree of chromosomal instability may also make cancer cells more vulnerable to the effects of chemotherapy or radiation therapy.

“In other words, there’s a threshold of genome instability,” said Zhang. “At low to medium-high levels, the cancer thrives. But at much higher levels, the cancer cells are more susceptible to the additional DNA damage caused by the treatment. This is a really key point.”

The researchers pointed out that they found no link between very high levels of genome instability and improved patient survival without adjuvant treatments.

Translating these findings into clinical advice and practice will take more research, the study authors caution. They are working to find that threshold of genome instability so that in the future, doctors and patients can make informed decisions about how to move forward.

“Future steps will include investigating the CES in prospective clinical studies for validation in carefully selected patient cohorts,” said Jain. “By establishing the clinical significance of the CES, oncologists will have greater confidence in guiding cancer patients toward treatments with the greatest benefit.”

Other co-authors of the study are Jian-Hua Mao at Berkeley Lab’s Division of Biological Systems and Engineering; Wei Zhu at the Cellular Biomedicine Group in Shanghai; and Ke Liu and James Brown at Berkeley Lab’s Division of Environmental Genomics and Systems Biology. Mao and Zhu provided critical expertise in bioinformatics for this research.

The National Institutes of Health supported this work.

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Researchers Identify Possible Pathway to Reboot Immune System After Bone-Marrow Transplants

New research has shown how a cell surface molecule, Lymphotoxin β receptor, controls entry of T-cells into the thymus; and as such presents an opportunity to understanding why cancer patients who undergo bone-marrow transplant are slow to recover their immune system.

The study, published in the Journal of Immunology, used mouse models to reveal an in vivo mechanism that researchers believe might also represent a novel pathway for immunotherapeutic targeting to support patients following transplantation.

The thymus, which sits in front of the heart and behind the sternum, imports T-cell precursors from the bone marrow and supports their development into mature T-cells that fight off dangerous diseases.

T-cells are often the last cells to recover in cancer patients receiving bone marrow transplants. Though the cancer is cured, patients are often left with an impaired immune system that can take years to recover.

The Birmingham team, supported by US-based collaborators at The Sanford Burnham Medical Research Institute and The Trudeau Institute, found that Lymphotoxin β receptor was required to allow the entry of T-cell progenitors to the thymus both in a healthy state, and during immune recovery following bone-marrow transplantation.

Significantly, the team also found that antibody-mediated stimulation of Lymphotoxin β receptor in murine models enhanced initial thymus recovery and boosted the number of transplant derived T-cells.

Professor Graham Anderson, from the University of Birmingham, explained, “The thymus is often something of an ignored organ, but it plays a crucial role in maintain an effective immune system.”

“Post-transplantation, T-cell progenitors derived from the bone marrow transplant can struggle to enter the thymus, as if the doorway to the thymus is closed. Identifying molecular regulators that can ‘prop open’ the door and allow these cells to enter and mature, could well be a means to help reboot the immune system.”

Beth Lucas, also at the University of Birmingham, added, “This is just one piece of the puzzle. It may be that there are adverse effects to opening the door to the thymus, but identifying a pathway that regulates this process is a significant step.”

Following these positive findings the team aim to move towards in-vitro samples of human thymus to examine the role that Lymphotoxin  receptor might play in regulation of thymus function in man.

The research was funded by the Medical Research Council (MRC) and Cancer Research UK (CRUK), together with support from the Biotechnology and Biological Sciences Research Council (BBSRC) and Arthritis Research UK (ARUK).

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Biomarkers May Help Better Predict Who Will Have a Stroke

People with high levels of four biomarkers in the blood may be more likely to develop a stroke than people with low levels of the biomarkers, according to a study published in the August 24, 2016, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Identifying people who are at risk for stroke can help us determine who would benefit most from existing or new therapies to prevent stroke,” said study author Ashkan Shoamanesh, MD, of McMaster University in Hamilton, Canada, and a member of the American Academy of Neurology. “Future research could also investigate whether lowering the levels of these biomarkers or blocking their action could be a way to prevent strokes. However, our study does not provide evidence that these markers are validated well enough to be implemented in clinical practice.”

For the study, researchers from the Boston University Schools of Medicine and Public Health measured the levels of 15 biomarkers associated with inflammation in the blood of people from the Framingham Heart Study Offspring Cohort who had never had a stroke. The 3,224 participants were an average age of 61 at the start of the study and were followed for an average of nine years. During that time, 98 people had a stroke.

Of the 15 biomarkers, four were associated with an increased risk of stroke. People with elevated homocysteine were 32 percent more likely to have a stroke. Those with high vascular endothelial growth factor were 25 percent more likely; those with high ln-C reactive protein were 28 percent more likely; and those with high ln-tumor necrosis factor receptor 2 were 33 percent more likely to have a stroke during the study.

Adding these four biomarkers to an existing method of predicting a person’s stroke risk based on factors such as age, sex, cholesterol and blood pressure, called the Framingham Stroke Risk Profile, improved the ability to predict who would develop a stroke.
Shoamanesh noted that the study was observational. It shows a relationship between high levels of the biomarkers and stroke; it does not establish that the high levels cause stroke. He also noted that the biomarkers were measured only once and researchers did not account for infections, chronic diseases or other conditions that could have affected the results. In addition, study participants are mainly of European ancestry and the results may not apply to other populations.

The study was supported by Framingham Heart Study’s National Heart, Lung, and Blood Institute contract, National Institute of Neurological Disorders and Stroke, National Institute on Aging and National Institutes of Health.

The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with 30,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.

To learn more about stroke, please visit http://www.aan.com/patients.

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New Potential Lung Cancer Biomarkers Identified

A team of West Virginia scientists have made a breakthrough in cancer research that could improve the results patients see from lung cancer treatments.

Scientists from the West Virginia University Cancer Institute and the Morgantown-based bio-analytic technology company Protea say they’ve identified changes that occur at the molecular level in lung cancer cells. Those changes may make the cells resistant to cancer-fighting drugs, something researchers say can be a common problem among cancer patients.

Protea Biosciences Group, Inc., recently announced the use of its proprietary bioanalytical technology to achieve the molecular profiling of live tumor cells while they are under treatment.

The team had presented their results at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans. The presentation, titled “Mass Spectrometry Imaging Determines Biomarkers of Early Adaptive Precision Drug Resistance in Lung Cancer”, identifies molecular changes occurring within drug resistant lung cancer cells.  The research used the Company’s proprietary mass spectrometry imaging (MSI) workflows to rapidly identify molecular changes occurring within residual tumor cells.

“Drug resistance emergence is a common problem that limits long term outcome benefits in the era of precision cancer therapy,” commented Erin Seeley, PhD., Clinical Imaging Principal Investigator at Protea. She added, “Today we present the use of our mass spectrometry imaging (MSI) technology to interrogate the biomolecular changes occurring within residual tumor cells under precision treatment with ALK-specific kinase inhibitor treatments.”

“Using Protea’s MSI technology, our team discovered several metabolites that were changing over a time course of treatment. Peptides were detected that showed differentiation with over 98% accuracy between treated and untreated xenograft tumors (FFPE); also MSI analysis of frozen tumors allowed for detection of the precision therapy drug, as well as lipids that were changing in expression as a result of treatment.”

A common problem in the treatment of cancer is that the tumors become resistant to the drug with which they are being treated.  The earlier the resistance is detected, the sooner the patient can be switched to a different therapy, thus increasing their chances of treatment success and cure.  The research presented by Protea and WVU scientists at the AACR Annual Meeting profiles the biomolecules being expressed (peptides, lipids, metabolites) in a mouse xenograft model and a cell line model of lung cancer that both show resistance to treatment with a particular class of drugs, known as kinase inhibitors.  The ability to rapidly identify the specific molecular changes that occur when a tumor becomes resistant to treatment will help guide the development of improved treatment strategies.

Further studies are planned to validate the use of the biomarkers to identify drug resistance in lung cancer. Protea’s mass spectrometry imaging (MSI) technology facilitates rapid interrogation of the molecular changes occurring within tumor cells, generating data within minutes on changes in the production of specific molecules in the tumor cells.

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New Study Implicates Unusual Class of Circular RNAs in Cancer

Cancer cells are notorious for their genomes gone haywire, often yielding fusion proteins — mash-ups of two disparate genes that, once united, assume new and harmful capabilities. Exactly how such genome scrambling impacts RNA, particularly the vast and mysterious world of non-coding RNA, has been largely unexplored.

Now, a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) offers some early answers by studying an intriguing class of non-coding RNAs known as circular RNAs. Published in the March 31 advance online issue of Cell, their findings reveal that circular RNAs – like their protein counterparts – are also affected by genomic rearrangements in cancer, resulting in abnormal fusions. Moreover, these fusion-circular RNAs are not mere bystanders; they appear to promote tumor growth and progression, underscoring their role in the disease.

“Cancer is essentially a disease of mutated or broken genes, so that motivated us to examine whether circular RNAs, like proteins, can be affected by these chromosomal breaks,” said senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. “Our work paves the way to discovering many more of these unusual RNAs and how they contribute to cancer, which could reveal new mechanisms and druggable pathways involved in tumor progression.”

When it comes to RNA, scientists’ worldview is in the midst of a significant shift. Long dismissed as a mere messenger, RNA is perhaps best known for its role ferrying instructions from the genome, which is cloistered in the nucleus, to more far-flung parts of the cell, where it is made into protein. Yet only 2 percent of the genome is copied (or “transcribed”) from DNA into RNA and then translated into protein. Scientists now recognize that much, if not all, of the remaining 98 percent — which had previously been deemed non-functioning— is in fact transcribed into RNA. The roles this vast swath of so-called “non-coding RNA” might play in human biology and disease now signify an area of intense research.

Curious about the possibility of circular RNAs contributing to cancer, Pandolfi and his colleagues set out to see if they could detect relevant changes in tumors known to harbor distinct fusion proteins, which result when different chromosomes abnormally join together, melding two separate genes into a new centaur-like gene. These chromosomal translocations are common in various types of leukemia, so the researchers examined two types: acute promyelocytic leukemia, which often carries a translocation between the PML and RARα genes; and acute myeloid leukemia, which can harbor a translocation between the MLL and AF9 genes.

The researchers found abnormal fusion-circular RNAs (f-circRNAs), corresponding to different exons associated with the PML-RARα gene fusion as well as the MLL-AF9 gene fusion. (Normally, multiple circular RNAs can be generated from a single gene, so it is not entirely surprising to find different f-circRNAs emerging from the same fusion gene.)

Remarkably, Pandolfi and his colleagues uncovered f-circRNAs in solid tumors, too — in samples from Ewing sarcoma, a form of soft tissue cancer, and lung cancer. Moreover, the team identified them using two distinct methods, PCR-based amplification as well as sequencing-based approaches, underscoring f-circRNAs as bona fide biological entities, rather than experimental artifacts.

“Our ability to readily detect these fusion-circular RNAs — and their normal, non-fused counterparts — will be enhanced by advances in sequencing technology and analytic methods,” said first author Jlenia Guarnerio, PhD, also of BIDMC. “Indeed, as we look ahead to cataloguing them comprehensively across all cancers and to deeply understanding their mechanisms of action, we will need to propel these new methodologies even further.”

To determine whether f-circRNAs play a functional role in cancer, the researchers introduced them experimentally into cells, causing the cells to increase their proliferation and tendency to overgrow — features shared by tumor cells. On the other hand, when the researchers blocked f-circRNA activity, the cells’ normal behaviors were restored.

The researchers also conducted experiments using a mouse model of leukemia. They focused on a specific f-circRNA associated with the MLL-AF9 fusion gene, called f-circM9. Although insufficient on its own to trigger leukemia, f-circM9 appears to work together with other cancer-promoting signals (such as the MLL-AF9 fusion protein) to cause disease. Additional studies suggest that f-circM9 may also help tumor cells persist in the face of anti-cancer drugs.

“These results are particularly exciting because they suggest that drugs directed at fusion-circular RNAs could be a powerful strategy to pursue for future therapeutic development in cancer,” said Pandolfi.

Circular RNAs were first identified more than three decades ago and largely dismissed as a rare cellular oddity. But a study published in 2012 by Patrick Brown’s group at Stanford University showed that they are present at high levels in diverse cell types, igniting scientists’ efforts to study and understand them. Surprisingly, circular RNAs — are among the most abundant non-coding RNAs in cells, driven in part by the molecules’ unusual chemical stability. Unlike linear RNAs, circular RNAs are not susceptible to RNA-degrading enzymes. This ability to persist makes them not only an interesting therapeutic target, but also a potential molecular beacon or biomarker that can facilitate the diagnosis of disease.

“Our knowledge of circular RNAs is really in its infancy,” explained Pandolfi. “We know that normally, they can bind proteins as well as DNA and microRNAs, but much more needs to be done to understand how fusion-circular RNAs work. We have only scratched the surface of these RNAs and their roles in cancer and other diseases.”

Study coauthors include BIDMC investigators Marco Bezzi, Jong Cheol Jeong, Stella V. Paffenholz, Kelsey Berry, Matteo M. Naldini, and Andrew H. Beck. Other coathors include Francesco Lo-Coco of the Università Tor Vergata in Italy, and Yvonne Tay of the National University of Singapore, in Singapore.

 

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New Funding Sought for Development of Diagnostic Test and Therapeutic Drug for Traumatic Brain Injury (TBI)

Medicortex Finland Oy, a start-up biotechnology company focused on the diagnosis and treatment of neurodegenerative conditions has recently launched a funding round and is seeking investors to help fund research and development of a therapeutic drug and companion diagnostic test for Traumatic Brain Injury (TBI). The company aims to identify a TBI biomarker and, on this basis, develop a diagnostic test for the evaluation of TBI presence and severity. The Company’s other mission is to develop a drug that would limit the long-term effects of TBI, including post-traumatic stress disorder and chronic traumatic encephalopathy.

Numerous studies show that even one mild TBI, also called concussions, can lead to long-term neurodegeneration, which can manifest as sleep disturbance, problems with concentration, nausea, and seizures. When left untreated, these symptoms can develop into more severe neurodegenerative conditions, such as Alzheimer’s or Parkinson’s diseases. As a result of repeated head trauma, many football players, boxers, and ice hockey players suffer from impaired memory and early-onset dementia.

The insidious and devastating consequences of TBI result from the cascade of physiological events that follow the trauma. In the hours, days, and weeks after TBI, the increased permeability of the neuronal membrane allows for an excessive influx of metal ions and circulating free radicals into the brain. These cause a series of protein degradation cascades and oxidation, leading to widespread molecular damage and neuronal cell death. In short, the damage expands and permanent neurodegeneration takes place if TBI is left untreated. Unfortunately, no drug or proper diagnostic test exist for TBI sufferers.

The people most likely to suffer from TBI include, among others, soldiers, athletes and sports professionals. Certainly, the world remembers Michael Schumacher, race car driver and Formula One winner, who suffered a ski accident and fought a serious TBI. No matter how much attention these stories receive, the real story of sports-related TBI lies in the sheer magnitude of the problem. The total annual costs of TBI in Europe exceed €100 billion and the costs show no decrease because the incidence of TBI is increasing steeply. The incidence rate is estimated to be 262 per 100,000 annually, but the true incidence might be even higher because of the lack of proper TBI diagnostics.

Medicortex Finland is working towards the identification of a TBI biomarker and incorporating it into a quick and reliable diagnostic kit that can be easily used by the first responders and healthcare professionals, but also by people with no medical profession. The ideal kit will not only diagnose the presence of TBI, but it will also quantify the severity of injury so that the recovery can be monitored. In the future, the kit will advance the TBI drug development that will again alleviate or even arrest the long-term neurodegeneration after TBI. The company is currently in the human proof-of-concept stage, is seeking an investment to support the fast evaluation of a TBI biomarker from human samples.