Messenger RNA–Based Vaccines for Cancer | Articles | Drug Discovery and Development Magazine

Nucleic acids are being extensively investigated for use in gene therapy and in genetic vaccinations in which foreign nucleic acid is translated into proteins by the host cells. Vaccines based on DNA and messenger RNA (mRNA) are able to stimulate all effectors of the adaptive immune response: B lymphocytes, cytotoxic T cells, and T helper cells. This makes them a useful tool in the creation of prophylactic vaccines for infectious diseases and for cancer immunotherapy.

Messenger RNA–Based Vaccines for Cancer | Articles | Drug Discovery and Development Magazine

Phenformin decreases size of lung tumors and increases survival in mice

In continuation of my update on metformin and phenformin
In a new study in the journal Cancer Cell, Shaw and a team of scientists at the Salk Institute for Biological Studies found that phenformin, a derivative of the widely-used diabetes drug metformin, decreased the size of lung tumors in mice and increased the animals' survival. The findings may give hope to the nearly 30 percent of patients with non-small cell lung cancer (NSCLC) whose tumors lack LKB1 (also called STK11).

The LKB1 gene turns on a metabolic enzyme called AMPK when energy levels of ATP, molecules that store the energy we need for just about everything we do, run low in cells. In a previous study, Shaw, an associate professor in Salk's Molecular and Cell Biology Laboratory and researcher in the Institute's new Helmsley Center for Genomic Medicine, demonstrated that cells lacking a normal copy of the LKB1 gene fail to activate AMPK in response to low energy levels. LKB1-dependent activation of AMPK serves as a low-energy checkpoint in the cell. Cells that lack LKB1 are unable to sense such metabolic stress and initiate the process to restore their ATP levels following a metabolic change. As a result, these LKB1-mutant cells run out of cellular energy and undergo apoptosis, or programmed cell death, whereas cells with intact LKB1 are alerted to the crisis and re-correct their metabolism.

"The driving idea behind the research is knowing that AMPK serves as a sensor for low energy loss in cells and that LKB1-deficient cells lack the ability to activate AMPK and sense energy loss," says David Shackelford, a postdoctoral researcher at Salk who spearheaded the study in Shaw's lab and is now an assistant professor at UCLA's David Geffen School of Medicine.

That led Shaw and his team to a class of drugs called biguanides, which lower cellular energy levels by attacking the power stations of the cell, called mitochondria. Metformin and phenformin both inhibit mitochondria; however, phenformin is nearly 50 times as potent as metformin. In the study, the researchers tested phenformin as a chemotherapy agent in genetically-engineered mice lacking LKB1 and which had advanced stage lung tumors. After three weeks of treatment, Shaw and his team saw a modest reduction in tumor burden in the mice.

Ref : https://www.cell.com/cancer-cell/abstract/S1535-6108%2812%2900518-1

Phenformin decreases size of lung tumors and increases survival in mice

Can Brightly Colored Fruits, Veggies Protect Against ALS? - Drugs.com MedNews

Researchers from Harvard School of Public Health have,  found that increasing consumption of carotenoids, particularly beta-carotene and lutein, might reduce the risk for this progressive neurological disease, which attacks nerve cells in the brain and spinal cord.

Carrots, yams and mangoes are rich in beta-carotenes, and spinach, collard greens and egg yolks are good sources of lutein. The study found, however, that diets rich in the antioxidants lycopene, beta-cryptoxanthin and vitamin C do not apparently reduce the risk for ALS, which causes the muscles to waste away and eventually results in paralysis.

"ALS is a devastating degenerative disease that generally develops between the ages of 40 and 70, and affects more men than women," senior study author Dr. Alberto Ascherio, a professor of epidemiology and nutrition at Harvard School of Public Health, said in a journal news release. "Understanding the impact of food consumption on ALS development is important."

Analyzing information on more than 1 million people, the researchers identified nearly 1,100 cases of ALS. The researchers found that increased overall carotenoid intake -- especially among those who ate diets rich in beta-carotene and lutein -- seemed to be linked to a lower risk for the devastating condition. 

Those who ate more carotenoids daily also were more likely to exercise, have an advanced degree, have increased vitamin C intake and take vitamin C and E supplements.

The researchers pointed out, however, that long-term vitamin C supplements did not lower people's risk for this degenerative disease.

"Our findings suggest that consuming carotenoid-rich foods may help prevent or delay the onset of ALS," Ascherio concluded. "Further food-based analyses are needed to examine the impact of dietary nutrients on ALS."

 Ref : http://onlinelibrary.wiley.com/doi/10.1002/ana.23820/abstract

Can Brightly Colored Fruits, Veggies Protect Against ALS? - Drugs.com MedNews

Meta-analysis links increased magnesium intake with fasting glucose and insulin reductions...

"Evidence from cross-sectional and longitudinal observational studies suggests that diets higher in magnesium are associated with reduced risk of insulin resistance and type 2 diabetes, whereas in intervention studies, supplemental magnesium improves measures of glucose and insulin metabolism in generally healthy adults, as well as in those with insulin resistance and type 2 diabetes," Adela Hruby and colleagues write. "However, little is known about potential interaction between magnesium intake and genetic variability on glycemic traits, in which genetic variants related to either magnesium transport and homeostasis or glucose and insulin metabolism may modify the pathways through which magnesium exerts its effects."

The researchers analyzed data from up to 52,684 nondiabetic men and women who participated in 15 studies included in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Dietary questionnaire or interview responses, or food diary entries were analyzed for magnesium content from food and beverages. Participants were genotyped for up to 25 single nucleotide polymorphisms related to fasting glucose, insulin or magnesium.  Average magnesium intake ranged from 224.7 milligrams to 479.7 milligrams per day. Reductions in both fasting glucose and fasting insulin were observed in association with increased magnesium. While a nominal association was found between one of the genetic variants examined in this study and fasting glucose and two variants showed nominal interactions with magnesium intake on fasting glucose and fasting insulin, no significant effects for the variations were observed......... 

Ref : http://jn.nutrition.org/content/early/2013/01/22/jn.112.172049.abstract?sid=0219d7a7-cc12-4709-8167-805f0663e750

More..

HSS involving resiniferatoxin receives U.S. patent to alleviate intractable pain

We know that, Resiniferatoxin (RTX) is a naturally occurring, ultrapotent capsaicin analog that activates the vanilloid receptor in a subpopulation of primary afferent sensory neurons involved in nociception (the transmission of physiological pain). RTX causes an ion channel in the plasma membrane of sensory neurons — the transient receptor potential vanilloid 1 — to become permeable to cations, most particularly the calcium cation; this evokes a powerful irritant effect followed by desensitization and analgesia. Research is being conducted at the National Institutes of Health and the University of Pennsylvania to design a novel class of analgesics from the latex of resin spurge (Euphorbia resinifera), a cactus-like plant commonly found in Morocco that contains high concentrations of RTX. Resiniferatoxin has a rating of 16,000,000,000 on the Scoville Scale making it one of the highest rated substances known.

Now U. S. Patent and Trademark Office recently issued a patent to the U. S. Department of Health and Human Services involving resiniferatoxin, or RTX, an experimental compound that represents a potential new class of drugs to alleviate the intractable pain that can occur in people with advanced cancer, severe arthritis, and other extremely chronic conditions.

HSS involving resiniferatoxin receives U.S. patent to alleviate intractable pain

Sanofi Canada announces new option for emergency treatment of anaphylaxis

We know that, Epinephrine (also known as adrenaline/adrenalin) is a hormone and a neurotransmitter. Epinephrine has many functions in the body, regulating heart rate, blood vessel and air passage diameters, and metabolic shifts; epinephrine release is a crucial component of the fight-or-flight response of the sympathetic nervous system. In chemical terms, epinephrine is one of a group of monoamines called the catecholamines. It is produced in some neurons of the central nervous system, and in the chromaffin cells of the adrenal medulla from the amino acids phenylalanine and tyrosine.

Now, Sanofi Canada announces a new option for the emergency treatment of anaphylaxis. Allerject™ is the first and only 'talking' epinephrine auto-injector in Canada. 

 

Sanofi Canada announces new option for emergency treatment of anaphylaxis

Intravenous iron dextran effective for restless leg syndrome

Intravenous low molecular weight iron dextran appears to provide effective long-lasting treatment for some patients with restless leg syndrome (RLS), even for those with normal serum ferritin levels, research indicates.

The results showed that 68% of 25 patients with RLS showed moderate or complete improvement of all RLS symptoms after treatment according to a Korean-translated version of the International RLS Severity (K-IRLS) scale and the PAM-RL device, which records periodic leg movements.

However, as reported in Sleep Medicine, the researchers saw no correlation between increases in cerebrospinal fluid (CSF) ferritin in response to therapy and clinical improvements.

"Although a relatively accessible measure, CSF ferritin is at best a crude measure of CNS [central nervous system] iron status and not necessarily reflective of regionally specific changes in iron status that are assumed to account for the symptom development," say Yong Won Cho, from Keimyung University School of Medicine in Daegu, South Korea, and colleagues.

"In addition, the narrow range of symptom severity in this study may have limited our ability to find any differences between CSF ferritin and subjective measures of the disease."

Intravenous iron dextran effective for restless leg syndrome

Everolimus treatment option for tuberous sclerosis patients

In continuation of my update on Everolimus

Everolimus treatment option for tuberous sclerosis patients

FDA Approves Gleevec for Children with Acute Lymphoblastic Leukemia

In continuation of my update on Gleevec

FDA Approves Gleevec for Children with Acute Lymphoblastic Leukemia

Exjade Approved for Inherited Blood Disorder - Drugs.com MedNews

We know that, Deferasirox (marketed as Exjade) is a rationally-designed oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias. It is the first oral medication approved in the USA for this purpose.

It was approved by the United States Food and Drug Administration (FDA) in November 2005. According to FDA (May 2007), renal failure and cytopenias have been reported in patients receiving deferasirox oral suspension tablets. It is approved in the European Union by the European Medicines Agency (EMA) for children 6 years and older for chronic iron overload from repeated blood transfusions.

Now  Exjade (deferasirox) has been approved by the U.S. Food and Drug Administration to remove excess iron in the blood among people with a genetic blood disorder called non-transfusion-dependent thalassemia (NTDT). Too much iron in the blood can damage vital organs, the agency said Wednesday in a news release. 

Thalassemia typically leads to the production of fewer red blood cells and less hemoglobin, a protein that carries oxygen throughout the body. NTDT is a milder form of thalassemia that unlike other forms, does not require frequent blood transfusions. Thalassemia affects about 1,000 people in the United States, the FDA said............

Exjade Approved for Inherited Blood Disorder - Drugs.com MedNews

NIH clinical trial begins for treatment of rare, fatal neurological disorder, January 23, 2013 News Release - National Institutes of Health (NIH)

 We know that, Cyclodextrins (sometimes called cycloamyloses) are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides). Cyclodextrins are produced from starch by means of enzymatic conversion. They are used in food, pharmaceutical,drug delivery, and chemical industries, as well as agriculture and environmental engineering. Hydroxypropyl Beta Cyclodextrin (HPβCD) is the chief active compound found in Procter and Gamble's deodorizing product "Febreze" under the brand name "Clenzaire".Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose (a fragment of starch). The 5-membered macrocycle is not natural. Recently, the largest well-characterized cyclodextrin contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape.

A clinical trial to evaluate a drug candidate called cyclodextrin as a possible treatment for Niemann-Pick disease type C1 (NPC), a rare and fatal genetic disease has already started on 23rd Jan, 2012. Scientists from the NIH’s National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) will conduct the clinical trial at the NIH Clinical Center. Reaching this trial stage required collaboration among government, industry, patient advocacy groups and academic researchers.

NIH clinical trial begins for treatment of rare, fatal neurological disorder, January 23, 2013 News Release - National Institutes of Health (NIH)

New drug protects against side effects of chemotherapy

 A drug developed at Linköping University in Sweden protects against the side effects of cancer treatments while strengthening the effects on the tumour. An international drug evaluation is now starting up on a larger group of patients. 

The results of the studies with the compound, known as calmangafodipir  [Ca₄Mn(DPDP)₅], were published in the latest issue of the cancer journal Translational Oncology with Professor Rolf G. G. Andersson as the main author.

The research was initiated on a substance called mangafodipir MnDPDP (see structure below), which was used as a contrast media in magnetic resonance scans. But pharmacologists at LiU discovered that it also protected healthy cells in connection with cancer treatments.

"We found that the substance could affect the formation of oxygen radicals, which are a cause of side effects in chemotherapy," says Professor Andersson.

For example, the number of white blood cells decreases drastically in almost all the patients, which opens the door to infections that could even be fatal.

The researchers began with cell tests, and then went on to mice infected with cancer cells. The mice were treated with chemotherapy and were administered mangafodipir at the same time. Tumour formation decreased while white blood cells were protected.

One problem was that a large portion of the manganese in the substance was released; as a consequence, the positive effect subsided. The free manganese can also be poisonous and cause brain damage. More at the ffollowing link...

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542842/

New drug protects against side effects of chemotherapy

Beta carotene may protect people with common genetic risk factor for type-2 diabetes

Stanford University School of Medicine investigators have found that for people harboring a genetic predisposition that is prevalent among Americans, beta carotene, which the body converts to a close cousin of vitamin A, may lower the risk for the most common form of diabetes, while gamma tocopherol, the major form of vitamin E in the American diet, may increase risk for the disease. 

Beta carotene may protect people with common genetic risk factor for type-2 diabetes

Drug combination extends pancreatic cancer patient survival, study suggests

A multi-center Phase III clinical trial demonstrates that Abraxane (below left structure) (nab-paclitaxel) plus gemcitabine is the first combination of cancer drugs to extend survival of late-stage pancreatic cancer patients compared to standard treatment. Their findings show that Abraxane plus gemcitabine (below right structure) was well tolerated and resulted in clinically meaningful outcomes compared to gemcitabine alone, the current standard of care. 

MPACT is the largest phase III clinical trial completed in advanced pancreatic cancer with more than 800 patients. Findings from the study showed a 59 percent increase in one-year median survival rates from less than a quarter of the patients (22 percent) to more than a third (35 percent). The two-year survival rate for this cancer is negligible, less than 4 percent, but that more than doubles (9 percent) with the nab-paclitaxel/gemcitabine combination.

The study showed significant improvement among some of the sickest patients including those with increased metastases. Significantly there was no increase in life-threatening toxicity. Other drug combinations that have demonstrated benefit have been limited by increased toxicities.

"This is a major improvement in a cancer with the lowest survival rates among all cancer types," said Dr. Ramesh Ramanathan, medical director of Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare and principal investigator for the clinical trial in the United States. "Advanced pancreatic cancer is fourth most common cause of cancer death in the United States and throughout the world. It is difficult to diagnose with a majority of the cases diagnosed at a late stage after the disease has already advanced."

Drug combination extends pancreatic cancer patient survival, study suggests

Novel technique reveals dynamics of telomere DNA structure: Chromosome-capping telomeres are a potential target for anti-cancer drugs

In continuation of my update on telomerase

"Most cancer cells use telomerase as one mechanism to maintain uncontrolled growth, so it is an important target for anti-cancer therapeutics," Stone said. "The G-quadruplex structures of telomere DNA inhibit the function of the telomerase enzyme, so we wanted to understand the mechanical stability of this structure."

Researchers used  "magnetic tweezers" system to stretch the DNA molecule, while a fluorescence microscopy technique was used to monitor small-scale structural changes in the DNA. 

"Unlike other DNA structures, the G-quadruplex structure is fairly brittle. It takes very little perturbation to make the whole thing fall apart," Stone said. "We also found that the unfolded state has a highly compacted conformation, which tells us that it still has interactions that favor the folding reaction."

These findings have implications for understanding the molecular mechanisms of telomere-associated proteins and enzymes involved in the unfolding reaction, as well as for rational design of anti-cancer drugs, Stone said. Small molecules that bind to and stabilize telomere DNA G-quadruplexes have shown promise as anti-cancer drugs.

The integration of fluorescence measurements and magnetic tweezers is a powerful method for monitoring DNA structural dynamics, and as biophysical techniques go, it is not hard to implement, Stone said. His lab worked with DNA molecules containing the G-quadruplex sequence from human telomere DNA, attaching one end of the DNA to a glass slide and the other end to a tiny magnetic bead. A magnet held above the sample pulled on the bead, exerting a stretching force on the DNA molecule that varied according to how close the magnet was to the sample.

Ref : http://nar.oxfordjournals.org/content/early/2013/01/08/nar.gks1341

Novel technique reveals dynamics of telomere DNA structure: Chromosome-capping telomeres are a potential target for anti-cancer drugs