Nontoxic strain of Salmonella tested as a cancer treatment

Salmonella has a unique characteristic that allows it to penetrate cell barriers and replicate inside its host. Now, scientists have developed a nontoxic strain to target cancer cells.

“The strain of Salmonella we are using is essential to the success of our study.”

Salmonella strains have a natural preference for infiltrating and replicating within the cancer cells of a tumor, making the bacteria an ideal candidate for bacteriotherapy,” says Robert Kazmierczak, a postdoctoral fellow in the division of biological sciences at the University of Missouri and a senior investigator at the Cancer Research Center.

Bacteriotherapy is the use of live bacteria as therapy to treat a medical condition, like cancer.

For the study, published in the journal PLOS ONE, researchers developed CRC2631, a Salmonella strain genetically modified to render the bacteria nontoxic and enhance its natural ability to target and kill cancer cells—without harming normal, healthy cells.

Cancer’s metabolism may be a way to kill it

The Salmonella strain was administered directly into the circulatory system of mice with prostate cancer.

“We found that the mice tolerated the treatment well and when examined, their prostate tumors decreased by about 20 percent compared to the control group,” Kazmierczak says.

“One of the most remarkable aspects of Salmonella is its ability to target, spread and persist inside the tumor. We are taking advantage of this ability by using Salmonella to carry or generate effective chemotherapeutic drugs, concentrating them at and throughout the tumor.

“The goal of this treatment is to develop a bacterial vector that can destroy the tumor from the inside out and reduce the amount of side effects endured by patients with cancer.”

T-cells break the rules when salmonella attacks

The CRC2631 strain is derived from a Salmonella sample that was stored in a test tube at room temperature for more than 50 years. The sample originates from the Demerec collection, a collection of mutant strains of Salmonella collected by geneticist Milisav Demerec and curated by Abraham Eisenstark, scientific director at the CRC and professor emeritus of biological sciences.

The collection contains more than 20,000 different samples, with half of the samples housed at the Cancer Research Center where researchers focus on three areas of cancer research: early detection, targeted treatment, and new, effective chemotherapy.

“The uniqueness of CRC2631 differentiates our Salmonella strains from other universities trying to achieve the same goal; it is one of a kind,” Eisenstark says. “The strain of Salmonella we are using is essential to the success of our study.”

The Cancer Research Center funded the work.

Source: University of Missouri

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In retrospect: Twenty-five years of low-cost solar cells

In 1991, an energy-efficient solar cell was reported that was both simple in design and relatively inexpensive. This invention has since inspired the development of solar cells that have even higher efficiencies.

Nature 538 463 doi: 10.1038/538463a

Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment

Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias.

Nature doi: 10.1038/nature20131

Local regulation of gene expression by lncRNA promoters, transcription and splicing

Mammalian genomes are pervasively transcribed to produce thousands of long non-coding RNAs (lncRNAs). A few of these lncRNAs have been shown to recruit regulatory complexes through RNA–protein interactions to influence the expression of nearby genes, and it has been suggested that many other lncRNAs can also act as local regulators. Such local functions could explain the observation that lncRNA expression is often correlated with the expression of nearby genes. However, these correlations have been challenging to dissect and could alternatively result from processes that are not mediated by the lncRNA transcripts themselves. For example, some gene promoters have been proposed to have dual functions as enhancers, and the process of transcription itself may contribute to gene regulation by recruiting activating factors or remodelling nucleosomes. Here we use genetic manipulation in mouse cell lines to dissect 12 genomic loci that produce lncRNAs and find that 5 of these loci influence the expression of a neighbouring gene in cis. Notably, none of these effects requires the specific lncRNA transcripts themselves and instead involves general processes associated with their production, including enhancer-like activity of gene promoters, the process of transcription, and the splicing of the transcript. Furthermore, such effects are not limited to lncRNA loci: we find that four out of six protein-coding loci also influence the expression of a neighbour. These results demonstrate that cross-talk among neighbouring genes is a prevalent phenomenon that can involve multiple mechanisms and cis-regulatory signals, including a role for RNA splice sites. These mechanisms may explain the function and evolution of some genomic loci that produce lncRNAs and broadly contribute to the regulation of both coding and non-coding genes.

Nature doi: 10.1038/nature20149

Activity trackers flop without cash motivation

New research shows that activity trackers—Fitbits, Jawbones, Garmins, etc.—are unlikely to help people become more active, especially since most stop wearing the devices within a few weeks or months.

Inactivity is responsible for 9 percent of global deaths, reduces productivity, and drives up health care costs. For this reason, governments, employers, and insurers are looking for strategies to increase activity levels.

“Activity trackers alone are not going to stem the rise in chronic diseases,” says lead author Eric Finkelstein of the Duke-NUS Medical School.

However, he further notes that “they could still be part of a comprehensive solution and there may be a role for low cost incentive strategies, although they would likely have to be permanent to avoid any undermining effect from taking them away.”

Giving up Fitbit can mean guilt or relief

For the study in The Lancet Diabetes & Endocrinology, researchers recruited 800 working adults from Singapore and randomly assigned them to a control group, a tracker only group, or tracker plus one of two types of rewards schemes.

One reward group accrued rewards in cash and the other had the rewards go to a charity of the individual’s choice. The rewards were based on meeting weekly step goals over a period of six months. The researchers assessed physical activity outcomes, including steps and activity bouts, and health outcomes, including weight and blood pressure at study conclusion and after one year, six months after incentives ended.

The findings show that regardless of physical activity levels of participants before the study began, activity trackers alone or when combined with rewards designated for charity did not increase activity levels. In fact, nearly half of participants were no longer wearing their trackers by the six-month assessment period.

Don’t bank on wearables to keep weight off

In contrast, both active and inactive individuals offered cash rewards significantly increased activity levels between baseline and six months and nearly 90 percent continued to wear the trackers.

However, at the end of twelve months, six months after the incentives were removed, this group showed poorer step outcomes than the tracker only group, suggesting that removing the incentives may have demotivated these individuals and caused them to do worse than had the incentives never been offered.

Despite the step differences, activity trackers, with or without incentives, did not lead to noticeable improvements in health outcomes.

Funding for this study came from the Singapore Ministry of Health’s Health Services Research Competitive Research Grant.

Source: National University of Singapore

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