Scientists at the Institute for Translational Immunology at Mainz University Medical Center have co-developed a novel drug that could effectively treat non-alcoholic fatty liver inflammation: the modified omega-3 fatty acid icosabutate. In the ongoing phase 2b clinical trial “ICONA”, the positive results seem to be confirmed: The compound prevented inflammation and scarring of the liver. To date, there is no established therapy and no approved drug for non-alcoholic fatty liver inflammation. The research results published in the renowned scientific journal “Journal of Hepatology” therefore indicate a breakthrough for the treatment of this disease.
More and more people in industrialized countries around the world are suffering from metabolic diseases such as obesity, impaired fat metabolism or type 2 diabetes mellitus. Many of these patients develop fatty liver disease, known as non-alcoholic fatty liver (NAFL). In Germany alone, about 30 percent of the population has NAFL. NAFL does not cause any symptoms. However, about one in six NAFL patients develops fatty liver inflammation, known as non-alcoholic steatohepatitis (NASH).
If fatty liver inflammation becomes chronic, it leads to liver fibrosis. The collagenous connective tissue in the liver increases and the liver becomes scarred. Consequential diseases of fibrosis caused by steatohepatitis can be liver cirrhosis (shrinking liver), liver failure and even liver cell cancer. Treatment to date has initially been aimed at changing the diet of those affected and prescribing more physical exercise. Among other things, this is intended to achieve weight loss. This can improve NASH. As in the treatment of obesity, however, weight loss is often insufficient in most patients. There is currently no drug therapy available. Although numerous active substances are being researched, their approval has often failed due to insufficient efficacy or because they cause undesirable side effects.
“Together with the company Northsea Therapeutics, we have developed a potential drug for NASH and tested it extensively in vitro and in vivo with regard to its efficacy: the structurally modified omega-3 fatty acid icosabutate. This is a completely new class of substances. Icosabutate improved both liver inflammation and liver fibrosis. In an initial study with high-risk patients, a daily capsule of our active ingredient icosabutate normalized elevated blood levels of liver inflammation and liver fibrosis very convincingly and rapidly. Based on these promising results, a Phase 2b clinical trial (‘ICONA’) was initiated in the U.S. in which patients with severe NASH and liver fibrosis are treated with icosabutate over a period of one year. Here, treatment success will also be assessed by liver biopsy at baseline and at the end.”
– Univ.-Prof. Dr. Dr. Detlef Schuppan, Director of the Institute for Translational Immunology
The development of the new drug is based on known substances from fish oil, the omega-3 fatty acids. In addition to their positive effect on the cardiovascular system, omega-3 fatty acids are also involved in several processes that can regulate liver inflammation and fibrosis. This served as the starting point for the search for a drug that could treat chronic liver inflammation.
The challenge of creating an effective drug for NASH from omega-3 fatty acids is that omega-3 fatty acids are needed almost everywhere in the body for general energy metabolism. The liver also uses the fatty acids to produce energy and build its cells. As a result, omega-3 fatty acids are quickly used up by the body, which is why they no longer have sufficient potential to inhibit liver inflammation. The high doses of omega-3 fatty acids required for clinical efficacy are poorly tolerated and have undesirable side effects.
“In our substance icosabutate, we have changed the structure of the omega-3 fatty acid so that this active ingredient cannot be incorporated into the liver cells or consumed as ‘fuel’. Thus, there is enough unused icosabutate fatty acid in the liver to dampen inflammation and fibrosis. In this regard, the modified omega-3 fatty acid icosabutate is 50 times more potent than the natural omega-3 fatty acid. We are optimistic that the compound we have developed will lead to the first effective therapy with clear benefits for the many people affected by NASH. This would be another major success for the translational development of a drug from basic research into clinical application – a central goal of our Institute for Translational Immunology,” said Professor Schuppan.
Stabilization of plastic exhaust systems during implementation
According to the exhaust specialist ATEC from Neu Wulmstorf, the Vario roof flange can be mounted on all roofs with high fitting accuracy. The selection is based on the roof pitch and the required nominal size. In addition, the flange is suitable for temperature classes T200 and T250 – and ATEC has had this certified with a general design approval.
The new product combines two components: first, the flange itself, which provides a stable connection between the roof elevation and the roof structure, and second, the optional seal, a self-adhesive vapor retarder. The company provides two versions: for roof pitches between 0° and 30°, and from 30° to 60°, each in eight nominal sizes between DN60/100 and DN250/315. It is also compatible with plastic and metal exhaust systems up to a nominal operating temperature of ≤ 250 °C.
The flange consists of a stainless steel clamp to which two retaining lugs/articulated brackets are welded at the factory. This is accompanied by a cover plate measuring 450 x 450 mm and 0.5 mm thick. With the help of malleable perforated strips, the exhaust pipe together with the Vario roof flange is screwed into place. This allows the Vario to be used flexibly both in new buildings and in existing properties.
Modern user interface impresses international jury
SIG’s new intuitive Human Machine Interface (HMI) “SIG CRUISER” has been awarded the prestigious iF DESIGN AWARD 2022 in Gold – one of the most important design awards in the world. This part of SIG’s next-generation filling technology enables customers to easily control their entire production process. The user interface is designed to make the operator’s job much easier, while reducing the need for training and prior experience.
The award has been presented annually since 1954 by the iF Industrie Forum Design for outstanding achievements in product design. The company impressed the 132-member jury, which is made up of independent design experts from around the world, and won the award in the “User Interface (UI)” category. Out of nearly 11,000 entries, SIG CRUISER was awarded gold as one of 73 outstanding design achievements.
The judges made the following statement, “With a user-centric approach and sound development methodology, SIG CRUISER provides consistency from the store floor to the top floor, ensuring quick response times and convenience for both the operator and the service team. The user interface is exceptionally simple and user-friendly in terms of operations, layout and graphics, allowing a single operator to control the entire line.”
Today’s competitive environment requires companies to increase production and margins and optimize available equipment. To get the most out of filling lines, it is critical to reduce the risk of downtime and to interconnect, automate and monitor lines for maximum efficiency. The new user interface makes it possible to control the entire filling line. It displays KPIs in an intuitive way.
“This prestigious global design award is the result of the good cooperation between SIG and our partner, HMI Project GmbH. We are very proud that SIG CRUISER stood out from thousands of submissions and convinced the 132-member jury to award an iF DESIGN AWARD in Gold.”
– Stefan Mergel, Senior Product Manager Equipment
Innovative insights into emergence and classification into subtypes
One of the deadliest tumor types is pancreatic cancer . The disease is often only discovered in locally advanced or metastasized tumor stages, when surgical intervention comes too late. Researchers led by Dr. Ivonne Regel of LMU Klinikum in Munich have now gained important new insights into the causes of tumor development. They have also succeeded in defining different tumor subtypes based on differences in their metabolic programs. Funded by the Wilhelm Sander Foundation, they are thus making a significant contribution to early detection and to individualized medicine in order to improve the chances of recovery for pancreatic cancer patients.
Pancreatic ductal adenocarcinoma, also known as pancreatic cancer, is a relatively rare but particularly malignant disease. It represents the fourth leading cause of cancer-related deaths in the European Union, and only about 10 percent of patients survive the first five years after diagnosis. This is due to aggressive growth and late diagnosis of the tumor. Pancreatic cancer often manifests itself only after other organs have already been affected and metastases are present. To improve the chance of cure for pancreatic cancer patients, it is of great urgency to find new biomarkers for early detection. Another essential step is to identify tumor-specific signaling pathways that cause aggressive disease progression in order to identify new targets for therapeutic approaches.
TLR3/IRF3/IRF7 signaling pathway critical for pancreatic cancer development
Pancreatic cancer development is a dynamic process involving tissue damage and inflammatory response in the pancreas. When pancreatitis occurs, the organ has a self-healing mechanism. Normal pancreatic cells can divide to replace damaged tissue. Molecules released during inflammatory and tissue-damaging processes are recognized by cell receptors, relaying signals that promote cell survival and division.
However, in pancreatic cells, this can contribute to cell degeneration and promote the development of pancreatic cancer. Researchers led by Dr. Ivonne Regel were able to show for the first time that the signaling pathway plays an important role in inflammatory responses not only in immune cells, but is also active in pancreatic cells of precursor lesions and tumor cells. This activation of the signaling pathway has an important function in pancreatic cancer development. Genetically-altered mice lacking a functional signaling pathway are unable to develop pancreatic carcinomas (see Figure). Similarly, it was genetically knocked out in pancreatic tumor cells using CRISPR/Cas9 gene scissors. These genetically modified tumor cells exhibited significantly less aggressive behavior in cell culture experiments and also showed greatly reduced metastasis in animal models.
“For the first time, we were able to demonstrate that an active signaling pathway in pancreatic cells contributes to the development of pancreatic cancer and also supports the formation of metastases.”
– Ivonne Regel
Dr. Regel’s team has made another exciting discovery: In pancreatic tumor cells, the signaling pathway surprisingly does not regulate known target genes; instead, evidence was found for epigenetic modifications. These are regulatory modifications to DNA and packaging proteins (histones) that influence the activity of genes. Thus, the current research results indicate that activation of the signaling pathway in tumor cells leads to high levels of transcription of specific tumor-promoting genes.
These genes primarily regulate tumor cell metabolism. This is particularly important because metabolites of tumor cells can be found in the blood of patients and can be used as biomarkers. “My team and I have succeeded in identifying different subtypes of pancreatic cancer from the blood of cancer patients based on differences in their metabolic programs” said Dr. Regel. “In further studies, we now want to find out to what extent the development of pancreatic cancer subtypes is regulated by the signaling pathway.”