A frontline malaria treatment that combines fast-acting dihydroartemisinin with long-lasting piperaquine is quickly losing power in Cambodia due to the rapid spread of drug-resistant parasites. The presence of piperaquine-resistant malaria parasites in several Cambodian provinces was confirmed earlier this year by National Institutes of Health researchers and their colleagues. Now, by comparing the complete genomes of 297 parasites isolated from Cambodian malaria patients to a reference malaria parasite genome, the team has identified two genetic markers that are strongly associated with the parasites’ ability to resist piperaquine.

A simple test, performed after collecting blood from a finger pinprick, can show whether a malaria patient has parasites with the genetic markers. If so, dihydroartemisinin-piperaquine therapy is likely to fail, say the study authors, and an alternative drug combination (artesunate-mefloquine) should be used. Information about the distribution of these drug resistance markers is being used by officials in Cambodia and neighbouring countries to map the extent and spread of piperaquine resistance and to help guide region-wide malaria treatment approaches.

National Institute of Allergy and Infectious Diseases (NIAID) scientist Rick Fairhurst, M.D., Ph.D., and Roberto Amato, Ph.D., of the Wellcome Trust Sanger Institute (WTSI), Cambridge, UK, led the research team. The first marker they identified is a change of one subunit in a gene on the parasite’s chromosome 13. Parasites with this genetic change are much more likely to be resistant to piperaquine than parasites without it. The marker, while associated with drug resistance, likely does not play a functional role in enabling parasites to resist piperaquine, according to the researchers. In contrast, the second resistance marker identified by the investigators may have such a role. That marker is an increased number of copies of two genes (plasmepsin II and plasmepsin III) in those parasites that resist piperaquine. Malaria parasites use plasmepsins to help them digest human blood and, although the exact mechanism of action of piperaquine is not known, it is believed that the drug targets plasmepsins.

Parasites may react to piperaquine by increasing plasmepsin production, and any parasites with extra copies of the plasmepsin II and III genes may be better able to withstand piperaquine treatment. Of note, parasites with increased piperaquine resistance appear to have increased susceptibility to the malaria drug mefloquine. This observation hints at the possibility of devising malaria treatment regimens that combine three or more drugs to exploit opposing resistance-susceptibility attributes.

National Institute of Healthwww.niaid.nih.gov/news-events/two-genetic-markers-predict-malaria-treatment-failure-found

In early May Siemens Healthcare unveiled its new brand name Siemens Healthineers. The new brand underlines Siemens Healthcare’s pioneering spirit and its engineering expertise in the healthcare industry. It is meant to describe the healthcare organization and its people – the people accompanying, serving and inspiring customers – the people behind outstanding products and solutions. As part of its Vision 2020 strategy Siemens AG announced nearly two years ago that its healthcare business would be separately managed as a company within the company with a new organizational setup. Siemens Healthineers will continue to strengthen its leading portfolio across the medical imaging and laboratory diagnostics business while adding new offerings such as managed services, consulting and digital services as well as further technologies in the growing market for therapeutic and molecular diagnostics.

In contrast to the general belief that the airways of an infant are sterile until after birth, University of Alabama at Birmingham researchers and colleagues have found that the infant airway is already colonised with bacteria or bacterial DNA when a baby is born — and this is true for infants born as early as 24 weeks gestation.

How microbes get into the airways and the purpose of this pre-birth colonisation are still unclear, but the pattern of colonisation appears to have an important link to later severe neonatal lung disease.

An early microbial imbalance, or dysbiosis, is predictive for the development of bronchopulmonary dysplasia, or BPD, a chronic lung disease of prematurity. The extremely low birth-weight, or ELBW, infants in this study had an average birth weight of 1 pound, 8 ounces. Researchers found that the ELBW infants who went on to develop life-threatening BPD showed abnormal microbial colonisation patterns at birth, as compared to pre-term infants who did not get BPD.

“Right at birth, your respiratory microbiome can possibly predict your risk for BPD,” said Charitharth Vivek Lal, M.D., assistant professor in the UAB Pediatrics Division of Neonatology and the lead investigator of this study.
Extremely premature infants are at risk for BPD, which is the most common lung pathology of these tiny infants and a significant cause of morbidity, mortality and health care expenditures. Adults and children who had BPD as infants have lungs that failed to develop properly and are more prone to worse lung function, asthma, lung infections and pulmonary hypertension.

The researchers also looked at the airway microbiomes of 18 ELBW infants with established BPD and found that their microbiomes had a decreased diversity of types of microbes, and the pattern was very different from those of ELBW infants shortly after birth or full-term infants at birth.

As to specific groups of microbes, the phylum Proteobacteria, which includes bacteria like E. coli, appeared to be involved in BPD pathology, and the genus Lactobaccillus, part of the phylum Firmicutes, appeared to be involved in disease protection.

Lal and colleagues found decreased Lactobacillus abundance in the airway microbiomes of 10 infants born to mothers who had chorioamnionitis — an infection of the membranes of the placenta and an independent risk factor for BPD — as well as decreased Lactobacillus abundance at birth in the airways of the BPD-predisposed, ELBW infants, as compared to BPD-resistant infants. Research elsewhere has suggested a beneficial role for Lactobacillus against airway diseases and for lung development.

“I predict that researchers will study the use of respiratory probiotics, and the role of the gut-lung microbiome axis in the future,” Lal said.

For five ELBW infants who later developed BPD, the researchers collected periodic airway microbiome samples from birth through 9 weeks and saw extremely similar patterns of change in the microbiomes over time.

As for the source of the microbes, Lal and colleagues wrote, “As it is commonly believed that colonization of neonates originates in the birth canal, we were surprised to find that the airway microbiome of vaginally delivered and caesarean section-delivered neonates were similar, which suggests that the microbial DNA in the airways is probably transplacentally derived, consistent with reports that the placenta has a rich microbiome.”

The researchers speculate that this transmission of bacteria or bacterial DNA to the in-utero infant could be via blood or amniotic fluid.

University of Alabama at Birmingham www.uab.edu/news/innovation/item/7505-discovery-of-infants-airway-microbiomes-may-help-predict-lung-disease

A pioneering University of Liverpool research team have published a study that identifies the mechanism in the human body that causes resistance of pancreatic cancer cells to chemotherapy.

Pancreatic cancer is one of the leading causes of cancer death and current therapies are not very effective. Thus, a better understanding of the molecular mechanisms that impair the response of cancer patients to chemotherapy, the standard treatment of care for this disease, is essential to design more effective treatments for this lethal disease.

Tumour associated macrophages (TAM) and fibroblasts are non-cancerous cells that are found within solid tumours, including pancreatic cancer. Accumulating evidence suggests that TAM and fibroblasts can support cancer progression, resistance to therapy and metastasis. However, the precise mechanisms by which these cells contribute to pancreatic cancer progression and response to therapy is not completely understood.

The research team led by Dr Ainhoa Mielgo Iza, a Sir Henry Dale Fellow, from the University’s Institute of Translational Medicine, has been studying how these cells contribute to chemo resistance in pancreatic cancer.

The study found that TAM and fibroblasts directly support chemotherapy resistance of pancreatic cancer cells by secreting insulin-like growth factors.

These proteins activate a survival signalling pathway on pancreatic cancer cells making them resistant to chemotherapy.

Analysis of biopsies from pancreatic cancer patients revealed that this survival pathway is activated in 72% of the patients.

Dr Mielgo, said: “These findings are very exciting because they uncover a mechanism that causes pancreatic cancer resistance to chemotherapy.

“Our research interest is to understand the complex interactions in the tumour microenvironment with the aim of finding new therapeutic targets for cancer.

“These results describe a combination treatment that could be more effective in treating this disease.”

University of Liverpool news.liverpool.ac.uk/2016/11/22/mechanism-found-that-causes-resistance-of-pancreatic-cancer-to-chemotherapy/

Newcastle researchers have developed a genetic test providing a rapid diagnosis of mitochondrial disorders to identify the first patients with inherited mutations in a new disease gene.

The team of medics and scientists at the Wellcome Trust Centre for Mitochondrial Research at Newcastle University, together with international collaborators, have identified mutations in a gene, known as TMEM126B, involved in energy production in patient’s muscles.

Using next generation sequencing they have now developed a rapid test which provides a result within 2-3 days – previous techniques took months.

Mitochondrial diseases affect the batteries of the cell and can lead to muscular weakness, blindness, fatal heart failure, learning disability, liver failure, diabetes and can lead to death in early infancy.

Charlotte describes the technique which has already identified six patients from four families affected by this form of mitochondrial disease.

She said: “Identifying a fault in Complex I, one of the building blocks of mitochondria which is responsible for causing disease combined with our custom gene capture and the latest sequencing technology means we can screen many more genes to diagnose this debilitating disease.

“It means families can get a rapid diagnosis within days rather than the weeks and months that testing can currently take. For families who are waiting on a genetic diagnosis before trying for another baby, or they may already be expecting their next child, time really is of the essence.”

The research has confirmed the identity of a mutation causing mitochondrial disease affecting Complex I, one of five complexes involved in energy production. The gene, TMEM126B, makes a protein necessary for assembly of the complex, with defects causing problems with energy generation in patient’s muscles.

Finding a genetic cause is important to families as it means that they can find out what is wrong with their child enabling doctors and scientists to help them understand the risks to their future children and help prevent them losing another child.

Newcastle Universities www.ncl.ac.uk/press/news/2016/07/newrapidgenetestformitochondrialdisease/