Posts Tagged ‘medicine’

Researchers from St. Jude Children’s Research Hospital have discovered that inhibiting an enzyme called cyclin-dependent kinase 2 (CDK2) protects mice and rats from noise- or drug-induced hearing loss. The study, which will be published March 7 in the Journal of Experimental Medicine, suggests that CDK2 inhibitors prevent the death of inner ear cells, which has the potential to save the hearing of millions of people around the world.

According to the World Health Organization, 360 million people worldwide, including 32 million children, suffer from hearing loss caused by congenital defects or other factors. These factors include infectious disease, use of certain medicines, or exposure to excessive noise. Yet, there are currently no FDA-approved drugs to prevent or treat hearing loss.

A team of researchers led by Dr. Jian Zuo screened over 4,000 drugs for their ability to protect cochlear cells from the chemotherapy agent cisplatin. Cisplatin is used to treat a variety of cancers but causes irreversible hearing loss in up to 70% of patients.

Zuo and colleagues identified multiple compounds that protected cochlear cells from cisplatin, several of which are already approved to treat other conditions. Three of the ten most effective compounds were inhibitors of an enzyme called CDK2. One of these CDK2 inhibitors, kenpaullone, was more effective than four other compounds that are currently in clinical trials for treating hearing loss.

Injecting kenpaullone into the middle ear protected both mice and rats from cisplatin-induced hearing loss. Moreover, kenpaullone also protected the hearing of mice to noise as loud as 100 dB. “Given that 100-dB noise is in the range of noise insults commonly experienced by people in our society, kenpaullone could have significant clinical application in treating noise-induced hearing loss,” says Zuo.

In the case of cisplatin-induced hearing loss, kenpaullone appears to protect hair cells by preventing CDK2 from stimulating the production of toxic reactive oxygen species from the cells’ mitochondria.

“The robust protection conferred by one-time local delivery of kenpaullone suggests that CDK2 inhibitors may transform the clinical prevention and treatment of cisplatin- and noise-induced hearing loss in patients,” Zuo says. “Modifications of the treatment regimens, additional optimization of the delivery methods via the use of hydrogels, and structural modifications of the compounds via medicinal chemistry could ensure even better results with CDK2 inhibitors in treating hearing loss in humans.”


Research published in The Lancet Public Health indicated that alcohol use disorder is a major risk factor for dementia, especially early-onset dementia.

“The relationships between alcohol use and cognitive health in general, and dementia in particular, are complex,” Michaël Schwarzinger, MD, of the Translational Health Economics Network, France, and colleagues wrote. “Moderate drinking has been consistently associated with detrimental effects on brain structure, and nearly every review describes methodological problems of underlying studies, such as inconsistent measurement of alcohol use or dementia, or both, and insufficient control of potential confounders. By contrast, heavy drinking seems detrimentally related to dementia risk, whatever the dementia type.”

To determine how alcohol use disorders effect dementia risk, especially among those aged younger than 65 years, researchers conducted a nationwide retrospective cohort of hospitalized adults in France discharged with alcohol-related brain damage, vascular dementia or other dementias between 2008 and 2013. Alcohol use disorder was the primary exposure, and dementia was the main outcome. Using the French National Hospital Discharge database, they studied the prevalence of early-onset dementia and determined whether alcohol use disorders or other risk factors were associated with dementia onset.

In total, 1,109,343 adults discharged from hospital in France were diagnosed with dementia and included in the study. Of those, 35,034 cases of dementia were attributable to alcohol-related brain damage, and 52,625 cases had other alcohol use disorders. Among the 57,353 early-onset dementia cases, 22,338 (38.9%) were attributable to alcohol-related brain damage and 10,115 (17.6%) had an additional diagnosis of alcohol use disorders.

Analysis revealed that alcohol use disorders were linked to a threefold increased risk for all types of dementia and “were the strongest modifiable risk factor for dementia onset” (adjusted HR = 3.34 [95% CI, 3.28–3.41] for women; HR = 3.36 [95% CI, 3.31–3.41] for men). Alcohol use disorders remained associated with an increased risk for vascular and other dementias even after excluding alcohol-related brain damage, according to the findings. Furthermore, chronic heavy drinking was also linked to all other independent risk factors for dementia onset, including tobacco smoking, high blood pressure, diabetes, lower education, depression and hearing loss.

“Our findings suggest that the burden of dementia attributable to alcohol use disorders is much larger than previously thought, suggesting that heavy drinking should be recognized as a major risk factor for all types of dementia,” Schwarzinger said in a press release. “A variety of measures are needed, such as reducing availability, increasing taxation and banning advertising and marketing of alcohol, alongside early detection and treatment of alcohol use disorders.”

Previous research has largely focused on modest alcohol use, and its possible beneficial effect, thus overlooking the effect of heavy alcohol use as a modifiable risk factor for dementia, according to a related comment written by Clive Ballard, MBChB, MRCPsych, and Iain Lang, PhD, of the University of Exeter Medical School, U.K.

“Although many questions remain, several can be answered using existing data, which would provide an opportunity to refine our understanding of the pathways of modifiable risk and develop optimal prevention strategies,” Ballard and Lang wrote. “In our view, this evidence is robust, and we should move forward with clear public health messages about the relationship between both alcohol use disorders and alcohol consumption, respectively, and dementia.” – by Savannah Demko

In one of the first successes of its kind, researchers from Case Western Reserve University School of Medicine and six other institutions have inhibited the spreading of cancer cells from one part of the body to another. In doing so, they relied on a new model of how cancer metastasizes that emphasizes epigenetics, which examines how genes are turned on and off.

In a study published in Nature Medicine, the investigators—including scientists from the National Cancer Institute and Cleveland Clinic—used innovative epigenetic-centered techniques to halt the spread of bone cancer (osteosarcoma) cells to the lungs in mice.

The large majority of deaths associated with osteosarcoma are due to the spreading of the cancer to the lungs, a process known as metastasis. Most human osteosarcoma cases occur in children and young adults between the ages of 10 and 30, with teens the most frequently affected age group. Clinical outcomes for patients with osteosarcoma have not improved for more than 30 years, and there are currently no approved targeted anti-metastatic therapies for the disease in wide clinical use.

“More than 90 percent of all cancer deaths are the result of tumor metastasis, not primary-site tumors,” said the study’s senior author, Peter Scacheri, professor of genetics and genome sciences at Case Western Reserve University School of Medicine and member of the Case Comprehensive Cancer Center. “While many of the genes responsible for metastasis have been identified, the mechanisms that control these genes are not well defined. Our findings demonstrate that altered gene-enhancer activity is fundamental to a cancer cell’s ability to metastasize.”

Gene enhancers are short segments of DNA that, when bound by specialized proteins called transcription factors, function like switches to activate genes. This process is critical for normal development, as when a single fertilized egg develops into the many different cell types that comprise the body.

There are tens of thousands of gene enhancers in each cell, far more than the number of genes; they will be in different “on” and “off” positions in, for example, eye and heart cells (or gradients thereof, like a dimmer switch’s effects on the brightness-level of a light). These distinctive “on and off” profiles lend cells their unique characteristics, even though they all have the same DNA.

But faulty enhancer regulation appears to contribute to tumor-formation and subsequent spreading of cancer cells. In addition, different cancers are distinguishable by different enhancer patterns.

In this new study, the authors show that the on-off switches of cancer cells that have metastasized are in different positions than in the cells of the source tumor.

“Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumors to form in the first place,” said the study’s lead author, James J. Morrow, a medical student in the Medical Scientist Training Program at Case Western Reserve University School of Medicine. “Unfortunately, searching for gene mutations that drive metastasis has not substantially improved outcomes for patients with metastatic disease. Five-year survival rates for cancer patients with regional or localized disease have significantly improved for many types of cancer. But with few exceptions, outcomes for patients with metastatic cancer have remained stagnant.

“It is well established that primary tumor formation is driven by a combination of genetic and epigenetic events,” he continued. “So based on the knowledge that enhancers drive both normal cell development and tumor-formation, we hypothesized that they may play a similar role in the transition of cancer cells from one developmentally distinct tissue to another during metastatic progression.”

Through epigenomic profiling experiments, the Case Western Reserve-led researchers consistently identified certain bunched clusters of enhancers—known as metastatic variant enhancer loci (Met-VELs)—near cancer genes in lung metastases of patients with osteosarcoma, indicating that they were central to the metastatic process. Using experimental mouse models, the researchers then showed that growth of osteosarcoma cells in the lung can be mitigated by using BET inhibitors (anti-cancer drugs currently in clinical trials), which broadly interrupt the function of Met-VELs in driving gene expression.

Second, they demonstrated that the metastatic capacity of osteosarcoma cells can be diminished by blocking expression of individual genes regulated by Met-VELs or the transcription factors driving that regulation. They verified that a particular Met-VEL-linked gene, Tissue Factor (F3), is essential for metastatic colonization. Specifically, interrupting the signaling and pro-coagulant (blood clotting) functions of F3 with antibodies inhibiting these functions was sufficient to prevent metastasis. Additionally, they showed that deleting a single Met-VEL regulating F3 expression via the TALEN gene-editing process achieved a similar effect.

“Our experiments show that removing a single enhancer of the F3 gene in tumor cells virtually eliminates their ability to metastasize in mice,” said Scacheri. “Collectively, our findings establish that enhancer elements endow tumor cells with metastatic capacity and that targeted inhibition of genes associated with enhancer alterations, or deleting altered enhancers themselves is sufficient to block metastatic colonization and proliferation. While our work focused on lung metastasis in osteosarcoma, the findings have implications for other types of metastatic cancer as well.”

The Case Western Reserve University School of Medicine focus on epigenetics in the new study represents a break with the prevailing model for metastasis, which largely explores mutations in the genes—not if or how certain genes are turned on or off. And the preponderance of current cancer research takes place on the early stages of disease, such as how tumors are formed and on what distinguishes cancer cells from normal cells, and not on metastasis. Additionally, most cancer medications and treatments today were developed to kill primary tumors, not cancer cells that have spread elsewhere.

Bipolar Disorder (BD) is a multifactorial brain disorder in which patients experience radical shifts in mood and undergo periods of depression followed by periods of mania. It has been known for some time that both environmental and genetic factors play important roles in the disease. For instance, being exposed to high levels of stress for long periods, and especially during childhood, has been associated with the development of BD.

Immediate early genes (IEGs) are a class of genes that respond very rapidly to environmental stimuli, and that includes stress. IEGs respond to a stressor by activating other genes that lead to neuronal plasticity, the ability of brain cells to change in form and function in response to changes in the environment. Ultimately, it is the process of neuronal plasticity that gives the brain the ability to learn from and adapt to new experiences.

One type of protein produced by IEGs is the so-called Early Growth Response (EGR) proteins, which translate environmental influence into long-term changes in the brain. These proteins are found throughout the brain and are highly produced in response to environmental changes such as stressful stimuli and sleep deprivation. Without the action played out by these proteins, brain cells and the brain itself cannot appropriately respond to the many stimuli that are constantly received from the environment.

Effective neuronal plasticity also depends on neurotrophins, which are regulatory factors that promote development and survival of brain cells. Brain-derived neurotrophic factor (BDNF) is the neurotrophin mostly found in the brain. It has been extensively investigated in BD patients and has been suggested as a hallmark of BD. Indeed, some studies have shown that the levels of BDNF in the serum of BD patients are reduced whenever patients undergo a period of depression, hypomania, or mania. Other studies have shown that regardless of mood state, BD patients present reduced levels of BDNF. Overall, changes in BDNF levels seem to be a characteristic found in BD patients that may contribute to the pathophysiology of the disease.

Now an international team of researchers from Universidade Federal do Rio Grande do Sul in Brazil, University of Arizona College of Medicine in the United States and McMaster University in Canada have published an article connecting the dots between these two players to explain the impaired cellular resilience observed in BD that in the grand scheme of things may relate to the impaired resilience presented by BD patients to respond to events, including stress.

In a previous study done by the group in 2016, one type of IEG gene known as EGR3, that normally responds to environmental events and stressful stimuli, was found repressed in the brain of BD patients, suggesting that when facing a stressor, the EGR3 in BD patients does not respond to the stimulus appropriately. Indeed, BD patients are highly prone to stress and have more difficulties dealing with stress or adapting to it if compared to healthy individuals. What the research group is now suggesting is that both EGR3 and BDNF may each play a critical role in the impaired cellular resilience seen in BD, and that each of these two genes may affect each other’s expression in the cell. “We believe that the reduced level of BDNF that has been extensively observed in BD patients is caused by the fact that EGR3 is repressed in the brain of BD patients. The two molecules are interconnected in a regulatory pathway that is disrupted in BD patients,” says Fabio Klamt, leading author of the article entitled “EGR3 immediate early gene and the brain-derived neurotrophic factor in bipolar disorder” and published on February 5th in the journal Frontiers in Behavioral Neuroscience.

The authors also add that the fact that EGR3 responds very quickly to environmental stimuli renders the molecule a potential drug target. “It is possible to imagine that EGR3 may be modulated in order to increase its expression and that of BDNF, which may have a positive impact on BD patients,” says Bianca Pfaffenseller, a scientist working at Hospital de Clínicas de Porto Alegre, in Brazil, and the first author of the study.

The idea that mental disorders should be seen as any other chronic disease in which the underlying biology plays an important role has replaced the old descriptions of mental illnesses as the result of bad psychological influences. As Nobel prize laureate Eric Kandel has said, “all mental processes are brain processes and therefore all disorders of mental functioning are biological diseases.” The perspective article authored by Fabio Klamt and colleagues supports this view by offering new insights into the underlying biology of this lifelong and devastating mental disorder affecting millions of people worldwide.

This article has been republished from materials provided by Universidade Federal do Rio Grande do Sul. Note: material may have been edited for length and content. For further information, please contact the cited source.

Pfaffenseller, B., Kapczinski, F., Gallitano, A., & Klamt, F. (2018). EGR3 immediate early gene and the brain-derived neurotrophic factor in bipolar disorder. Frontiers in Behavioral Neuroscience, 12, 15.

Is your child having a tough time sleeping properly? You may need to keep a check on his/her body mass index (BMI) as a new research suggests that there is a co-relation between the two and can lead to cancer in adulthood.

“Childhood obesity very often leads to adult obesity. This puts them at greater risk of developing obesity-related cancers in adulthood,” said study lead author Bernard Fuemmeler, Professor and Associate Director for Cancer Prevention and Control at the Virginia Commonwealth University.

For the study, researchers enrolled 120 children, with an average age of eight, whose mothers had participated in the Newborn Epigenetic Study both pre-birth and during early childhood.

To track the sleep-wake cycle, the children wore accelerometers continuously for 24 hours a day for a period of at least five days.

They found that shorter sleep duration, measured in hours, was associated with a higher BMI z-score (body mass index adjusted for age and sex).

Each additional hour of sleep was associated with a .13 decrease in BMI z-score and with a 1.29 cm decrease in waist circumference.

More fragmented rest-activity rhythms and increased intradaily variability — a measure of the frequency and extent of transitions between sleep and activity — were also associated with greater waist circumferences.

The study results, to be presented at Obesity and Cancer: Mechanisms Underlying Etiology and Outcomes, indicate that while sleep duration is important, examining markers of sleep quality may also be useful in designing childhood obesity prevention strategies.

“Today, many children are not getting enough sleep. There are a number of distractions, such as screens in the bedroom, that contribute to interrupted, fragmented sleep. This, perpetuated over time, can be a risk factor for obesity,” Fuemmeler said.

“Because of the strong links between obesity and many types of cancer, childhood obesity prevention is cancer prevention.”

Proper sleep in children may prevent cancer later

A team of American and Russian computer scientists has developed an algorithm that can rapidly search databases to discover novel variants of known antibiotics — a potential boon in fighting antibiotic resistance.

In just a few hours, the algorithm, called VarQuest, identified 10 times more variants of peptidic natural products, or PNPs, than all previous PNP discovery efforts combined, the researchers report in the latest issue of the journal Nature Microbiology. Previously, such a search might have taken hundreds of years of computation, said Hosein Mohimani, assistant professor in Carnegie Mellon University’s Computational Biology Department.

“Our results show that the antibiotics produced by microbes are much more diverse than had been assumed,” Mohimani said. VarQuest found more than a thousand variants of known antibiotics, he noted, providing a big picture perspective that microbiologists could not obtain while studying one antibiotic at a time.

Mohimani and Pavel A. Pevzner, professor of computer science at the University of California, San Diego, designed and directed the effort, which included colleagues at St. Petersburg State University in Russia.

PNPs have an unparalleled track record in pharmacology. Many antimicrobial and anticancer agents are PNPs, including the so-called “antibiotics of last resort,” vancomycin and daptomycin. As concerns mount regarding antibiotic drug resistance, finding more effective variants of known antibiotics is a means for preserving the clinical efficacy of antibiotic drugs in general.

The search for these novel variants received a boost in recent years with the advent of high-throughput methods that enable environmental samples to be processed in batches, rather than one at a time. Researchers also recently launched the Global Natural Products Social (GNPS) molecular network, a database of mass spectra of natural products collected by researchers worldwide. Already, the GNPS based at UC San Diego contains more than a billion mass spectra.

The GNPS represents a gold mine for drug discovery, Mohimani said. The VarQuest algorithm, which employs a smarter way of indexing the database to enhance searches, should help GNPS meet its promise, he added.

“Natural product discovery is turning into a Big Data territory, and the field has to get prepared for this transformation in terms of collecting, storing and making sense of Big Data,” Mohimani said. “VarQuest is the first step toward digesting the Big Data already collected by the community.”

Reference: Gurevich, A., Mikheenko, A., Shlemov, A., Korobeynikov, A., Mohimani, H., & Pevzner, P. A. (2018). Increased diversity of peptidic natural products revealed by modification-tolerant database search of mass spectra. Nature Microbiology, 1.


Scientists have developed a noninvasive blood test that can detect signs of eight types of cancer long before any symptoms of the disease arise.

The test, which can also help doctors determine where in a person’s body the cancer is located, is called CancerSEEK. Its genesis is described in a paper published Thursday in the journal Science.

The authors said the new work represents the first noninvasive blood test that can screen for a range of cancers all at once: cancer of the ovary, liver, stomach, pancreas, esophagus, colon, lung and breast.

Together, these eight forms of cancer are responsible for more than 60% of cancer deaths in the United States, the authors said.

In addition, five of them — ovarian, liver, stomach, pancreatic and esophageal cancers — currently have no screening tests.

“The goal is to look for as many cancer types as possible in one test, and to identify cancer as early as possible,” said Nickolas Papadopoulos, a professor of oncology and pathology at Johns Hopkins who led the work. “We know from the data that when you find cancer early, it is easier to kill it by surgery or chemotherapy.”

CancerSEEK, which builds on 30 years of research, relies on two signals that a person might be harboring cancer.

First, it looks for 16 telltale genetic mutations in bits of free-floating DNA that have been deposited in the bloodstream by cancerous cells. Because these are present in such trace amounts, they can be very hard to find, Papadopoulos said. For example, one blood sample might have thousands of pieces of DNA that come from normal cells, and just two or five pieces from cancerous cells.

“We are dealing with a needle in a haystack,” he said.

To overcome this challenge, the team relied on recently developed digital technologies that allowed them to efficiently and cost-effectively sequence each individual piece of DNA one by one.

“If you take the hay in the haystack and go through it one by one, eventually you will find the needle,” Papadopoulos said.

In addition, CancerSEEK also screens for eight proteins that are frequently found in higher quantities in the blood samples of people who have cancer.

By measuring these two signals in tandem, CancerSEEK was able to detect cancer in 70% of blood samples pulled from 1,005 patients who had already been diagnosed with one of eight forms of the disease.

The test appeared to be more effective at finding some types of cancer than others, the authors noted. For example, it was able to spot ovarian cancer 98% of the time, but was successful at detecting breast cancer only 33% of the time.

The authors also report that CancerSEEK was better at detecting later stage cancer compared to cancer in earlier stages. It was able to spot the disease 78% of the time in people who had been diagnosed with stage III cancer, 73% of the time in people with stage II cancer and 43% of the time in people diagnosed with stage I cancer.

“I know a lot of people will say this sensitivity is not good enough, but for the five tumor types that currently have no test, going from zero chances of detection to what we did is a very good beginning,” Papadopoulos said.

It is also worth noting that when the researchers ran the test on 812 healthy control blood samples, they only saw seven false-positive results.

“Very high specificity was essential because false-positive results can subject patients to unnecessary invasive follow-up tests and procedures to confirm the presence of cancer,” said Kenneth Kinzler, a professor of oncology at Johns Hopkins who also worked on the study.

Finally, the researchers used machine learning to determine how different combination of proteins and mutations could provide clues to where in the body the cancer might be. The authors found they could narrow down the location of a tumor to just a few anatomic sites in 83% of patients.

CancerSEEK is not yet available to the public, and it probably won’t be for a year or longer, Papadopoulos said.

“We are still evaluating the test, and it hasn’t been commercialized yet,” he said. “I don’t want to guess when it will be available, but I hope it is soon.”

He said that eventually the test could cost less than $500 to run and could easily be administered by a primary care physician’s office.

In theory, a blood sample would be taken in a doctor’s office, and then sent to a lab that would look for the combination of mutations and proteins that would indicate that a patient has cancer. The data would then go into an algorithm that would determine whether or not the patient had the disease and where it might be.

“The idea is: You give blood, and you get results,” Papadopoulos said.