Folate and Vitamin B12 Reduce Disabling Schizophrenia Symptoms in Some Patients

From Science Daily website (see original article).

Mar. 6, 2013 — Adding the dietary supplements folate and vitamin B12 to treatment with antipsychotic medication improved a core symptom component of schizophrenia in a study of more than 100 patients.
The study focused on negative symptoms of schizophrenia -- which include apathy, social withdrawal, and a lack of emotional expressiveness.
While the level of improvement across all participants was modest, results were more significant in individuals carrying specific variants in genes involved with folate metabolism.
The report from a team based at Massachusetts General Hospital (MGH) will appear in the journal JAMA Psychiatry (formerly Archives of General Psychiatry) and has been issued online.

"The symptoms of schizophrenia are complex, and antipsychotic medications provide no relief for some of the most disabling parts of the illness.
These include negative symptoms, which can be particularly devastating," says Joshua Roffman, MD, MMSc, of the MGH Department of Psychiatry, corresponding author of the JAMA Psychiatry paper.
"Our finding that folate plus vitamin B12 supplementation can improve negative symptoms opens a new potential avenue for treatment of schizophrenia.
Because treatment effects differed based on which genetic variants were present in each participant, the results also support a personalized medical approach to treating schizophrenia."

An essential nutrient, folate (or folic acid) is required for the synthesis of DNA and neurotransmitters and plays a role in the control of gene expression. Adequate folate intake during pregnancy can reduce the risk of birth defects -- in particular neural tube defects -- and studies have suggested that folate deficiency during pregnancy significantly increases the risk of schizophrenia among offspring.
Earlier research by members of the MGH-based team associated low blood folate levels with more severe negative symptoms among patients with schizophrenia.

The current study was designed specifically to investigate whether supplementation with folate and B12 -- which can magnify the effects of folate -- reduced negative symptoms of schizophrenia.
A 2011 pilot study found symptom improvement only among patients carrying a variant in a folate-pathway gene called MTHFR that reduced the gene's activity. To get a clearer picture of folate's effect on negative symptoms, the current study enrolled 140 patients with schizophrenia at community mental health centers in Boston, Rochester, N.Y., and Grand Rapids, Mich.

Participants were all taking antipsychotic medications -- which have been shown to alleviate positive symptoms, such as hallucinations and delusions, but not negative symptoms -- and were randomized to receive daily doses of either folate and vitamin B12 or a placebo for 16 weeks.
Every two weeks their medical and psychiatric status was evaluated, using standard symptom assessment tools along with measurements of blood levels of folate and homocysteine, an amino acid that tends to rise when folate levels drop.
Nutritional information was compiled to account for differences in dietary intake of the nutrients.
Participants' blood samples were analyzed to determine the variants they carried of MTHFR and three other folate-pathway genes previously associated with the severity of negative symptoms of schizophrenia.

Among all 140 participants in the study protocol, those receiving folate and vitamin B12 showed improvement in negative symptoms, but the degree of improvement was not statistically significant compared with the placebo group.
But when the analysis accounted for the variants in the genes of interest, intake of the two nutrients did provide significant improvement in negative symptoms, chiefly reflecting the effects of specific variants in MTHFR and in a gene called FOLH1. Variants in the other two genes studied did not appear to have an effect on treatment outcome.

While a low-functioning variant in FOLH1 had been associated with more severe negative symptoms in previous research, in this study it was the high-functioning FOLH1 variant that predicted a better treatment outcome.
Measurement of participants' blood folate levels throughout the study provided an explanation for this unexpected finding. Those with the low-functioning FOLH1 variant started the trial with substantially lower folate levels, suggesting a problem with folate absorption.
Although supplementation enabled their blood folate levels to eventually catch up with those of participants with the high-functioning variant, it was probably too late to produce symptom improvement during the 16-week trial period.

"For participants who did show a benefit, it took the full 16 weeks of treatment for that benefit to appear," Roffman explains.
"While we don't know why this is the case, changes in gene expression -- which take time -- are a likely explanation.
Folate plays a critical role in DNA methylation, which regulates gene expression, so it's plausible that its effects on negative symptoms act through gene expression changes.
Participants with the low-functioning FOLH1 variant might eventually show a benefit of folate supplementation if treated for a longer period of time, but that needs to be investigated in future studies."

He adds that, while the benefits of supplementation for the overall group were modest, the lack of effective treatment for negative symptoms and the safety of folate and vitamin B12 supplementation support the need for larger-scale trials.
In addition, the impact of genotype on this study's results suggests the need to investigate the role of folate pathway variants in conditions such as dementia and cardiovascular disease, in which low folate appears to increase risk but supplementation trials have had inconclusive results.

"We are now conducting a clinical trial of 1-methylfolate, which bypasses some of these folate-pathway enzymes and might have greater efficiency among individuals with low-functioning variants," explains Roffman, an assistant professor of Psychiatry at Harvard Medical School.
"Understanding more about the basic neural mechanisms of folate in patients with schizophrenia could help us generate more targeted and effective interventions to reduce and possibly even prevent symptoms."

Fish Peptide May Inhibit Cancer Metastasis

From Science Daily website (see original article).

Mar. 19, 2013 — Researchers at the University of Maryland School of Medicine have identified a peptide, or protein, derived from Pacific cod that may inhibit prostate cancer and possibly other cancers from spreading, according to preclinical research published online in the Proceedings of the National Academy of Sciences (PNAS).

"The use of natural dietary products with anti-tumor activity is an important and emerging field of research," says senior author Hafiz Ahmed, Ph.D., assistant professor of biochemistry and molecular biology at the University of Maryland School of Medicine and scientist at the Institute for Marine and Environmental Technology (IMET).
"Understanding how these products work could allow us to develop foods that also act as cancer therapeutics and agents for immunotherapy."

Most people who succumb to cancer die because tumor cells invade the surrounding tissue and migrate into the nearby blood and lymph vessels, a process known as metastasis.
For example, prostate cancer typically spreads to the bones, lungs and liver. Cancer cells that metastasize to other parts of the body grow new blood supplies and eventually overcome the person's organ systems.

"This study is among the first to explore the therapeutic utility of a bioactive cod TFD-containing glycopeptide to inhibit prostate cancer from progressing," says Dr. Ahmed, who also is affiliated with the University of Maryland Marlene and Stewart Greenebaum Cancer Center.
The TFD (Thomsen-Friedenreich disaccharide) antigen in the fish protein is hidden in normal human cells but is exposed on the surface of cancer cells and is believed to play a key role in how cancer spreads.

Polar fish, such as northern cod, express glycoproteins that are rich in the TFD antigen, which protect them from freezing.
The research team developed a special form of TFD, called TFD100, purified from Pacific cod.

Using animal models, the researchers found that TFD100 binds to galectin-3, a protein that is overexpressed in prostate cancer cells, and blocks its interaction with the TFD antigen found on the surface of the cells.
Galectin-3 (gal3) enables cancer cells to adhere to the walls of blood vessels and also kills activated T-cells, a type of white blood cell, which helps the cancer cells to spread throughout the body and evade the immune system.
The researchers observed that TFD100 prevents cancer cells from attaching to the vessel walls, suppresses T-cell death and boosts the immune response.

"Because the gal3-TFD interaction is a key factor driving metastasis in most epithelial cancers, this high-affinity TFD100 should be a promising anti-metastatic agent for the treatment of various cancers, including prostate adenocarcinoma," the researchers conclude in the study, which was published online March 11 in PNAS' Early Edition.

"This research breaks new ground in our ongoing quest to discover new ways to prevent cancers from metastasizing to distant parts of the body," says E. Albert Reece, M.D., Ph.D., M.B.A., Vice President for Medical Affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine.
"If we could one day offer patients a natural dietary supplement, derived from fish proteins, which could help to block that process, we could have a significant impact on improving patients' outcomes and survival."

Co-investigator Dhan V. Kalvakolanu, Ph.D., a professor of microbiology and immunology at the School of Medicine, notes that additional research is needed to develop a dietary supplement from the cod peptide that could complement chemotherapy and other standard treatments.
"No single drug on its own is going to offer protection against advanced cancers. We need a multi-pronged approach to successfully treat this disease," he adds.

The study was conducted by researchers from Dr. Ahmed's laboratory, in collaboration with Dr. Kalvakolanu and other investigators at the University of Maryland Greenebaum Cancer Center and the IMET. Prasun Guha, Ph.D., a postdoctoral fellow in Dr. Ahmed's laboratory, was the study's lead author.

Tumors Deliberately Create Conditions That Inhibit Body's Best Immune Response

From Science Daily website (see original article).

Mar. 1, 2013 — New research in the Journal of Clinical Investigation reveals that tumours in melanoma patients deliberately create conditions that knock out the body's 'premier' immune defence and instead attract a weaker immune response unable to kill off the tumour's cancerous cells.

The study also highlights a potential antibody biomarker that could help predict prognosis and identify which patients are most likely to respond to specific treatments.

The research, led by Dr Sophia Karagiannis and Professor Frank Nestle at King's College London, UK, was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London.

Karagiannis and colleagues have previously shown that, in patients with melanoma, antibodies are produced that can attack tumour cells.
Despite this, the patient's immune system is often ineffective in preventing the cancer from progressing.

The body's B cells (part of the immune system) produce a total of 5 different antibody classes. The most common, IgG, comprises 4 types (or subclasses) of which the researchers have shown that IgG1 subclass antibodies are the most effective at activating immune cells, while antibodies of the IgG4 subclass are thought to be the least efficient.

In this new research, the authors analysed tumour tissue and blood donated by 80 patients from the melanoma clinic of St John's Institute of Dermatology at Guy's and St Thomas', as well as tissue and blood from healthy volunteers.

By analysing the lesions found in melanoma, the authors show that melanoma tumours not only create conditions that attract IgG4, the weakest possible response, but also that IgG4 antibodies interfere with the action of any IgG1 antibodies circulating.
"We were able to mimic the conditions created by melanoma tumours and showed that B cells can be polarised to produce IgG4 antibodies in the presence of cancer cells," says Dr Karagiannis.
In the presence of healthy cells, the body's immune response functions normally, and IgG1 are the main antibodies circulating.

To better understand the functional implications of IgG4 subclass antibodies in cancer, the authors engineered these two antibodies (IgG1, IgG4) against a tumour antigen and demonstrated that unlike IgG1, the IgG4 antibody was ineffective in triggering immune cells to kill cancer cells.
Importantly, IgG4 also blocked the tumour cell killing actions of IgG1, thus preventing this antibody from activating immune cells to destroy tumours.

Additionally, using samples from 33 patients, the authors found that patients with higher IgG4 levels in their blood are more likely to have a less favourable prognosis compared to those whose blood levels of IgG4 are closer to normal levels.
This suggests that IgG4 may help assist in predicting disease progression.

"This work bears important implications for future therapies since not only are IgG4 antibodies ineffective in activating immune cells to kill tumours but they also work by blocking antibodies from killing tumour cells," says Dr Karagiannis.
"The latter means that IgG4 not only prevents the patient's more powerful antibodies from eradicating cancer, but could also explain why treatments may be hindered by those native IgG4 antibodies found in patients, making therapeutic antibodies less effective."

"Now, with the help of our NIHR Biomedical Research Centre, more work needs to be done on developing IgG4 as a potential clinical and prognostic biomarker which can improve patient care by informing clinical decisions and helping to identify patients most likely to respond to treatments," concludes Professor Nestle.
Therefore, these findings are expected to inform the design and help improve the potency and efficacy of future therapies for cancer.
"This study can also inform the rational design of novel strategies to counteract IgG4 actions."

The authors are now broadening the study by examining larger groups of patients.
The team is analysing blood and sera from patients with melanoma and from patients with other cancers to determine whether the presence of IgG4 could inform patient outcomes or predict responses to therapy.
They are also analysing the mechanisms of IgG4 blockade of new and existing therapeutic antibody candidates, and developing new antibody candidates which may be less prone to IgG4 blockade.