When researchers at the University of São Paulo (USP) in Brazil treated human melanoma cell lines with a synthetic compound similar to curcumin, one of the pigments that give turmeric (Curcuma longa) its orange colour, they identified genes with altered expression in potentially invasive tumours and malignant cells resistant to chemotherapy.
According to the scientists, if further studies confirm the importance of these genes to disease progression and increasing chemoresistance, it will be possible to explore their future use as biomarkers to assist diagnosis and even as therapeutic targets.
“Previous research by collaborators had already shown that DM-1, a compound analogous to curcumin, has anti-tumour activity at low doses. We set out to understand which genes this substance modulates and why it is toxic to melanoma but not to normal cells,” said Érica Aparecida de Oliveira, a postdoctoral scholar at USP’s School of Pharmaceutical Sciences (FCF).
As Oliveira explained, there are hundreds of papers attesting to the anti-oxidant, anti-tumoural, anti-microbial and anti-inflammatory properties of curcumin in the scientific literature. However, the therapeutic usefulness of this compound in its natural form is limited owing to poor absorption, rapid metabolization, and water insolubility. To solve this problem, scientists have developed synthetic analogues with minor structural modifications to make the molecule more stable in the organism.
DM-1 (sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) was synthesized some years ago by José Agustín Pablo Quincoces Suárez, a professor at Bandeirantes University (UNIBAN).
“Experiments with animals conducted by collaborators showed that treatment with DM-1 can promote a reduction in tumour volume. DM-1 has also proved toxic to chemoresistant melanoma cells,” Oliveira said.
To unpack DM-1’s mechanism of action, Oliveira resorted to a toxicogenomics platform developed by the research group of FCF-USP professor Gisele Monteiro, a fellow researcher at the investigation. Such platform is comprised of a collection of 6,000 frozen yeast strains, all mutants of the species Saccharomyces cerevisiae, widely used as baker’s and brewer’s yeast.
“This yeast’s genome has 6,000 genes, and a different gene has been knocked out in each of these mutants, so we were able to study the effects of the compound in a highly specific manner, gene by gene,” Oliveira said.
The 6,000 mutant yeast strains were thawed, spread on plates with 96 small wells, and treated with DM-1. The strains that did not grow in the presence of the curcumin analogue were discarded, leaving an initial group of 211 genes that were affected by the treatment.
The next step was to filter the genes in order to identify those with homologues in the human genome since some might be associated with functions specific to yeast. The researchers came up with a second list containing 79 candidate genes, thanks to the aid from bioinformatics tools and from the expertise of Helder Nakaya , another fellow researcher and also a professor at FCF-USP.
“We then began to look at public repositories of genomic data from cancer patients, such as The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), to understand how these genes talked to each other,” Oliveira said.
The analysis showed most to be associated with cell signalling pathways that favoured tumour progression when active. Examples included the pathways mediated by mitogen-activated protein (MAP) kinase and epidermal growth factor receptor (EGFR).
The next step was to investigate which genes were important to the progression of melanoma specifically. This entailed using bioinformatics to focus on the analysis of genomic sequences from melanoma patients.
“We performed a data mining exercise to find genes with altered expression during melanoma progression,” Oliveira said. “We identified seven genes that appeared to be important, and when we looked at the public databases, we could see that the expression of these genes was indeed altered in many patients.”
In vitro tests with non-chemoresistant parent melanoma cells showed that treatment with DM-1 induced cell death, mainly because it increased expression of a gene known as TOP-1. When this gene is active, it leads to DNA transcription errors and hence causes genomic instability in cells.
In chemoresistant melanoma cells, cytotoxicity was caused mainly by increased expression of the gene ADK, which is involved in energy production for cells.
“Like curcumin, which can interact with multiple cellular targets and modulate multiple signaling pathways, DM-1 also acts in different ways to promote toxicity in both parent and drug-resistant melanoma cells,” Oliveira said.
EurekAlerthttps://tinyurl.com/ya7hhwwk

In a new study New York University College of Dentistry (NYU Dentistry) researchers investigating the catabolic effect of parathyroid hormone (PTH) in hyperparathyroidism (HPT) showed, for the first time, that monocyte chemoattractant protein-1 (MCP-1) is required for catabolic responses to PTH. HPT is a condition in which an abnormally high concentration of PTH in the blood accelerates bone loss.
The research team, led by Nicola C. Partridge, PhD, professor and chair of the Department of Basic Science and Craniofacial Biology at NYU Dentistry, had previously found that MCP-1 is important in producing an anabolic effect of PTH, in which bone formation is increased, and they wanted to know if it was also important in causing a catabolic effect, in which bone is broken down.
In the present study, the researchers focused on the role of MCP-1 in PTH-induced osteoclast formation. Osteoclasts are cells that break down the bone. Increased osteoclast formation causes bones to become thinner and weaker. The researchers recreated the hyperparathyroid state in mice by constantly elevating their hyperparathyroid levels. Over a two-week period, they continuously infused female wild-type and MCP-1 knockout mice with human PTH. They showed that the ability of PTH to increase osteoclast formation in vitro is markedly impaired in cells from MCP-1 knockout mice and concluded that MCP-1 is an important chemokine, or signalling protein, in PTH-induced osteoclast formation and bone resorption.
The findings support the possibility that MCP-1 could be a marker for how PTH works in humans with hyperparathyroidism, as elevated serum MCP-1 has been shown to be correlated with elevated serum PTH levels in women. Notably, within minutes after humans undergo parathyroid adenoma surgery, MCP-1 serum levels decrease.
Because high serum levels of MCP-1 cause the white cells and osteoclasts to be stimulated, this process could have systemic effects as well as effects on bone. “MCP-1 is a chemokine, which induces cells to move along a gradient recruiting white cells and osteoclasts in tissues,” says Dr. Partridge. “Accordingly, there could also be effects on adipose tissue, the heart, and inflammatory conditions.”
In the United States, about 1,000 people develop HPT each year, with osteoporosis the most common manifestation. According to the National Institutes of Health, there are approximately 1.5 million osteoporotic fractures in the U.S. each year that lead to half a million hospitalizations, over 800,000 emergency room encounters, more than 2,600,000 physician office visits, and the placement of nearly 180,000 individuals in nursing homes. Hip fractures are by far the most devastating type of fracture, accounting for about 300,000 hospitalizations each year. About one in five people sustaining a hip fracture ends up in a nursing home.  
NYU College of Dentistryhttps://tinyurl.com/y7nzipw9

A simple blood test that detects tumour cells circulating in the blood shows promise as a new way to predict high or low risk of a breast cancer relapse.
“Late recurrence five or more years after surgery accounts for at least one-half of recurrences of breast cancer, and there are no tests that identify who is at highest risk. We found that in women who were cancer-free five years after diagnosis, about 5 percent had a positive circulating tumour cells (CTC) test,” said lead researcher Joseph A. Sparano, MD, vice chair of the ECOG-ACRIN Cancer Research Group, Philadelphia, and associate director for clinical research at Montefiore Medical Center, Albert Einstein Cancer Center, New York.
“More importantly …”, Dr. Sparano continued, “…we also found that a positive test was associated with a 35 percent recurrence risk after two years, compared with only 2 percent for those with a negative CTC test.”
The concept is to explore the use of the CTC blood test in a new way. Currently, the test is FDA-approved for use by physicians to monitor response to treatment in patients with advanced breast, colon or prostate cancer, but not early stage cancer. A rise in the number of circulating tumour cells in the blood in patients with advanced disease may indicate trouble before it shows up on a scan. In this study, the research team evaluated this test in a different setting—individuals alive and cancer-free about five years after their diagnosis and potentially cured, but still at risk for having a recurrence of their disease.
”Our ultimate goal is to use blood tests like this to tailor treatment in a way that minimizes recurrence risk for those at high risk, and spare treatment for those at low risk who may be unlikely to benefit from it,” Dr. Sparano said. “The findings of this analysis provide strong evidence to further evaluate this new risk assessment approach using CTC and other blood-based tests in this setting”.
The test was done on a single blood sample provided by 547 breast cancer patients who had been diagnosed more than five years prior and treated as part of a large ECOG-ACRIN breast cancer treatment trial, E5103. This group of patients had stage two or three breast cancer, and the cells in their tumours were HER2-negative.
Many women in E5103 remain cancer free and are being followed for their breast cancer status as part of standard care. Dr. Sparano and colleagues set up a biobank and invited these patients to contribute additional specimens for future research into the reasons for late recurrence. The biobank was established by ECOG-ACRIN and the Coalition of Cancer Cooperative Groups with funding from the Breast Cancer Research Foundation, National Cancer Institute, and Susan G. Komen.
ECOG-ACRIN Cancer Research Grouphttps://tinyurl.com/ydgym4c3

Siemens Healthineers has now confirmed that it has completed the acquisition of Epocal Inc. from Abbott to complete its blood gas portfolio. The closing of the deal occurred October 31, 2017. Financial details of the transaction were not disclosed.
In integrating Epocal Inc.’s offerings into its POC Ecosystem™ solution, Siemens Healthineers enables customized testing offerings based on individual facility needs – whether that is handheld testing, benchtop solutions or central lab applications – to help improve process efficiency. The epoc^® product line will integrate seamlessly into the Siemens Healthineers POC Ecosystem solution for easy connection from many manufacturers’ point-of-care analysers to hospital information systems, providing a flexible, long-term solution.
“Health networks have varying needs for blood gas testing across physicians’ offices, clinics, emergency departments, laboratories and even in ambulances. Having any one solution is limiting and may not meet all patient needs, which is why customized testing solutions are so important for improving patient care,” said Peter Koerte, President, Point of Care Diagnostics, Siemens Healthineers. “With a complete offering for blood gas diagnostics, we can help healthcare providers and point-of-care coordinators improve their workflows by offering the right test in the right setting at the right time.” www.siemens.com/epoc

A research team led by National University Health System (NUHS) and Duke-NUS Medical School has used genomic technologies to better understand intestinal metaplasia (IM), a known risk factor for gastric (stomach) cancer. Patients with IM are six times more likely to develop stomach cancer than those without. This study is an important part of an ambitious investigation to understand why some people develop stomach cancer, while others do not. The research could also help detect patients who are infected with the Helicobacter pylori bacteria, which is also linked to the disease.
Stomach cancer is the third deadliest cancer in the world according to World Health Organization (WHO) statistics, and claims more than 300 lives yearly in Singapore. The disease is believed to be caused by infection with Helicobacter pylori but is potentially treatable if detected early. Unfortunately, more than two-thirds of stomach cancer patients are only diagnosed at an advanced stage.
"Previous genetic studies on IM have mainly focused on patients who were already diagnosed with stomach cancer but these are limited in their ability to predict who are likely to develop the disease and how the disease will progress," said Professor Patrick Tan, co-lead investigator and Professor, Duke-NUS Medical School. Professor Tan is also Deputy Executive Director, Biomedical Research Council, Agency for Science, Technology, and Research, and a Senior Principal Investigator at the Cancer Science Institute of Singapore. "This new study is the first to comprehensively map out the genetic changes in IM in a cohort of stomach cancer-free subjects, which helps us better predict the possible occurrence and progression of the disease."
Dr Yeoh Khay Guan, co-lead investigator and Deputy Chief Executive, NUHS as well as Dean, NUS Yong Loo Lin School of Medicine added, "Our study is the largest series of IM to be studied in detail by genetic analysis. These new findings help us understand why some people have a higher risk of progression to stomach cancer, and identify those who may benefit from closer follow-up to prevent cancer or to detect it early so that it can be cured."
The researchers leveraged the near 3,000 participants-strong Gastric Cancer Epidemiology Programme (GCEP) cohort, recruited with the support of patients and doctors from four local public hospitals (National University Hospital, Tan Tock Seng Hospital, Singapore General Hospital, Changi General Hospital), to show that a comprehensive analysis of the genetic patterns of IM can predict its subsequent progression towards stomach cancer. The genetic analysis of IM helps to identify those with a higher risk of progression to stomach cancer, adding further information to what is available by microscopic examination alone.
The research team is using this new information to identify biomarkers that can be applied in future in the clinic to identify people who have a high risk of progression to stomach cancer.
EurekAlertwww.eurekalert.org/pub_releases/2018-01/nuos-lgs010518.php