An Anti-Cancer Antibiotic

An antibiotic, Nigericin, has anti-cancer activity, and one mechanism is through targeted suppression of Wnt signaling.  Abstract:

Nigericin, an antibiotic derived from Streptomyces hygroscopicus that works by acting as an H+, K+ and Pb2+ ionophore, has exhibited promising anticancer activity. The main purpose of this study is to investigate its inhibitory effects on Wnt/β-catenin signaling pathway in colorectal cancer (CRC) cells and clarify the underlying mechanism. We exposed two CRC lines (SW620 and KM12) to increasing concentrations of nigericin for different time periods and the 50% inhibiting concentration (IC50) values were evaluated. Our data showed that nigericin treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in CRC cells. The subsequent experiments in vitro and in vivo implied that nigericin could significantly suppress the tumor growth, migration and invasion, and induce the apoptosis of CRC cells. Our results of western blot and immunofluorescence assay showed that nigericin could suppress the Wnt/β-catenin signaling pathway in CRC cells with dose-dependent increased expressions of downstream effectors and target proteins. To further elucidate the inhibitory effects of nigericin via a β-catenin-dependent signaling mechanism, we established the stably β-catenin over-expression CRC cells. Western blot, SuperTOPflash luciferase reporter and immunoprecipitation assays all confirmed β-catenin as a critical intermediary and player in Wnt/β-catenin pathway, and nigericin exerted anti-cancer effects on CRC cells by directly targeting the β-catenin destruction complex. These results suggested that Wnt/β-catenin signaling might have an essential role in CRC progression. Nigericin targeting Wnt/β-catenin signaling might provide new insight into the molecular mechanism of nigericin towards cancer cells, and suggest possible clinical application in CRC

Asthma Clinical Trial: Dupliumab

Antibody clinical trial for asthma; abstract;

Background Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown. Methods We randomly assigned 210 patients with oral glucocorticoid-treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed. Results The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%). Conclusions In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214 .).

Breast Cancer Microbiota

New discoveries are demonstrating the importance of tumor microbiota: bacteria associated with particular cancers. Here is a paper concerned with the breast cancer microbiota, and shows that certain species of bacteria found in breast cancer tissue and surrounding microenvironment contribute to gene expression that influences cancer progression. The microbiota-cancer link will continue to provide new findings that could impact therapeutics.  Perhaps antibiotics could be part of the toolkit?  Abstract:

The inflammatory tumoral-immune response alters the physiology of the tumor microenvironment, which may attenuate genomic instability. In addition to inducing inflammatory immune responses, several pathogenic bacteria produce genotoxins. However the extent of microbial contribution to the tumor microenvironment biology remains unknown. We utilized The Cancer Genome Atlas, (TCGA) breast cancer data to perform a novel experiment utilizing unmapped and mapped RNA sequencing read evidence to minimize laboratory costs and effort. Our objective was to characterize the microbiota and associate the microbiota with the tumor expression profiles, for 668 breast tumor tissues and 72 non-cancerous adjacent tissues. The prominent presence of Proteobacteria was increased in the tumor tissues and conversely Actinobacteria abundance increase in non-cancerous adjacent tissues. Further, geneset enrichment suggests Listeria spp to be associated with the expression profiles of genes involved with epithelial to mesenchymal transitions. Moreover, evidence suggests H. influenza may reside in the surrounding stromal material and was significantly associated with the proliferative pathways: G2M checkpoint, E2F transcription factors, and mitotic spindle assembly. In summary, further unraveling this complicated interplay should enable us to better diagnose and treat breast cancer patients.

New Inroads Against Multiple Sclerosis

Read this.  Excerpts:

Medical progress against multiple sclerosis (MS) took a major leap forward in 2017 with the approval by the US Food and Drug Administration (FDA) of ocrelizumab, a drug that has shown success against 2 different forms of the disease. The year also brought further signs that it may be possible to biochemically reverse damage wrought by MS.

So, there’s a potentially effective monoclonal antibody drug, and there are possibilities of reversing the damage.  Stem cells are always useful for repair.

One of the key epidemiologic points about MS is that it has increased in frequency, and although there are now 203 genes that influence MS risk, all of these influences are very small effects, and the majority of susceptibility is not genetic and is almost certainly environmental. What in the environment is responsible for triggering MS is one of the great questions in MS research. It's unanswered but is likely to be a virus or bacterium. 

Dr Cohen:I would add that the microbe may not only be external to the person, but something in their own microbiome. It probably is not one single culprit, but many potential culprits. Or the distribution, the presence of some or absence of other microbial agents, may be what leads to susceptibility.

Once again, the microbiome.  Remember that your microbiome is influenced by diet.

Dr Hauser:It's likely that the microbiome has a substantial effect on MS in 2 ways. The first is the molecular mimicry, where some cell component of a bacterium or virus resembles a protein or substance in the brain. The second is that our microbiota influence the regulatory tone of our immune system, and that could lead to differences in the trajectory of disease after it begins. 

We don't yet know what the likely microbial culprit or culprits are. The strongest epidemiologic link to multiple sclerosis remains a late onset infection with the Epstein-Barr virus (EBV), [perhaps] the occurrence of infectious mononucleosis, but we really don’t know if EBV is causally linked or is a surrogate for some other infectious agent.

That’s also useful to know, and another avenue to explore for prevention of therapy, mostly the former.

Review On Antimicrobial Resistance

Left, a phage.  By Adenosine - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8643737

Here is an interesting review on antimicrobial resistance. Such resistance, particularly resistance to antibiotics, is becoming an increasingly significant health concern. Note the mention of phage therapy, which has long been in use in other countries, including some areas of Eastern Europe. That has promise, as one has the wrong types of phages are avoided.  I believe more study on phage therapy should be conducted in the USA. Abstract:

PURPOSE:

To describe the current standards of care and major recent advances with regard to antimicrobial resistance (AMR) and to give a prospective overview for the next 30 years in this field.

METHODS:

Review of medical literature and expert opinion were used in the development of this review.

RESULTS:

There is undoubtedly a large clinical and public health burden associated with AMR in ICU, but it is challenging to quantify the associated excess morbidity and mortality. In the last decade, antibiotic stewardship and infection prevention and control have been unable to prevent the rapid spread of resistant Gram-negative bacteria (GNB), in particular carbapenem-resistant Pseudomonas aeruginosa (and other non-fermenting GNB), extended-spectrum β-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE). The situation appears more optimistic currently for Gram-positive, where Staphylococcus aureus, and particularly methicillin-resistant S. aureus (MRSA), remains a cardinal cause of healthcare-associated infections worldwide. Recent advancements in laboratory techniques allow for a rapid identification of the infecting pathogen and antibiotic susceptibility testing. Their impact can be particularly relevant in settings with prevalence of MDR, since they may guide fine-tuning of empirically selected regimen, facilitate de-escalation of unnecessary antimicrobials, and support infection control decisions. Currently, antibiotics are the primary anti-infective solution for patients with known or suspected MDR bacteria in intensive care. Numerous incentives have been provided to encourage researchers to work on alternative strategies to reverse this trend and to provide a means to treat these pathogens. Although some promising antibiotics currently in phase 2 and 3 of development will soon be licensed and utilized in ICU, the continuous development of an alternative generation of compounds is extremely important. There are currently several promising avenues available to fight antibiotic resistance, such as faecal microbiota, and phage therapy.

Conservative Antibiotic Use is Prudent

The over-prescription, over-use, and wrong-use of antibiotics have helped fuel the epidemic of antibiotic resistance. Less, more conservative use of these drugs would be prudent. Using antibiotics when they are not needed not only fuels resistance, but is costly and can have a negative impact on the normal human bacterial microbiome. In general, all medications should be used appropriately and not indiscriminately used in cases where there would be little to no benefit (or even harm).

For uncomplicated respiratory infections, strategies that delay the patient’s pick-up or use of antibiotics can result in less antibiotic use with equal satisfaction, according to a new study.

Patients who had to go pick up their prescriptions from the primary care office or who delayed taking the antibiotics experienced slightly greater symptoms for a slightly longer time during their illness than people who got antibiotics immediately, but all groups had similar satisfaction levels.

Most respiratory infections, like pharyngitis or bronchitis, are caused by viruses, not bacteria, and antibiotics do not modify the infections significantly. But most patients with symptoms of these infections still receive an antibiotic in the U.S., the authors write.

Using antibiotics when they do little to help puts the patient at risk of unnecessary side effects and helps make the targeted bacteria resistant to the drugs.