New substance overcomes treatment-resistance in leukemia

Haematologists from Goethe University Frankfurt, working with a Russian pharmaceutical company, have developed a new active substance that effectively combats the most aggressive forms of Philadelphia chromosome-positive leukemia

The chances of patients with Philadelphia chromosome-positive leukemia (Ph+) being cured has greatly increased in recent years. Nevertheless, a high percentage of patients have developed resistance to available medication. But now, haematologists from Goethe University Frankfurt, working with a Russian pharmaceutical company, have developed a new active substance that effectively combats the most aggressive forms of Philadelphia chromosome-positive leukemia, both in vitro and in vivo. They have reported this in the current edition of the specialist journal 'Leukemia'.

Patients with the Philadelphia chromosome develop chronic myelogenous leukemia (CML) or acute lymphatic leukemia (Ph+ ALL). These are the first types of leukemia that are able to be treated due to the development of targeted molecular therapy. Selective kinase inhibitor active substances act directly on the cancer-inducing gene BCR/ABL. However, after a while, the treatment becomes ineffective for many patients -- either due to BCR/ABL mutations or due to other mechanisms that are as yet unknown. At present, there is only one substance, Ponatinib, which is able to overcome nearly all clinical resistance. Unfortunately, Ponatinib can only be used with extreme caution due to some of its life-threatening side-effects.

Moscow-based company Fusion Pharma has developed an innovative kinase inhibitor, PF-114 with the aim of having the same effect on Ph+ leukemia as Ponatinib, but with reduced side-effects. In the current edition of 'Leukemia', the team led by Dr. Afsar Mian, Professor. Oliver Ottoman and lecturer Dr. Martin Ruthardt from the Haematology Department of Medical Clinic II, have reported that PF-114 is as effective as Ponatinib against resistant Ph+ leukemia.

"These results provide the basis for the administration of PF-114 in treatment-resistant patients with Ph+ leukemia. The favorable efficacy and good side effect profile now need to be further tested on patients in clinical phase I studies," explained Dr. Ruthardt. "PF-114 would not have reached this level of development without our colleagues in Frankfurt. On the basis of this data, in the first half of 2015, we will be able to start international phase I studies," explains Dr. Ghermes Chilov, CEO of Fusion Pharma, the company that financed the project.

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Bioinformatics Department

An Ebola virus protein can cause massive inflammation and leaky blood vessels

Ebola GP protein covers the virus' surface and is shed from infected cells during infection. A study published on November 20th in PLOS Pathogens reports that shed GP can trigger massive dysregulation of the immune response and affect the permeability of blood vessels.

Ebola virus has seven genes. One of them, called GP, codes for two related proteins: a shorter secreted one and a longer one that spans the viral wall and sticks out of its surface. During virus infection, some of the surface GP is cut off by a human enzyme and is subsequently shed from infected cells. High levels of both shed and secreted GP are found in the blood of infected humans and animals. Rather than working with intact Ebola virus, Viktor Volchkov and colleagues from the Claude Bernard University of Lyon, International Center for Infectiology Research (CIRI), INSERM, France, produced shed and secreted GP in tissue culture and used these proteins to test their effects on human cells. They found that shed but not secreted GP can bind to immune cells, called macrophages and dendritic cells, both also targets of Ebola virus infection. Upon binding of shed GP, these immune cells start releasing massive quantities of immune-modulators. Both shed GP and these immune-modulators are soluble proteins that can travel in the blood stream, and this might explain how through continuing production and release of shed GP an initial immune response to the virus gets amplified and can spiral out of control, leading to high fever, massive inflammation, and possibly the shock that kills many Ebola patients.

Figure: The role of shed GP during Ebola Infection

The scientists also found that the effects of shed GP on the immune cells depends on a molecule called TLR-4. Blocking TLR-4 with specific antibodies prior to exposing immune cells to shed GP damped the cells' reaction and eliminated much of the release of immune modulators.

Besides massive and destructive inflammation, fatal Ebola disease is also associated with loss of blood vessel integrity--hence the name Ebola hemorrhagic fever. To examine a possible contribution of GP to these symptoms, the researchers examined the effects of secreted and shed GP on permeability of endothelial cells (which form blood vessels). They found that shed GP directly--as well as through the cocktail of immune-modulators produced by immune cells upon binding of shed GP--can increase permeability of endothelial cells.

While the results of the study need to be confirmed in the context of infected animals or humans, the authors conclude that their data "support a role for EBOV shed GP in the creation of excessive and dysregulated host inflammatory responses and an increased vascular permeability." They also speculate that "anti-TLR4 antibodies could be used to reduce the inflammatory reaction caused by shed GP."

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Bioinformatics Department

Body weight heavily influenced by gut microbes: Genes shape body weight by affecting gut microbes

Our genetic makeup influences whether we are fat or thin by shaping which types of microbes thrive in our body, according to a study by researchers at King's College London and Cornell University. By studying pairs of twins at King's Department of Twin Research, researchers identified a specific, little known bacterial family that is highly heritable and more common in individuals with low body weight. This microbe also protected against weight gain when transplanted into mice.

Picture showing different microbes found in gut

Previous research has linked both genetic variation and the composition of gut microbes to metabolic disease and obesity. Despite these shared effects, the relationship between human genetic variation and the diversity of gut microbes was presumed to be negligible.

In the study, funded by National Institutes of Health (NIH), researchers sequenced the genes of microbes found in more than 1,000 fecal samples from 416 pairs of twins. The abundances of specific types of microbes were found to be more similar in identical twins, who share 100 per cent of their genes, than in non-identical twins, who share on average only half of the genes that vary between people. These findings demonstrate that genes influence the composition of gut microbes.

The type of bacteria whose abundance was most heavily influenced by host genetics was a recently identified family called 'Christensenellaceae'. Members of this health-promoting bacterial family were more abundant in individuals with a low body weight than in obese individuals. Moreover, mice that were treated with this microbe gained less weight than untreated mice, suggesting that increasing the amounts of this microbe may help to prevent or reduce obesity.

Picture showing comparison between treated and non treated mice.

 Several findings show that specific groups of microbes living in our gut could be protective against obesity and that their abundance is influenced by our genes. The human micro biome represents an exciting new target for dietary changes and treatments aimed at combating obesity.

This is a crowd-sourcing experiment that allows anyone with an interest in their diet and health to have their personal microbes tested genetically using a simple postal kit and a small donation. This is the first study to firmly establish that certain types of gut microbes are heritable that their variation across a population is in part due to host genotype variation, not just environmental influences. These results will also help us find new predictors of disease and aid prevention.

Comparative Effect of Organics and Biofertilizers on Growth and Yield of Maize (Zea mays. L)

A field experiment to study the “Comparative efficiency of organics and biofertilizers on growth and yield of maize (Zea mays L.)” was conducted during Kharif 2011 at farmer field in Beluguli village, Chikkanayakanahalli taluk (Tumkur district). The maize cultivar Nithyashree (NAH 2049) was used in the study. The field experiment was laid out in Randomized Complete Block Design with fourteen treatments and three replications. Results of the treatment (T13) having recommended dose of NPK + Azotobacter chroococcum + Bacillus megaterium + Pseudomonas fluorescence + enriched compost has showed highest plant height at 30, 60, 90 days after sowing and at harvest (120 days) (31.70, 180.93, 186.07 and 188.13 cm respectively). The highest total dry matter production at harvest (375.80 g) and yield parameters like Weight of cob (207.63 g), Grain yield per plant (158.93 g), Grain yield per ha (54.53 q) and Test weight of seeds (33.10 g) was also found highest in this treatment and available nutrient content in soil after crop harvest i.e., nitrogen (185.40 Kg ha-1), phosphorous (38.83 Kg ha-1) and potassium (181.47 Kg ha-1) was also found highest in the same treatment combination.

Influence of biofertilizers and different sources of organics on growth of maize.

The germination was not significantly influenced by treatments. However, maximum germination was recorded (96.90%) with the application of recommended dose of NPK + A. chroococcum + B. megaterium+ P. fluorescence+ enriched compost(T13).This is due to better soil condition with application of organics and biofertilizers. This is in conformity with the results of Amruthesh et al. (2003) and Hameeda et al. (2008) who observed such increased germination due to biofertilizers application. Among the different growth parameters, significant increase in the plant height was observed till the end of crop growth period. The treatment (T13) receiving recommended dose of NPK + A. chroococcum + B. megaterium+ P. fluorescence+ enriched compostrecorded maximum plant height at 30, 60, 90 days after sowing and at harvest (31.77, 180.93, 186.07 and 188.13 cm). Increased plant height may be due to the application of recommended dose of NPK and microbial consortia of nitrogen fixer, phosphate solubilizer and PGPR bacterium with nutrient rich organic source like enriched compost. The increase in growth of maize could be attributed to the enhanced nutrient use efficiency in the presence of organic fertilizer. Many organic materials release nutrients slowly and may reduce the leaching losses, particularly N (Nevens and Reheul, 2003 and Naveed et al. 2008).The number of days taken for fifty per cent tasseling by maize did not differed significantly due to treatment effects. However, maximum days taken for fifty per cent tasseling were recorded (51.87 days) with recommended dose of NPK + A. chroococcum + B. megaterium+ P. fluorescence+ enriched compost (T13).

Conclusion

The findings of this study have clearly showed that combined application of Azotobacter chroococcum, Bacillus megateriumand Pseudomonas fluorescence along with recommended dose of NPK and enriched compost has resulted in obtaining highest plant growth, crop yields and dry matter production.

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Bitechnology Department