Sysmex Corporation and Siemens Healthcare Laboratory Diagnostics announced on April 13, 2016 an extension to their long-standing partnership through at least 2020. The contract extension adds a minimum of two additional years to the global supply, distributorship, and sales and service agreement for hemostasis products. The partnership enables laboratory customers around the world to continue to benefit from the largest portfolio of hemostasis systems and reagents. The companies, which began collaborating more than 20 years ago, also agreed to continue joint hemostasis product development activities that will streamline and optimize testing in laboratories throughout the world.

Siemens Healthcare and Sysmex provide hemostasis products used to test for blood clotting disorders, preoperative bleeding risk management, and the monitoring of patients on anticoagulant therapy medications. In the past few years alone, the companies have introduced several cutting-edge INNOVANCE reagents and multiple new platforms for various laboratory settings, including the recent worldwide launch of the Sysmex CS-2500 System, and the U.S. launch of the Sysmex CS-5100 System with optional track-based automation.

“We are pleased to extend our longstanding partnership with Siemens Healthcare,” said Hisashi Ietsugu, Chairman and CEO, Sysmex Corporation. “With the aging population, hemostasis testing has become even more important. Our partnership provides our customers with the innovative technologies needed to manage the increase in testing volumes, while providing accurate results for improved patient care.”

“The continued collaboration and twenty-year partnership between Siemens and Sysmex is rare in the rapidly changing world of diagnostics,” said Franz Walt, President, Siemens Healthcare Laboratory Diagnostics. “As a leader in hemostasis testing, our combined mission to offer best-in-class solutions has enabled us to meet the needs of diverse laboratories throughout the world.”

In early May Siemens Healthcare unveiled its new brand name Siemens Healthineers. The new brand underlines Siemens Healthcare’s pioneering spirit and its engineering expertise in the healthcare industry. It is meant to describe the healthcare organization and its people – the people accompanying, serving and inspiring customers – the people behind outstanding products and solutions. As part of its Vision 2020 strategy Siemens AG announced nearly two years ago that its healthcare business would be separately managed as a company within the company with a new organizational setup. Siemens Healthineers will continue to strengthen its leading portfolio across the medical imaging and laboratory diagnostics business while adding new offerings such as managed services, consulting and digital services as well as further technologies in the growing market for therapeutic and molecular diagnostics.

Cancerous tumours must be fed. Their unregulated growth requires a steady stream of blood flow and nutrients. Thus, one way that researchers have tried to wipe out cancer is to target cells undergoing the metabolic shifts that enable a tumour’s rapid growth.

Yet new findings from University of Pennsylvania researchers suggest that such efforts might have missed a key pathway that enables the changes in metabolism that benefit tumours. Their work finds that mitochondrial stress alone can trigger metabolic shifts through a pathway that involves p53, a protein widely known to play multiple important roles in cancer.

“In all five cancer cell lines we looked at, we saw that p53 was induced when mitochondrial function was affected,” said senior author Narayan Avadhani, the Harriet Ellison Woodward Professor of Biochemistry in Penn’s School of Veterinary Medicine’s Department of Biomedical Sciences. “This led to our discovery that it’s possible to promote tumour growth independent of the HIF-1α pathway, which had up to this point been a prime target of therapeutic interventions.”

The study points to a new factor that could inform our understanding of how cancer progresses. It’s possible that markers of metabolic stress could even serve as a biomarker for a cancer’s aggressiveness or likelihood to spread.

Avadhani teamed with Penn Vet’s Anindya Roy Chowdhury, the lead author and a research associate, and Serge Y. Fuchs, professor of cell biology, as well as Ph.D. student Apple Long and Anil Rustgi, the T. Grier Miller Professor of Gastroenterology, both of Penn’s Perelman School of Medicine. Avadhani and Fuchs are also members of Penn Vet’s Mari Lowe Center for Comparative Oncology Research.

Mitochondrial stress induces expression of nearly 120 genes involved in cell metabolism.
In earlier studies, Avadhani and colleagues had shown that disrupting mitochondria could lead to tumour growth. Mitochondria are often referred to as the “powerhouses” of cells because they produce ATP, the molecular energy currency that cells utilize to perform their diverse functions. In related work, the researchers had also observed that subjecting mitochondria to stress also triggered an increase in p53 but, until now, hadn’t conducted follow-up on that finding.

Because p53 is mutated in nearly 50 percent of human cancers, it is widely believed to have a tumour-suppressor function. The researchers decided to take a more detailed look into the connection between mitochondrial stress and p53.

They experimentally depleted mitochondrial DNA to induce mitochondrial stress in six cell lines, including several cancer cell lines, and found that p53 levels increased in response to the mtDNA depletion in each type of cell. Because HIF-1α activity is known to play both complementary and contradictory roles in cancer to p53, they next looked to see how that protein responded. They found that p53 inhibited HIF-1α activity.

Looking specifically at a human colon cancer cell line in which p53 was experimentally deleted, they again found a relationship with HIF-1α: Its activity was six-times higher in the colon cancer cell line with p53 depleted than in the wild type colon cancer cell line, a further indication that p53 inhibits HIF-1α.

To ensure that this was not strictly associated with depletion of mitochondrial DNA, the researchers induced mitochondrial stress using other means, including with chemicals agents and by disrupting the membrane, and found that all induced p53.

Further investigation revealed that p53 reduced HIF-1α levels in the nucleus and the cytoplasm of cells and that genes responsive to HIF-1α were blunted when mitochondrial DNA was depleted. Notably, they found that the expression of several genes involved with glycolysis, a metabolic process by which cells break down sugar to make energy, jumped dramatically in cells in which mtDNA was depleted. Some of these were the same genes that HIF-1α normally regulates, pointing to mitochondrial stress as a similar but completely separate pathway by which a metabolic shift can occur in cancer cells.

Finally, the team demonstrated that, in cells with depleted mtDNA, p53 physically interferes with HIF-1α by preventing it from binding to gene promoters that it would normally and by promoting ubiquitination of HIF-1α, a process that tags the protein for degradation in the cell.

The findings point to a new direction and possible new targets for preventing the metabolic shift that can foster a supportive environment for cancer growth.

Penn’s School Veterinary Medicine www.vet.upenn.edu/about/press-room/press-releases/article/penn-team-finds-mitochondrial-stress-induces-cancer-related-metabolic-shifts

A small stretch of ribonucleic acid called microRNA could make the difference between a healthy adult brain and one that’s prone to disorders including schizophrenia.

Scientists at the Salk Institute discovered that miR-19 guides the placement of new neurons in the adult brain, and the molecule is disrupted in cells from patients with schizophrenia. The findings pave the way toward a better understanding of how the adult brain controls the growth of new neurons and how it can go wrong.

“This is one of the first links between an individual microRNA and a specific process in the brain or a brain disorder,” says senior author Rusty Gage, professor in Salk’s Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.

While most RNA molecules contain the instructions for making proteins—the physical workhorses of cells—microRNAs don’t encode proteins. Instead, they’re active themselves, binding to other strands of RNA to block them from creating proteins. Previously, scientists have shown that levels of microRNA molecules are altered in brain disorders but not which microRNAs are responsible.

“People have broadly studied microRNAs in the brain quite a bit,” says Jinju Han, a senior research associate at Salk and first author of the new paper. “But there are more than 2,000 microRNAs and only a few have been looked at in any depth.”

In a few discrete areas of the human brain, new cells can emerge during adulthood. Gage, Han and their colleagues found that levels of miR-19 changed more than levels of any other microRNA when precursors to new brain cells in these areas (called neural progenitor cells) were coaxed to become neurons in the adult brain.

“The microRNA miR-19 has been implicated in cancer and people never thought it was related to the brain,” says Han. “But we saw that its levels changed quite dramatically when stem cells differentiated into neurons.”

The researchers went on to show that when miR-19 was blocked in neural progenitor cells, levels of RNA corresponding to a gene called Rapgef2 were altered. Moreover, new neurons did not migrate to the correct areas of the brain.

Because the incorrect migration of new brain cells has been implicated in neuropsychiatric disorders like schizophrenia, Gage’s group next analysed the levels of miR-19 and Rapgef2 in neural progenitor cells that had been created by reprogramming skin cells from schizophrenic patients. Although the patients had no mutations in the gene for Rapgef2, they had high levels of miR-19 that corresponded with low levels of both the RNA and protein for Rapgef2. The team is now studying the role of miR-19 in mouse models of schizophrenia, as well as looking at cells from broader cohorts of human patients.

Because miR-19 has been linked to cancers—including breast cancer, prostate cancer and B cell lymphoma—researchers have already been working to develop drugs that block the molecule. But the new results, Han says, suggest that such drugs could have an effect on the brain. “This means that if miR-19 is being targeted in cancer, effects on the brain need to be carefully considered,” she says. “But it also means that people might use these therapies to treat neuropsychiatric disorders.” More work is needed, though, to see whether the results hold true in humans.

Salk Institute www.salk.edu/news-release/small-molecule-keeps-new-adult-neurons-from-straying-may-be-tied-to-schizophrenia/

Scientists have captured new images of a calcium-shuttling molecule that has been linked to aggressive cancers. The three-dimensional structure could help researchers develop novel therapies and diagnostic tools for diseases that are caused by a malfunction in calcium adsorption.

Alexander Sobolevsky’s lab at Columbia University Medical Center is studying a family of proteins called “Transient receptor potential (TRP)” channels. These proteins line surfaces inside the body, such as the intestine, and form pores that help calcium cross a dense barrier of lipid and protein called the membrane to reach the interior of the cell.

“Scientists have found that a TRP channel variant, called TRPV6, is present in excess amounts in the tumour cells of some cancer patients,” says senior author Alexander Sobolevsky, PhD, who is an assistant professor in the Department of Biochemistry and Molecular Biophysics at Columbia University Medical Center. “And patients who have higher quantities of TRPV6 seem to have a more aggressive form of the disease.”

In order to uncover how these channels guide calcium into the cell, and how disease can occur when this process becomes unregulated, Sobolevsky’s lab used a technique called X-ray crystallography. This process involved growing crystals of TRPV6 and exposing them to an X-ray beam. The scientists then used the diffraction pattern produced by the X-rays to map out a 3D model of the protein.

The structure—which represents a single frozen state of the channel—reveals that the surface of TRPV6 pore is lined with negative charges. This configuration helps attract calcium ions, which are positively charged. The calcium ions are then shuffled from location to location inside of the pore, up to three molecules at a time, as they pass through into the cell.

“In future, we could use this model to design drugs that can target some types of tumour cells by plugging up TRP channels on their surfaces,” says Sobolevsky.

Ordinarily the calcium ingested from our diet is used by the body to regulate a variety of processes including the beating of the heart, muscle contractions, and brain signalling. In addition to various forms of cancer, altered calcium uptake and TRPV6 expression has also been linked to Crohn’s and kidney stone diseases in mouse models. Further research needs to be done to determine the extent that alteration in TRP channel activity leads to disease progression.

Columbia University Medical Center newsroom.cumc.columbia.edu/blog/2016/07/15/new-structure-calcium-shuttling-molecule-help-scientists-target-aggressive-cancers/