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Sorin Pedala

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2267

Researchers made a breakthrough in cancer treatment

Researchers at Memorial Sloan-Kettering Cancer Center and Eureka Therapeutics, have made a breakthrough that could revolutionize the fight against cancer. It seems that they have developed a monoclonal antibody (ESK1) that targets a protein which is associated with several types of cancers and which is found inside the cancer cells.

The new monoclonal antibody is different from the others used before in medicine because it can interfere with proteins found inside the cell, not on the surface of cancer cells. ESK1, the recently discovered humanized monoclonal antibody,  targets  a protein called WT1, an oncogenic protein that is associated with several cancers such as leukemia but also different types of breast cancer, colorectal cancer, ovarian cancer or myeloma. WT1 is critical in cancer development because it is one of the proteins that promote tumor proliferation. What is remarkable is that this protein (WT1) is found in only few healthy cells. In other words, treatment would be less harmful and with only few side effects . It is known that many drugs used in chemotherapy have plenty of adverse reactions and are generally directed towards rapidly dividing cells, such as gastrointestinal cells, hair follicle cells, etc.. Therefore perhaps the best known side effects of oncology treatment are nausea, vomiting (due to damage to the digestive system) and hair loss.

stem cell

stem cell

ESK1 mimicks the function of an important part of the immune system, that of T cell receptor. T lymphocytes have a receptor that recognizes  proteins that are found inside the cell. Once they fulfill their functions,  these proteins are fragmented and then HLA molecules, which are also part of the immune system, carry portions of these proteins (peptides) on the cell surface. When detecting abnormal peptides, T cells destroy these cells.

Cheng Liu, PhD, President and Chief Executive Officer of Eureka Therapeutics, wanted to mention that ESK1 is a paradigm change in the human monoclonal antibody therapeutics. “This research suggests that human antibody therapy is no longer limited to targeting proteins present outside cancer cells, but can now target proteins within the cancer cell itself,” he added.

David A. Scheinberg, MD, PhD, Chair of the Sloan-Kettering Institute’s Molecular Pharmacology and Chemistry Program and an inventor of the antibody, said this is a new approach to attack WT1, which is an important target in cancer treatment . He added that there has not been a  way to create small molecules that inhibit the function of WT1. However research has shown that now  you can use monoclonal antibodies that recognizes proteins associated with cancer cells and destroy them.

2093

Researchers discover why melanoma develops resistance to treatment

Researchers from Massachusetts General Hospital (MGH)  have discovered why melanoma develop resistance to therapies targeting BRAF / MEK pathway growth. New findings provide a better understanding of the mechanisms underlying melanoma resistance to treatment. It seems that BRAF inhibition alters metabolic activity in cancer cells and this change promotes resistance to treatment.

Melanoma is one of the most aggressive cancers, with a 5-year survival rate of less than 10%. Treatment of choice consists of surgical excision which is completed by radiotherapy, chemotherapy, immunotherapy, etc.. David E. Fisher, MD, PhD, chief of Dermatology at Massachusetts General Hospital (MGH), said they were surprised to learn that melanoma cells treated with vemurafenib, which is a BRAF inhibitor, changes the way cell produce energy. He added that BRAF inhibitors is a major step forward in the treatment of melanoma, because it causes tumor to shrink in most patients, and this prolongs survival by several months. Unfortunately,in  many patients relapse occur. It is therefore essential to find some strategies in order that these responses to treatment persist more. Most cases of melanoma occur due to mutations in the BRAF gene, which is why BRAF inhibitors are used to decrease tumor size. But the researchers found that when BRAF inhibitors are combined with drugs targeting MEK, which is involved in the same pathway of tumor growth, treatment response is stronger.

melanoma develops resistance to treatment

Vemurafenib

The most common way to convert glucose into energy consists of oxidative phosphorylation that occurs in mitochondria, some cellular organelles specialized in producing energy. But it seems that cancer cells are able to produce energy through another mechanism that does not involve the mitochondria. The research done by investigators at the MGH Cancer Center reveals that an increased activity of BRAF reduces the level of a transcription factor called MITF, which in turn leads to suppression of oxidative phosphorylation. Also, reduction of MITF level decreases the level of PGC1,  which is a protein that regulates the proper functioning of the mitochondria. In contrast, melanoma cells treated with BRAF inhibitors have high levels of MITF, with increased oxidative phosphorylation and an increase in the number of mitochondria. Resistance to treatment with BRAF inhibitors occurs due to the switch to oxidative phosphorylation to supply the energy needed by cancerous cells.

Fisher, the Wigglesworth Professor of Dermatology at Harvard Medical School, said the research indicates that combined treatment with mitochondrial inhibitors could increase the effectiveness of BRAF inhibitors in melanoma: “Several small molecules that target mitochondrial metabolism have been identified by investigators here at the MGH and elsewhere, and laboratory investigations of specific combinations of BRAF inhibitors with mitochondrial antagonists are currently underway.”

2253

Reseachers are investigating new method that predict progression of Barrett’s esophagus to esophageal adenocarcinoma

According to an article published in Cancer Prevention Research, the risk of malignant degeneration of Barrett’s esophagus to esophageal adenocarcinoma can be predicted using microARNs. Barrett esophagus means damage of the esophageal epithelium and is considered a premalignant condition that may progress to esophageal adenocarcinoma. Xifeng Wu, MD, chair of the Department of Epidemiology, Division of Cancer Prevention and Population Sciences at The University of Texas MD Anderson Cancer Center in Houston, said that if in the past esophageal adenocarcinoma represented a rare cancer, the incidence has increased now 6 times in the last 3 decades and now represents more than 80% of cancers of all new cases of esophageal cancer. He added that to decrease mortality in esophageal adenocarcinoma, the best solution is to detect cancer in its early stages and even better in detecting precancerous conditions such as Barrett’s esophagus.

Barrett's esophagus

Barrett’s esophagus

Barrett’s esophagus is a condition whose etiology is not known exactly, but the most common Barrett’s esophagus is associated with gastroesophageal reflux disease. So an important role in causing this condition consists in exposure to gastric acidity. It should be noted that there are cases of congenital Barrett’s esophagus but is rare. Biopsy and histopathology examination are the gold standard in diagnosis and treatment can consist of proton pump inhibitors, antireflux surgery, endoscopic ablation etc.

Wu and his team of researchers at the University of Texas conducted many studies and found that an important role in cancer development is represented by microRNAs. It seems that in cancer there is an aberrant expression of microRNAs. Therefore, they evaluated the expression of  microARNs in normal esophageal epithelium, in Barrett’s esophagus and in esophageal adenocarcinoma of different histological grades. Thus researchers found that the expression of these microRNAs is present both in Barrett’s esophagus and in esophageal adenocarcinoma in a similar manner, indicating that the presence of these markers are events that occur early in Barrett’s esophagus. Wu said that the aberrant expression of these microRNAs may be one of the events that lead to cancer.

Another discovery made during the research was that a small number of microARNs was significantly different between the two types of conditions: Barrett’s esophagus and esophageal adenocarcinoma. It seems that what differentiates Barrett esophagus of esophageal adenocarcinoma is downregulation of the microRNA miR-375 ( which means  decreasing the number of receptors) and upregulation of five microRNAs of the miR-17-92 and homologue family (which means increasing the number of receptors).

2133

Potential treatment for pancreatic cancer is linked to substance P

An article published in Molecular Cancer Research by scientists at North Dakota State University, reveals potential mechanism of severe pain in pancreatic cancer. It seems that substance P ( SP), a neurotransmitter involved in pain development, has an important role in pancreatic cancer, and may be one possible target for cancer treatment.

The mechanism by which pain occurs in pancreatic cancer is not clear. One possible explanation lies in nerve invasion by pancreatic tumor. Therefore, the researchers wanted to find what is the underlying mechanism of perineural invasion on pancreatic cancer and the mechanism by which substance P induces pain in this type of cancer. Substance P is a neuropeptide that functions as a neurotransmitter and is secreted by cells of the central nervous system but also by APUD system cells (Amine Precursor Uptake and Decarboxylation), which are found in the gastrointestinal tract.

Panceas

Panceas

It seems that substance P is distributed not only in the nervous system, but also in pancreatic cells. In addition, researchers have found that NK-1R is overexpressed in pancreatic cancer cells. Studies conducted so far revealed that NK-1R antagonists inhibits the effects of substance P, which causes tumor growth and dissemination in the body. In addition, it appears that substance P is involved in neurite outgrowth and dissemination of pancreatic cancer cells in the posterior nerve roots.

Erxi  Wu, assistant professor of pharmaceutical sciences, co-author of the paper, said that the study shows that substance P plays an important role in dissemination of pancreatic cancer and perineural invasion, and that blocking NK-1R signaling system, so the effects of substance P, may be a possible strategy for pancreatic cancer treatment.
In pancreatic cancer, one of the major symptoms is pain, besides general manifestations such as weight loss, fatigue, anorexia, etc.. Because it is sometimes severe, pain is the main symptom that sends the patient to the doctor. One mechanism of pain is nerve invasion by the tumor, so the occurrence of pain means that the cancer is large enough in size so that it compresses nerves.

It should be noted that pancreatic cancer behaves differently depending on location (pancreas is composed of head, body and tail). A tumor that occurs in the head of the pancreas  has early symptoms: jaundice, itching, discolored feces, urine highly colored, diffuse pain etc. A tumor in the pancreatic body and tail has fewer symptoms: severe abdominal pain and, sometimes, splenomegaly.

Major treatment of pancreatic cancer is surgical (Whipple operation, for example) and is indicated for both tumor resection and digestive complications treatment. Besides surgery, radiotherapy and chemotherapy can prolong survival of patients with pancreatic cancer.

2823

Multiple Sclerosis Treatment

According to a study published in PLoS ONE, researchers have made new progress in the treatment of multiple sclerosis. It seems that researchers at Karolinska Institutet have found that a new drug, imatinib, used to treat cancer, can improve and even slow the progression of multiple sclerosis.

Multiple sclerosis is an autoimmune inflammatory disease characterized by relapses and remissions  that gradually lead to permanent neurological deficits. Most often multiple sclerosis starts with optic neuritis, that is by impaired vision, or paraparesis (motor deficit), vertigo, numbness or urinary disorders (acute urinary retention or incontinence). One thing worth noting is that multiple sclerosis can lead to any neurological symptom. In Sweden MS affects approximately 17,000 people usually aged between 20 and 40 years. There is no cure for this disease so that drugs currently in use are aimed to only improve symptoms.

Multiple Sclerosis

Multiple Sclerosis

In multiple sclerosis there is a change in blood-brain barrier permeability allowing the passage of white blood cells that attack myelin in the central nervous system. It seems that this autoimmune attack is directed not only on myelin but also on axons and oligodendrocytes. In this way progressive demyelination occurs, along with neuronal death and reactive gliosis which translate into different clinical neurological deficits.

Assistant Professor Ingrid Nilsson at Karolinska Institute’s Department of Medical Chemistry and Biophysics, says it is an urgent need for effective drugs with minimal side effects to help patients multiple sclerosis in their relapse period. Relapse treatment consists of administration of corticosteroids (methylprednisolone) for 3-5 days, while chronic treatment includes interferon, glatiramer acetate or immunosuppressants: cyclosporine, cyclophosphamide, metrotexat etc. These drugs have many important side effects (liver damage, cardiac toxicity, infertility, infections, etc.) and have limited effectiveness. Recently there have been approved new drugs to treat multiple sclerosis such as monoclonal antibodies (natalizumab).

Researchers at Karolinska Institutet have tried to find a method to improve neurological symptoms by sealing the blood-brain barrier. They did many experiments on rats, that is they administered imatinib and found that the drug slows the progression of the disease and improves neurological symptoms. Also, imatinib has reduced the autoimmune reaction and the number of white blood cells that pass the blood-brain barrier. “Administering imatinib enabled us to slow down the progress of the disease and ameliorate neurological symptoms by preventing the influx of white blood cells from the blood into the nerve tissue,” said Dr. Nilsson. Because the drug proved effective,  researchers now want  to verify the efficacy of  imatinib in treating multiple sclerosis in clinical trials.

2661

New abnormal protein may help diagnose and treat ALS and frontotemporal dementia

According to a study published in the journal Neuron, a new protein that may help diagnose neurodegenerative diseases like amyotrofic lateral sclerosis (ALS), or Lou Gehrig’s disease, or frontotemporal dementia (FTD), has been identified. It seems that the new protein found, that could serve as a marker for these diseases, is formed as a result of genetic abnormalities. Senior author Dr. Leonard Petrucelli, Chair of Neuroscience at Mayo Clinic in Florida, said that by identifying this protein that accumulates abnormally in the brains of patients it was discovered not only a biomarker but also a potential treatment for this debilitating diseases. Dr. Petrucelli and his team discovered the protein while studying the brain tissue of patients with ALS and frontotemporal dementia. C9RANT, the new protein identified, occurs due to repetition of sequences of nucleotides in non-coding region of the gene C9ORF72.

ALS

ALS

It should be noted that this protein was identified only after the researchers created an antibody specific for C9RANT. It seems that patients who carry the C9ORF72 gene mutation also have the  protein C9ORF72 in cerebrospinal fluid and this is may help not only to identify patients with ALS and frontotemporal dementia but also for tracking high risk patients. In other words C9RANT is not only an indicator of disease but also a prognostic factor. “Simply put, an error in the highly regulated cellular process through which proteins are generated causes the abnormal production of C9RANT,” explains Dr. Petrucelli.

Amyotrophic lateral sclerosis, or Lou Gehrig’s disease, is a neuraodegenerative disorder that affects the central and peripheral motor neurons. Clinically, the disease is manifested by asymmetric motor deficit ( distal or proximal), dysarthria (speech disorder), fasciculations, etc.. What is of note is that the survival time since diagnosis is approximately 3-5 years. In addition, it is worth to mention that there is no cure for this disease although researchers are trying to find a drug to prolong survival.

Frontotemporal dementia is also a degenerative disease that is characterized by progressive loss of memory, confusion, irritability and loss of inhibitions. Frontotemporal dementia is due to atrophy in frontal and temporal lobes  which leads to changes in behavior and personality of the patient. The cause of the disease is not certainly known but the mechanism of this disease seems to be accumulation of abnormal proteins. It is already known that in some forms of dementia, such as Alzheimer’s disease, one of the major events in the pathology of the disease is the accumulation of tau protein, which is toxic and causes cell death.

1965

Kidney Stones Related to Vitamin C Supplements

The latest research done by a team from the Karolinska Institutet from Sweden reveals that men who take vitamin C on a regular basis have a higher risk to develop kidney stones. However, researchers didn’t find the same results in men who take multivitamins on a regular basis, probably due to the fact that multivitamins contain a lower quantity of vitamin C. The study was recently published in the journal JAMA Internal Medicine.

The information for the study was gathered from a very large population of men from two Swedish counties, Ă–rebro and Västmanland. More than 23 thousand male patients were monitored overt the course of 11 years. None of the patients had any history of kidney stones at the start of the trial. However, they were either taking vitamin C supplements or were having a normal diet. Across the trial period, 436 patients developed kidney stones and required further medical attention. This led the research team to study whether or not the vitamin C supplements had an impact on the development of kidney stones. The same analysis was then conducted on the patients who were taking multivitamins.

According to the results of the study, vitamin C supplements, usually in the form of 1g tablets, double the risk of developing kidney stones. However, the same results show that multivitamins don’t increase the risk of kidney stones. The research team reports that this effect is probably caused by the dose and combination of various nutrients. Therefore, the recent observations do not apply to a normal daily intake of vitamin C, taken from vegetables and fruit. The RDI (Recommended Daily Intake) of vitamin C in Sweden is 75mg, whilst the average vitamin C supplement contains 1g per tablet.

“As with all research, the results should be corroborated by other studies for us to be really sure”, notes the  leader of the study, associate professor Agneta Ă…kesson. She also added that information about how women react to vitamin C supplements is unknown for now. As a conclusion, Ă…kesson says that due to the fact that there are no known or documented benefits of vitamin C supplements, the best thing we could do is for patients to stop taking them, especially if they have a history of kidney stones.

2786

New target for rheumatoid arthritis identified

Researchers at Hospital for Special Surgery have discovered a new target in the treatment of rheumatoid arthritis. They are investigating a protein (IRHOM2) that could be an alternative to tumor necrosis factor alpha blockers (TNF blockers). Rheumatoid arthritis is a systemic autoimmune disease, that affects approximately 1% of the world population. This disease mainly involves joint damage, but it can affect other parts of the body such as the pleura, pericardium, kidneys, skin, etc..

rheumatoid arthritis

rheumatoid arthritis

In rheumatoid arthritis, systemic inflammatory response is generated mainly by TNF-alpha, a protein that is involved in several inflammatory diseases. When produced in excessive amounts, TNF alpha leads to inappropriate activation of the immune system resulting in inflammation. Based on this hypothesis, researchers have thought that this could be an effective therapeutic target in the treatment of rheumatoid arthritis. Therefore, there are a number of TNF alpha blockers: etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), which help patients suffering from this disease.

However, treatment based on TNF alpha inhibitors has several disadvantages, such as that it is quite expensive. In addition, as with any medication, not all patients respond to treatment. Therefore, the necessity of  a new therapeutic alternative that could help patients with this disease. In the study, researchers found that TNF alpha works with another protein called TACE (TNF-alpha converting enzyme), and they thought that blocking TACE would have the same effect as blocking TNF-alpha. But it seems that without the TACE patients are prone to intestinal infections and skin lesions.

Another discovery was that these proteins are regulated by some molecules TACE called IRHOM1 and IRHOM2 and it seems that the absence of IRHOM2 inhibits TNF alpha release. Furthermore, experiments on laboratory animals have shown that rats that did not have IRHOM2, did not develop skin infections or intestinal lesions. Therefore, the next step was to test whether blocking IRHOM2  would protect against the disease. Indeed, the results showed that mice genetically engineered  to be deficient in IRHOM2 did not develop rheumatoid arthritis. “With IRHOM2, we have a unique and unprecedented opportunity to inactive TACE only in certain cell types, and not in others, and there is currently no other effective way of doing that”, said Carl Blobel, M.D., Ph.D., program director of the Arthritis and Tissue Degeneration Program at HSS.

This means that if scientists could find antibodies or pharmacological compounds to block TACE function in immune cells, patients with rheumatoid arthritis could benefit from a new treatment. Dr. Jane Salmon, an author of the study, said that these compounds would theoretically have less toxicity than TNF alpha blockers because they block TNF alpha release only in the cells involved in inflammation.

2303

Beta carotene and tocopherol may influence type-2 diabetes onset

Researchers at Stanford University School of Medicine have made some interesting discoveries about type II diabetes. It seems that beta carotene which is a precursor of vitamin A, reduces the risk of diabetes, while another vitamin (gamma tocopherol, ie vitamin E) may increase the risk of diabetes.
Investigators arrived at these conclusions after analyzing the relationship between gene variants underlying genetic predisposition to diabetes and high levels of certain substances in the blood that are found in patients with diabetes. It seems that patients with increased genetic risk of diabetes mellitus have low levels of beta carotene in the blood while gamma tocopherol level is high.

Beta carotene

Tocopherol

Diabetes is one of the most common metabolic diseases, and the incidence is increasing. Major types are type I diabetes, or juvenile diabetes, which called so because it is usually diagnosed in young adults and is insulin dependent, and type II diabetes, which is usually diagnosed in older people. Atul Butte, MD, PhD, associate professor of systems medicine in pediatrics, points out that type II diabetes affects 15% of the world population and that its incidence is increasing. Although type II diabetes is mainly due to lifestyle, in this type of diabetes, the role of genes is quite important. It seems that diabetes is a combination of environmental factors with genetic factors.

The findings made by scientists at Stanford University School of Medicine have led them to investigate whether beta-carotene and gamma-tocopherol are protective and respectively harmful factors of diabetes. In addition, researchers found that the two markers interact with the same gene variant that influences diabetes risk ( SLC30A4), which indicates that it plays an important role in the pathogenesis of diabetes.

Previous studies based on “genome-wide association studies” or GWAS, have shown that approximately 60% of Americans wear in the genome two copies of that gene variant that appears to increase the risk of developing diabetes. Several years ago the team of researchers led by Butte made similar studies based on EWAS, or environment-wide association study. These studies aimed at identifying exogenous substances that are associated with the disease. It was found that 5 substances may be associated with diabetes including beta carotene, that is vitamin A, and gamma-tocopherol, which is vitamin E.

“We can’t say, based on just this study, that ‘vitamin E is bad for you,'” said first author, Chirag Patel, PhD. Therefore, researchers want to investigate in laboratory animals whether the two substances (carotene and tocopherol) have a role in preventing or accelerating diabetes onset.

2078

Researchers are investigating blood-based biomarkers for earlier diagnosis of Parkinson’s disease

According to a study published in the latest issue of the Journal of Parkinson’s Disease, Parkinson’s disease could be diagnosed early through blood tests. Parkinson’s disease is a degenerative disease that usually occurs in people over 60 years, but there are situations where the disease occurs in younger people, that is around the age of 40 years. It should be noted that Parkinson’s disease is a degenerative disease that is characterized by low levels of dopamine neurons in the brain. It also should be noted that it is one of the rare neurological disease that can be kept under control relatively well with medication.

A drawback is that the diagnosis of the disease arises late because when motor symptoms occur, the number of dopaminergic neurons in the brain is already very low. Major symptoms are bradykinesia, resting tremor, rigidity and postural instability. Although Parkinson’s disease is associated particularly with tremor this occurs only in 30% of cases, and is a resting tremor, which is emphasized by emotions, gets better during voluntary movements and disappears in sleep. Because of stiffness, patients may not be able to move at all, which is called akinesia. Also, people with Parkinson’s had a specific posture and a characteristic walking. Besides motor symptoms, there are also some non-motor signs such as cognitive disorders (depression), or transit disorders (constipation, dysphagia), or impaired urination (dysuria, urinary difficulty, etc.).

Parkinson's disease

Biomarks

Parkinson’s disease is one of the most common neurodegenerative diseases and statistics show that there are a million people who suffer from this disease in the U.S. and 5 million worldwide. If this illness were diagnosed early, the chances to control the disease would be much higher and the risk of complications would decrease considerably.

Lead investigator Sok Kean Khoo, PhD, of the Center for Neurodegenerative Genomic Microarray Core Facility Science and at the Van Andel Institute, Grand Rapids, Michigan, said plasma is an amazing resource where you can find biomarkers to identify the disease. Based on this hypothesis, the researchers thought that in plasma of patients with Parkinson’s disease there are specific miRNAs related to PD. In a pilot study conducted on 64 people (half with Parkinson’s disease, half healthy), researchers found nine pairs of PD-predictive classifiers and 13 most-differentially expressed miRNAs as biomarkers that could potentially help identify patients with Parkinson’s disease . Dr Khoo said that although more research must be done, however, this study offers new opportunities to the exploration of circulating miRNAs not only for diagnosis but also for prognosis and therapy of Parkinson’s disease.