Researchers analyze molecular characteristics of cerebrospinal fluid from LMM patients

Patients with advanced melanoma who develop metastases in the leptomeninges, the fluid filled membranes surrounding the brain and spinal cord, have an extremely dismal prognosis. Most patients only survive for 8 to 10 weeks after diagnosis. One reason for this poor prognosis is that very little information is known about the molecular development of leptomeningeal melanoma metastases (LMM), making it difficult to develop effective therapies. Researchers in Moffitt Cancer Center's Donald A. Adam Melanoma and Skin Cancer Center of Excellence and the Department of Neuro-Oncology sought to change this by performing an extensive analysis of the molecular characteristics of the cerebrospinal fluid of patients with LMM. Their findings were published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

Cancer development and progression are highly regulated by intricate interactions between cancer cells and the surrounding environment. Melanoma cells that invade and metastasize into the leptomeninges interact with the surrounding cerebrospinal fluid. Moffitt researchers wanted to improve their understanding of the development of LMM by analyzing the protein and RNA composition of cerebrospinal fluid from patients with LMM. They compared the molecular profiles of 8 control patients without LMM to 8 patients with LMM, including one LMM patient who had an extraordinary response to treatment and was still alive more than 35 months after diagnosis.

They discovered that the cerebrospinal fluid from LMM patients was enriched for proteins involved in innate immunity, proteases and the IGF-signaling pathway. The most commonly altered protein was TGF-β1. Interestingly, the one patient who had an extraordinary response to treatment displayed high levels of these proteins at baseline, but expression levels decreased as the patient responded to treatment. However, the protein expression patterns in the remaining LMM patients who had poor responses to treatment were high at baseline and remained high throughout treatment and disease progression.

The researcher team, led by Keiran Smalley, Ph.D., director of the Donald A. Adam Melanoma and Skin Cancer Center of Excellence and Peter Forsyth, M.D., Chair of the Department of Neuro-Oncology, hypothesized that the cerebrospinal fluid of LMM patients could impact melanoma cells by modulating their molecular profile. They confirmed this hypothesis by incubating cerebrospinal fluid from the LMM patients with melanoma cells and discovered that the fluid was able to induce activation of proteins and signaling pathways involved in malignant progression, including the PI3K/AKT pathway, integrins, B cell signaling, mitotic cell cycle progression, TNFR, TGF-β and oxidative stress.

Their findings demonstrate that the cerebrospinal fluid from LMM patients who did not respond to treatment promoted survival of melanoma cells, while the cerebrospinal fluid from the extraordinary responder did not promote survival. These observations suggest that molecules exist within the cerebrospinal fluid that can stimulate melanoma cell survival and prevent cell death. The researchers reported that one of these survival molecules is TGF-β. The patient who responded well to treatment had very low to undetectable levels of cerebrospinal fluid TGF-β, while those patients who did not respond to treatment had much higher levels of TGF-β.

The researchers hope that their data will provide important knowledge about LMM and offer insights into potential therapeutic targets.

It is likely that the environment of LMM is a key regulator of both disease progression and therapeutic response. Improved knowledge about the microenvironment of LMM may allow novel therapeutic strategies to be developed that can delay disease progression."

Keiran Smalley, Ph.D., director of the Donald A. Adam Melanoma and Skin Cancer Center of Excellence.

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New tumor-driving mutations discovered in the under-explored regions of the cancer genome

In an unprecedented pan-cancer analysis of whole genomes, researchers at the Ontario Institute for Cancer Research (OICR) have discovered new regions of non-coding DNA that, when altered, may lead to cancer growth and progression.

The study, published today in Molecular Cell, reveals novel mechanisms of disease progression that could lead to new avenues of research and ultimately to better diagnostic tests and precision therapies.

Although previous studies have focused on the two per cent of the genome that codes for proteins, known as genes, this study analyzed mutation patterns within the vast non-coding regions of human DNA that control how and when genes are activated. 

"Cancer-driver mutations are relatively rare in these large non-coding regions that often lie far from genes, presenting major challenges for systematic data analysis," says Dr. Jüri Reimand, investigator at OICR and lead author of the study. 

"Powered by novel statistical tools and whole genome sequencing data from more than 1,800 patients, we found evidence of new molecular mechanisms that may cause cancer and give rise to more-aggressive tumours."

The research group analyzed more than 100,000 sections of each patient's genome, focusing on the often-overlooked non-coding regions that interact with genes through the three-dimensional genome. One of the 30 key regions discovered was predicted to have a significant role in regulating a known anti-tumour gene in cancer cells, despite being more than 250,000 base pairs away from the gene in the genome. The group performed CRISPR-Cas9 genome editing and functional experiments in human cell lines to explore the cancer-driving properties of this non-coding region.

"We characterized several non-coding regions potentially involved in oncogenesis, but we've just scratched the surface," says Reimand. "With our algorithms and the rapidly growing datasets of patient cancer genomes and epigenetic profiles, we look forward to enabling future discoveries that could lead to new ways to predict how a patient's cancer will progress and ultimately new ways to target a patient's disease or diagnose it more precisely."

Reimand's research group developed the statistical methods behind this study and made them freely available for the research community to use. These methods have been rigorously tested against other algorithms from around the world.

"Looking into the non-coding genome is really important because these vast sections regulate our genes and can switch them on and off. Mutations in these regions can cause these regulatory switches to act abnormally and potentially cause - or advance - cancer," says Helen Zhu, student at OICR and co-first author of the study. "We've shown that our method, called ActiveDriverWGS, can excavate these regions and pinpoint specific areas that are important to cancer growth."

"Although these candidate driver mutations are rare, we now have the first experimental evidence that one of the mutated regions regulates cancer genes and pathways in human cell lines," says Dr. Liis Uusküla-Reimand, Research Associate at The Hospital for Sick Children (SickKids) and co-first author of the study. "As the research community collects more data, we plan to look deeper into these regions to understand how the mutations alter gene regulation and chromatin architecture in specific cancer types to enable the development of new precision therapies to patients with these diseases."

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Protein that fights plant bacteria identified

A team from the Centre for Cellular and Molecular Biology (CCMB) has identified a new plant‐bacterial interaction which renders the plant to be resistant to bacterial infection. 

The bacterium Xanthomonas oryzae pv. oryzae, causes a bacterial blight infection in rice. This infection is fatal for rice crops, and farmers could lose up to 60% of their crops owing to this disease.
Dr Ramesh V Sonti, along with senior scientist Dr Hitendra K Patel and research scholar Sohini Deb, studied the interplay of the interactions of these effector molecules and their role in the rice plant.

They found that a bacterial effector, named XopQ, suppresses rice immune responses by interacting with certain members of a class of proteins in the rice plant cells, known as the 14‐3‐3 proteins. In an interesting experiment, they altered the sequence of the effector protein at one particular position. 

Consequently, they found that this mutant form of the bacterial effector protein, is now unable to suppress the plant immune responses. Instead, it makes the plant resistant to bacterial infection, by interaction with another different 14‐3‐3 protein. 

Understanding the molecular players in plant immune response pathway offers new ways of blocking the bacterial hijack as well as strengthening the defence responses of the plant cells. Findings of the study have been published in the journal of 'Molecular Plant Pathology,' a publication of the British Society for Plant Pathology. 

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Exercise can help beat cocaine addiction

Exercise can help prevent relapses into cocaine addiction, claims a study.

“Cocaine addiction is often characterised by cycles of recovery and relapse, with stress and negative emotions, often caused by withdrawal itself, among the major causes of relapse,” said a senior research scientist.

Using animal models, he found that regular aerobic exercise (one hour on a treadmill, five times a week) decreased stress-induced cocaine-seeking behaviour. Exercise also altered behavioural and physiological responses to stress.

Individuals who are addicted to cocaine have altered neural, behavioural and physiological responses to stress. Recent research  demonstrated how exercise can alter the brain’s mesolimbic dopamine pathway, which is linked to the rewarding and reinforcing properties of drugs such as cocaine.

In addition, exercise has been shown to reduce stress hormones and elevate mood, which could assist in alleviating anxiety and negative emotions associated with withdrawal,” reported the study.

Studies already have shown that aerobic exercises (or cardio) is an effective strategy against many physical health problems, including heart disease, diabetes, and arthritis, along with certain mental health issues, such as stress, anxiety, and depression.

“Our results suggest that regular aerobic exercise could be a useful strategy for relapse prevention, as part of a comprehensive treatment program for recovering cocaine abusers. Further research is necessary to see if these results also hold true for other addictive drugs,” the lead researcher said. 

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Head injuries lead to serious brain diseases- Here's all you need to know

 In a recent study, biologists discovered how head injuries adversely affect individual cells and genes that can lead to serious brain disorders. The researchers studied more than 6,000 cells in 15 hippocampal cell types -- the first study of individual cell types subject to brain trauma. Each cell has the same DNA, but which genes are activated varies among different cell types. Among the 15 cell types are two that were previously unknown, each with a unique set of active genes.
The life scientists provide the first cell 'atlas' of the hippocampus -- the part of the brain that helps regulate learning and memory -- when it is affected by traumatic brain injury. The team also proposed gene candidates for treating brain diseases associated with traumatic brain injuries, such as Alzheimer's disease and post-traumatic stress disorder.
"Every cell type is different," said  co-senior author of the study.  The biologists found that hundreds of genes are adversely affected by mild traumatic brain injury, such as a concussion. These altered genes can later lead to Alzheimer's, Parkinson's and other diseases.
The researchers reproduced a concussion-like brain injury in mice and studied other mice that did not receive a brain injury. The researchers analysed thousands of cells in the hippocampus of both groups of mice.
The mice without an injury had very low levels in 14 of the 15 cell types of a gene called TTR that regulates metabolism, controls thyroid hormones and performs other functions. Brain trauma increased the level of Ttr in essentially all of the cell types, the researchers found.
They concluded TTR is important to brain health and may function to bring more thyroid hormone to the brain to maintain metabolism. A thyroid hormone called T4 was injected in mice. T4 improved traumatic brain injury-induced learning deficits and reversed changes in 93 genes that affect learning and memory.
This reversal in damage caused by traumatic brain injury is a major new finding. After brain injury, metabolism is substantially reduced. The biologists think T4 may "reboot" metabolism.
Researchers found evidence that at least 12 of 15 cell types are negatively affected by brain trauma, some more strongly than others. They were able to see how genes that have been linked to Alzheimer's disease acted within different cell types, providing new details about where these genes act when they are affected by brain trauma.
"We are learning which cell types we may want to target in future research," said  a senior author of the study. "Maybe Alzheimer's disease-related genes do not have to be active in all different cell types."
For the first time, the biologists found several genes that are affected by traumatic brain injury, which has recently been linked to neurotic behaviour in humans. Traumatic brain injury has been associated with depression, anxiety, and schizophrenia. This research could lead to new treatments for these conditions. 

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Migraine- Facts that one should be aware of

 Migraine headache is a result of specific changes within the brain. It causes severe head pain that is often accompanied by sensitivity to light, sound, or smells.Migraine headache is characterized by a severe headache usually affecting one side of the head. There are other symptoms along with headache like nausea/vomiting, sensitivity to light and sound. Some patients experience neurological phenomena like changes in vision, temporary loss of sensation and altered sensation, a phenomenon known as an aura (flashes of light, zigzag patterns, bright spots, tingling in the arms and the legs). Migraine headache can last for 2 to 3 days. 

 Other types of headaches can also cause severe pain, and not all headaches are migraines. For example, some people describe the pain of cluster headaches as the worst pain they have experienced.

The exact cause of migraines is not known. Changes in neurotransmitter levels within the brain are thought to play a role. Migraines are diagnosed by the typical clinical signs and symptoms.

Migraines can be triggered by many factors, for example:
Hormonal changes 
Stress and extreme physical exertion
Strong stimuli like loud noises
Certain foods
Obesity 
Alcohol and caffeinated drinks and beverages 
Salty and processed foods
Altered sleeping habits 
Oral contraceptives and certain vasodilators (nitroglycerin) 
Preservatives like MSG (monosodium glutamate) and Aspartame (sweetener) 
Sunshine, certain odours, travel, etc can trigger migraine.


Migraine treatment usually is with over-the-counter (OTC) or prescription medications.

Symptoms: The symptoms depend on the stage of a migraine attack. The stages of a migraine attack can be: 

1. Prodrome, Aura, Headache or attack, and Postdrome. 
2. Prodorme: One to two days prior to the migraine attack, patient may experience; 
   • Mood swings. 
   • Cravings for food. 
   • Increased yawning. 
   • Stiff neck. 
   • Constipation and frequent thirst and urination. 

In case of an aura (during or before a migraine), there may be visual, motor, speech, and sensory illusions and disturbances such as, 

• Loss of vision. 
• A strange sensation of needles pricking an arm or a leg. 
• One side of the body becomes weak and numb. 
• There are visual illusions such as the appearance of flashes of light, zigzag patterns, bright spots. 
• There is a problem in hearing and speaking. 
• In some cases, there may be a hemiplegic migraine (the limb becomes weak). 

During a Migraine Attack (lasts for 4 to 72 hours), there may be 

1. A throbbing pain on either one or both sides of the head 
2. Blurred vision, light-headedness. 
3. Nausea and vomiting
4. Sensitivity to light and sound 
5. Sensitivity to touch and smell (though rare) 

In Postdrome (after a migraine), there can be 

1. Mood swings. 
2. A person may be sensitive to light and sound. 
3. Dizziness and weakness 
4. Confusion 
5. Extreme fatigue

Treatment and Prevention: 

1. Medicines under supervision to abort an attack of migraine and special drugs to stop attacks. 
2. Lifestyle changes are helpful to decrease attacks: 
   • Avoid your trigger for migraine. 
   • Follow regular sleep -wake cycle. 
   • Regular exercise, meditation. 
   • Avoidance of alcohol, caffeine containing beverages. 
3. Other treatment options that can be availed from pain specialist:
4. Transcutaneous supraorbital nerve stimulation
5. Intramuscular stimulation. 
6. Botulinum toxin injection
7. Occipital nerve block.

   When Should I See a Doctor for a Migraine? 

   Call a doctor or other health care professional if any of the following occur:

8. A change in frequency, severity, or features of the migraine commonly experienced
9. A new, progressive headache that lasts for days
10. A headache brought on by coughing, sneezing, bearing down, straining while on the toilet, or other physical straining
11. Significant unintentional loss of body weight
12. Weakness or paralysis that lasts after the headache

Go to a hospital emergency department if any of the following occur:
Having the worst headache ever, especially if the headache had a sudden onset
Headache associated with trauma to the head or loss of consciousness
Fever or stiff neck associated with headache
Decreased level of consciousness or confusion
Paralysis of one side of the body
Seizure

Natural Home Remedies for Pain

Most people with this type of headache can manage the pain of mild-to-moderate attacks at home by:

1. Using a cold compress on the area of pain
2. Resting with pillows comfortably supporting the head or neck
3. Resting in a room with little or no sensory stimulation (from light, sound, or odors)
4. Withdrawing from stressful surroundings
5. Sleeping
6. Drinking a moderate amount of caffeine

 How Can I Prevent Migraines?

Migraine triggers should be identified and avoided. Making individual lifestyle changes is very important. Changes may include avoiding certain types of foods and certain emotional situations. If missing meals triggers headaches, the person should make every effort to eat on a regular basis. In some instances, the use of biofeedback may help reduce the severity and frequency of attacks.

Regular follow-up care with a doctor or other health care professional is a must. Keep a pain journal to monitor the frequency of attacks and the medications you use can be very helpful. It may take several doctor visits before an effective treatment plan is found.
After the headaches are under control, the prognosis is very good. Patience is key. As noted previously, it may take several attempts before an effective treatment plan is found.
No one treatment or drug is effective for every person. A drug that works well for one patient may not provide any relief for another. A combination of different medications is sometimes needed to treat resistant headaches.

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