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How cancer drugs find their targets

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In the watery inside of a cell, complex processes take place in tiny functional compartments called organelles. Energy-producing mitochondria are organelles, as is the frilly golgi apparatus, which helps to transport cellular materials. Both of these compartments are bound by thin membranes.

But in the past few years, research at Whitehead Institute and elsewhere has shown that there are other cellular organelles held together without a membrane. These organelles, called condensates, are tiny droplets which keep certain proteins close together amidst the chaos of the cell, allowing complex functions to take place within. “We know of about 20 types of condensate in the cell so far,” says Isaac Klein, a postdoc in Richard Young’s lab at the Whitehead Institute and oncologist at the Dana-Farber Cancer Institute.

Now, in a paper published in Science on June 19, Klein and Ann Boija, another postdoc in Young’s lab, show the mechanism by which small molecules, including cancer drugs, are concentrated in these cellular droplets — a finding that could have implications for the development of new cancer therapeutics. If researchers could tailor a chemical to seek out and concentrate in one kind of droplet in particular, it might have a positive effect on the delivery efficiency of the drug. “We thought, maybe that’s an avenue by which we can improve cancer treatments and discover new ones,” says Klein.

“This [research] is part of a revolutionary new way of looking at the organization within cells,” says MIT Institute Professor Phillip Sharp, a professor of biology at the Koch Institute for Integrative Cancer Research and a co-author on the study. “Cells are not little pools of soup, all mixed together. They are actually highly organized, compartmentalized units, and that organization is important in their function and in their diseases. We’ve just started to understand that, and this new paper is a really important step, using that insight, to understand how to potentially treat diseases differently.”

Condensates and drug delivery

To explore how different properties of condensates inside the cell’s nucleus affected the delivery of cancer drugs, Boija and Klein selected a few example condensates to study. These included splicing speckles, which store cellular materials needed for RNA splicing; nucleoli, where ribosomes are formed; and a new kind of droplet Young’s lab discovered in 2018 called a transcriptional condensate. These new condensates bring together all the different proteins needed to successfully transcribe a gene. 

The researchers created their own suite of four different fluorescently-labeled condensates by adding glowing tags to marker proteins specific to each kind of droplet. For example, transcriptional condensates are marked by the droplet-forming protein MED1, splicing speckles by a protein called SRSF2, and nucleoli by FIB1 and NPM1. 

Now that they could tell individual droplets apart by their cellular purpose, the team, along with the help of Nathanael Gray, a chemical biologist at Harvard University and the Dana-Farber Cancer Institute, created fluorescent versions of clinically important drugs. The tested drugs included cisplatin and mitoxantrone, two anti-tumor medicines commonly used in chemotherapy. These therapeutics were the perfect test subjects, because they both target proteins that lie within nuclear condensates. 

The researchers added the cancer drugs to a mixture containing various droplets (and only droplets, none of the actual drug targets), and found that the drugs sorted themselves into specific condensates. Mitoxantrone concentrated in condensates marked by MED1, FIB1 and NPM1, selectively avoiding the others. Cisplatin, too, showed a particular affinity for droplets held together by MED1. 

“The big discovery with these in vitro studies is that a drug can concentrate within transcriptional condensate independent of its target,” Boija says. “We used to think that drugs come to the right place because their targets are there, but in our in vitro system, the target is not there. That’s really informative — it shows the drug is actually being concentrated in a different way than we thought.”    

To understand why some drugs were drawn into transcriptional condensates, they screened a panel of chemically-modified dyes and found that the important part of many drugs — the part that led them to concentrate in transcriptional condensates — is the molecules’ aromatic ring structure. Aromatic rings are stable, ring-shaped groupings of carbon atoms. The aromatic ring in some drugs are thought to stack with rings in MED1’s amino acids, leading the drug to concentrate in transcriptional condensates. 

Being able to tailor a drug to enter a certain condensate is a powerful tool for drug developers. “We found that if we add an aromatic group to a molecule, it becomes concentrated within the transcriptional condensate,” Boija says. “It’s that type of interaction that is important when we design new drugs to enter transcriptional condensates — and maybe we can improve existing drugs by modifying their structure. This will be very exciting to look into.”

Where drugs concentrate affects how well they fight cancer

In order for this tool to be practically useful in drug development, the researchers had to make sure that concentration in specific droplets would actually impact the drugs’ performance. Boija and Klein decided to test this using cisplatin, which is drawn to transcriptional condensates by MED1 and works to fight cancer by adding clunky platinum molecules to DNA strands. This damages tumor cells’ genetic material. When the researchers administered cisplatin to a mixture of different condensates, both in the test tube and in cells, the drug preferentially altered DNA that lay within transcriptional condensates. 

This could explain why cisplatin and other platinum drugs are effective against so many diverse cancers, says Young, who is also a professor of biology at MIT; cancer-causing genes often carry regions of DNA called super enhancers, which are extremely active in transcription, leading to very large transcriptional condensates. “We now think the reason that drugs like cisplatin can work well in patients with diverse cancers is because they’re becoming selectively concentrated at the cancer-causing genes, where these large transcriptional condensates occur,” he says. “The effect is to have the drug home in on the gene that’s causing each cancer to be so deadly.”

A drug resistance mystery, solved        

The new insights in condensate behavior also provided some answers to another question in cancer research: why people become immune to the breast cancer drug tamoxifen.Tamoxifen works by attaching itself to estrogen receptors in the cancer cells, preventing them from getting the hormones they need to grow and eventually slowing or stopping the formation of new cancer cells altogether. The drug is one of the most effective treatments for the disease, reducing recurrence rates for ER+ breast cancers by around 50 percent.     

Unfortunately, many patients quickly develop a resistance to tamoxifen — sometimes as soon as a few months after they start taking it. This happens in a variety of ways — for example, sometimes the cancer cells will mutate to be able to kick the tamoxifen out of the cells, or simply produce fewer estrogen receptors for the drug to bind. One form of resistance was associated with an overproduction of the protein MED1, but scientists didn’t know why. 

With their newfound knowledge of how a drug’s activity is affected by where it concentrates, Boija and Klein had a hypothesis: The extra MED1 might increase the size of the droplets, effectively diluting the concentration of tamoxifen and making it more difficult for the drug to bind its targets. When they tested this in the laboratory, the team found that more MED1 did indeed cause larger droplets, leading to lower concentrations of tamoxifen. 

A new toolset for drug designers

The ability to better understand the behavior of drugs in cancer cells — how they concentrate, and why the cancer could become resistant to them — may provide drug developers with a new arsenal of tools to craft efficient therapeutics.

“This study suggests that we should be exploring whether we can design or isolate drugs that are concentrated in a given condensate, and to understand how existing drugs are concentrated in the cell,” says Phil Sharp. “I think this is really important for drug development — and I think [figuring it out] is going to be fun.”


Source: http://news.mit.edu/2020/how-cancer-drugs-find-their-targets-could-lead-new-drug-development-toolset-0626

Biotechnology

China Warns Spread of An ‘Unknown Pneumonia’ Deadlier Than COVID-19

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Unknown pneumonia in Kazakhstan
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Unknown pneumonia in Kazakhstan – Chinese Embassy Warns Citizens.

A warning about unknown pneumonia has been issued by the Chinese embassy in Kazakhstan, which says pneumonia has caused more than 600 deaths in the central Asian country in June.

The Chinese embassy said the new disease has a fatality rate much higher than Covid-19, in an advisory issued for its citizens living in the former Soviet Bloc country.

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China’s northwest Xinjiang Uyghur Autonomous Region borders with Kazakhstan.

In the first six months of the year, the ‘unknown pneumonia’ caused 1,772 deaths, of which 628 deaths occurred in June alone. A statement issued by the embassy on its WeChat platform said these deaths included those of Chinese citizens also.

The embassy added that the fatality rate of this unknown pneumonia in Kazakhstan is much higher than Covid-19.

However, it’s not clear if the Chinese officials have any more information about this particular pneumonia or if there is any specific reason to call it unknown.

And there isn’t any clarity if the World Health organization is informed about this “unknown pneumonia.”

The Chinese embassy reminded the Chinese nationals in Kazakhstan to be aware of the situation and increase prevention strategies to lower the infection risks.

The number of patients infected with the new pneumonia is two to three times higher than that of Covid-19, Kazakhstan’s healthcare minister said on Wednesday.

To contain the spread of novel coronavirus, Kazakhstan had implemented a lockdown on March 16, which was later lifted in May. Due to an increase in the number of cases, the restrictions were reimposed again.

The country could be facing a second wave of infections, president Kassim-Jomart Tokayev said. According to the Hong Kong-based South China Morning Post, Kazakhstan’s President Kassym-Jomart Tokayev said on Wednesday that it was too early to relax restrictions as the situation was still serious.

In fact, the country was facing a second wave of Covid-19 coupled with a huge uptick in pneumonia cases, he added.

Nearly 300 people diagnosed with the unknown pneumonia are being hospitalized every day in Kazakhstan, the health care department chief in the capital Nur-Sultan, Saule Kisikova, told the news agency Kazinform.

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Source: https://www.biotecnika.org/2020/07/unknown-pneumonia-in-kazakhstan-chinese-embassy-warns-citizens/

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Life Sciences Fund Launches with €76M to Invest in Nordic Biotech

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Stockholm and Copenhagen-based Eir Ventures has announced the closure of its first fund at €76M, which will be used to invest in biotechs and other life science companies, with a focus on the Nordics.

The fund is backed by Saminvest, a venture capital company founded by the Swedish Government; Vækstfonden, the Danish state’s investment fund; Novo Holdings; and the European Investment Fund.

Although the fund will cover the whole of Europe and the USA, particular focus will be placed upon biotech innovations from leading universities and incubators in the Nordics. This region currently has a pronounced imbalance between investment opportunities and available venture capital.

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In particular, the number of venture funds in the region has declined substantially since the early 2000s, and no fully pan-Nordic investor exists because most of the remaining funding sources tend to be bound to individual countries.

The available local capital is substantially below what the available investment opportunities could warrant, and thus there is a big opportunity for a new fund like Eir Ventures,” said Stephan Christgau, Managing Partner of Eir Ventures. “The so-called ‘Medicon Valley,’ comprising the greater Copenhagen region and southern Sweden, has had a 23% growth in output of scientific papers in the last 10 years, the highest growth rate of any of the ten largest life science clusters in Europe.”

Eir Ventures plan to invest in 12 to 18 biotech companies with this fund. Although the fund will not focus on specific therapeutic areas, there are a number of strengths within the region, including endocrinology, stem cells, central nervous system diseases, and oncology, along with expertise around peptide and oligonucleotide drugs.

We also hope that we can play our part in enhancing the Nordic life science ecosystem and bring even more international talent as well as capital into the Nordics,” Christgau said.

Interestingly, the announcement marks the closure of the fourth Europe-centered life sciences venture fund in the last month. It follows the €185M closing of Forbion’s Growth Opportunities fund this week, which will focus on investments in public European biotechs and those close to going public. In the last few weeks, there has also been Epidarex Capital’s launch of a €122M UK-targeted fund and Biogeneration Ventures’ €105M fund, which focuses on creating European medical biotech startups. 

According to Christgau, there has been “no concerted effort” to coordinate the closing of these funds. Instead, he believes it could be a coincidental result of Covid-19 pandemic restrictions lifting, thus allowing deals to be brought to completion.


Image from Shutterstock

Source: https://www.labiotech.eu/policy-legal-finance/eir-ventures-biotech-investments/

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Liquid metal synthesis for better piezoelectrics: Atomically-thin tin-monosulfide

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Potential materials for future wearable electronics and other motion-powered, energy-harvesting devices

RMIT-UNSW collaboration applies liquid-metal synthesis to piezoelectrics, advancing future flexible, wearable electronics, and biosensors drawing their power from the body’s movements.

Materials such as atomically-thin tin-monosulfide (SnS) are predicted to exhibit strong piezoelectric properties, converting mechanical forces or movement into electrical energy.

This property, along with their inherent flexibility, makes them likely candidates for developing flexible nanogenerators that could be used in wearable electronics or internal, self-powered biosensors.

However to date, this potential has been held back by limitations in synthesising large, highly crystalline monolayer tin-monosulfide (and other group IV monochalcogenides), with difficulties caused by strong interlayer coupling.

The new study resolves this issue by applying a new liquid-metal technique, developed at RMIT, to synthesise the materials.

Subsequent measurements confirm that tin-monosulfide synthesised using the new method displays excellent electronic and piezoelectric properties.

The resulting stable, flexible monolayer tin-monosulfide can be incorporated in a variety of devices for efficient energy harvesting.

The work started over two and a half years ago and strong collaborative work between RMIT and UNSW allowed its fruition. Ms Hareem Khan, the first author of the paper, showed remarkable perseverance to surmount many technical challenges to demonstrate the viability of the concept, with Prof Yongxiang Li.

LIQUID METAL SYNTHESIS

The unprecedented technique of synthesis used involves the van der Waals exfoliation of a tin sulphide (SnS), that is formed on the surface of tin when it is melted, while being exposed to the ambient of hydrogen sulfide (H2S) gas. H2S breaks down on the interface and sulfurises the surface of the melt to form SnS.

The technique is equally applicable to other monolayer group IV monochalcogenide, which are predicted to exhibit the same strong piezoelectricity.

This liquid metal based method allows us to extract homogenous and large scale monolayers of SnS with minimal grain boundaries.

Measurements confirm the material has high carrier mobility and piezoelectric coefficient, which translates into exceptional peak values of generated voltage and loading power for a particular applied strain, impressively higher than that any previously reported 2D nanogenerator.

High durability and flexibility of the devices are also demonstrated.

This is evidence that the very stable as-synthesised monolayer SnS can be commercially implemented into power-generating nanodevices.

They can also be used for developing transducers for harvesting mechanical human movements, in accordance to the current technological inclinations towards smart, portable and flexible electronics.

The results are a step towards piezoelectric-based, flexible, wearable energy-scavenging devices.

It also presents an unprecedented synthesis technique for large (wafer) scale tin-monosulfide monolayers.

PIEZOELECTRIC MATERIALS

Piezoelectric materials can convert applied mechanical force or strain into electrical energy.

Best known by name in the simple ‘piezo’ lighter used for gas BBQs and stovetops, piezo-electric devices sensing sudden changes in acceleration are used to trigger vehicle air bags, and more-sensitive devices recognise orientation changes in mobile phones, or form the basis of sound and pressure sensors.

Even more sensitive piezoelectric materials can take advantage of the small voltages generated by extremely small mechanical displacement, vibration, bending or stretching to power miniaturised devices, for example biosensors embedded in the human body, removing the need for an external power source.

THE STUDY

Liquid metal-based synthesis of high performance monolayer SnS piezoelectric nanogenerators was published in Nature Communications in July 2020 (DOI 10.1038/s41467-020-17296-0).

The study represents a collaboration between two Australian Research Council Centres of Excellence: the Centre for Exciton Science, and the Centre for Future Low-Energy Electronics Technologies (FLEET). ARC funding also comes from the Discovery Project, DECRA and ARC Laureate programs, and from the RMIT Vice-Chancellor Fellowship.

Facilities and advice from the Australian Microscopy & Microanalysis Research Facility (RMMF), RMIT Micro Nano Research Facility (MNRF) and the Centre for Advanced Solid and Liquid based Electronics and Optics (CASLEO) was critical to the success of the study, as was assistance from the CSIRO for PESA measurements.

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http://www.fleet.org.au/blog/liquid-metal-synthesis-for-better-piezoelectrics-atomically-thin-tin-monosulfide/

Source: https://bioengineer.org/liquid-metal-synthesis-for-better-piezoelectrics-atomically-thin-tin-monosulfide/

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