Category Archives: Medicine

Solid, Liquid, Or Gas? Technique Quickly Identifies Physical State of Tissues and Tumors (Medicine)

The method could be a route to quicker, less invasive cancer diagnoses.

As an organism grows, the feel of it changes too. In the initial stages, an embryo takes on an almost fluid-like state that allows its cells to divide and expand. As it matures, its tissues and organs firm up into their final form. In certain species, this physical state of an organism can be an indicator of its developmental stage, and even the general state of its health.

Now, researchers at MIT have found that the way in which a tissue’s cells are arranged can serve as a fingerprint for the tissue’s “phase.” They have developed a method to decode images of cells in a tissue to quickly determine whether that tissue is more like a solid, liquid, or even a gas. Their findings are reported this week in the Proceedings of the National Academy of Sciences.

The team hopes that their method, which they’ve dubbed “configurational fingerprinting,” can help scientists track physical changes in an embryo as it develops. More immediately, they are applying their method to study and eventually diagnose a specific type of tissue: tumors.

In cancer, there has been evidence to suggest that, like an embryo, a tumor’s physical state may indicate its stage of growth. Tumors that are more solid may be relatively stable, whereas more fluid-like growths could be more prone to mutate and metastasize.

The MIT researchers are analyzing images of tumors, both grown in the lab and biopsied from patients, to identify cellular fingerprints that indicate whether a tumor is more like a solid, liquid, or gas. They envision that doctors can one day match an image of a tumor’s cells with a cellular fingerprint to quickly determine a tumor’s phase, and ultimately a cancer’s progression.

“Our method would allow a very easy diagnosis of the states of cancer, simply by examining the positions of cells in a biopsy,” says Ming Guo, associate professor of mechanical engineering at MIT. “We hope that, by simply looking at where the cells are, doctors can directly tell if a tumor is very solid, meaning it can’t metastasize yet, or if it’s more fluid-like, and a patient is in danger.”

Guo’s co-authors are Haiqian Yang, Yulong Han, Wenhui Tang, and Rohan Abeyaratne of MIT, Adrian Pegoraro of the University of Ottawa, and Dapeng Bi of Northeastern University.

Triangular order

In a perfect solid, the material’s individual constituents are configured as an orderly lattice, such as the atoms in a cube of crystal. If you were to cut a slice of the crystal and lay it on a table, you would see that the atoms are arranged such that you could connect them in a pattern of repeating triangles. In a perfect solid, as the spacing between atoms would be exactly the same, the triangles that connect them would typically be equilateral in shape.

Guo took this construct as a template for a perfectly solid structure, with the idea that it could serve as a reference for comparing the cell configurations of actual, less-than-perfectly-solid tissues and tumors.

“Real tissues are never perfectly ordered,” Guo says. “They are mostly disordered. But still, there are subtle differences in how much they are disordered.”

Following this idea, the team started with images of various types of tissues and used software to map triangular connections between a tissue’s cells. In contrast to the equilateral triangles in a perfect solid, the maps produced triangles of various shapes and sizes, indicating cells with a range of spatial order (and disorder).

For each triangle in an image, they measured two key parameters: volumetric order, or the space within a triangle; and shear order, or how far a triangle’s shape is from equilateral. The first parameter indicates a material’s density fluctuation, while the second illustrates how prone the material is to deforming. These two parameters, they found, were enough to characterize whether a tissue was more like a solid, liquid, or gas.

“We’re directly calculating the exact value of both parameters, compared to those of a perfect solid, and using those exact values as our fingerprints,” Guo explains.

Vapor tendrils

The team tested its new fingerprinting technique in several different scenarios. The first was a simulation in which they modeled the mixing of two types of molecules, the concentration of which they increased gradually. For each concentration, they mapped the molecules into triangles, then measured each triangle’s two parameters. From these measurements, they characterized the phase of the molecules and were able to reproduce the transitions between gas, liquid, and solid, that was expected.

“People know what to expect in this very simple system, and this is what we see exactly,” Guo says. “This demonstrated the capability of our method.”

The researchers then went on to apply their method in systems with cells rather than molecules. For instance, they looked at videos, taken by other researchers, of a growing fruitfly wing. Applying their method, they could identify regions in the developing wing that morphed from solid to a more fluid state.

“As a fluid, this may help with growth,” Guo says. “How exactly that happens is still under investigation.”

He and his team also grew small tumors from cells of human breast tissue and watched as the tumors grew appendage-like tendrils — signs of early metastasis. When they mapped the configuration of cells in the tumors, they found that the noninvasive tumors resembled something between a solid and a liquid, and the invasive tumors were more gas-like, while the tendrils showed an even more disordered state. 

“Invasive tumors were more like vapor, and they want to spread out and go everywhere,” Guo says. “Liquids can barely be compressed. But gases are compressible — they can swell and shrink easily, and that’s what we see here.”

The team is working with samples of human cancer biopsies, which they are imaging and analyzing to hone their cellular fingerprints. Eventually, Guo envisions that mapping a tissue’s phases can be a quick and less invasive way to diagnose multiple types of cancer.

“Doctors typically have to take biopsies, then stain for different markers depending on the cancer type, to diagnose,” Guo says. “Perhaps one day we can use optical tools to look inside the body, without touching the patient, to see the position of cells, and directly tell what stage of cancer a patient is in”

This research was supported in part by the National Institutes of Health, MathWorks, and the Jeptha H. and Emily V. Wade Award at MIT.

Featured image: MIT researchers have developed a way to decode images of cells to determine whether a tissue is more like a solid, liquid, or even a gas. These visual “fingerprints” may help to quickly diagnose and track various cancers. Credit: breast cancer cell by Anne Weston, Francis Crick Institute, edited by MIT News

Provided by MIT

Researchers Pinpoint How PARP Inhibitors Combat BRCA1 and BRCA2 Tumor Cells (Medicine)

Key Takeaways

  • PARP inhibitors, used to treat patients with cancer of the breast, ovaries, prostate and pancreas, work by inducing persistent DNA gaps in tumor cells with BRCA1 and BRCA2 mutations.
  • The discovery offers the potential to monitor tumors for the development of resistance to PARP inhibitor therapy, and to identify drug combinations that could prevent drug resistance and improve the efficacy of cancer therapies.

This work finally explains why PARP inhibitors kill BRCA-mutant cells selectively.

— Zou Lee, PhD, Scientific co-director, Mass General Cancer Center 

A team of Massachusetts General Hospital (MGH) researchers has discovered how an important class of anti-cancer drugs called PARP inhibitors works, a finding that could help improve treatment and prolong survival for patients with breast cancer and other malignancies.

PARP (poly[ADP-ribose] polymerase) inhibitors such as olaparib (Lynparza), rucaparib (Rubraca) and niraparib (Zejula) are used to treat patients with cancers of the breast, ovaries, prostate and pancreas, and are particularly effective against tumors carrying mutations in the BRCA1 and BRCA2 tumor suppressor genes.

PARP inhibitors, like many other classes of anti-cancer drugs, are known to work by interfering with the ability of cancer cells to repair themselves after experiencing damage to their DNA, but exactly how PARP inhibitors selectively kill cancer cells was poorly understood.

But as Zou Lee, PhD, and colleagues found, PARP inhibitors work by creating gaps in tumor-cell DNA that remain present through multiple cell cycles (the process by which cells replicate: grow, divide, repeat). They also found that BRCA1/2 mutant cancer cells cannot respond to these gaps and therefore fail to repair properly, leading to the death of tumor cells. 

These findings provide a mechanistic explanation of the selectivity of PARP inhibitors toward cancer cells, and they also offer new opportunities to improve the use of PARP inhibitors in the clinic,” says Zou, scientific co-director of the Mass General Cancer Center and the Center for Cancer Research, and professor of Pathology at Harvard Medical School.

“This work finally explains why PARP inhibitors kill BRCA-mutant cells selectively,” he adds.

The research findings by Zou and colleagues Antoine Simoneau, PhD, and Rosalinda Xiong, both from the MGH Department of Pathology, are published in the journal Genes and Development.

The discovery has the potential to help clinical researchers better identify cells that are sensitive to PARP inhibitors, and to indentify potential mechanisms by which cancer cells may develop resistance to PARP inhibitors, Zou says.

“We can actually monitor BRCA-mutant cells during PARP inhibitor therapy, and then watch them if they change during the therapy, and then we can predict when they will become resistant to the drugs,” he explains.

Zou and colleagues propose development of a clinical test to determine whether BRCA-mutant cells are slowing in growth in the second cell cycle during PARP inhibitor treatment.

“We think that this slowdown is the reason for the development of resistance to PARP inhibitors. If the cells don’t slow down, they should be sensitive to the drugs, but if they do slow down they may be developing resistance,” he says.

Because the ability of BRCA-mutant cells to slow down and thus develop resistance to PARP inhibitors is dependent on a master checkpoint protein (kinase) labeled ATR, it should be possible to combine PARP inhibitors with another class of drugs in development that are designed to inhibit ATR, thereby preventing resistance to PARP inhibitors.

The work is supported by grants to Zou from the National Institutes of Health.

Reference: Antoine Simoneau, Rosalinda Xiong, Lee Zou. The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells. Genes & Development, 2021; DOI: 10.1101/gad.348479.121

Provided by Massachusetts General Hospital

Research Deepens Understanding of Rare Vaccine-Induced blood Clotting Condition (Medicine)

A national study involving UCL has deepened understanding of the symptoms, signs and outcomes of patients with a novel blood-clotting condition associated with the Oxford/AstraZeneca vaccine.

The rare condition, known as vaccine-induced immune thrombocytopenia and thrombosis (VITT), is characterised by a blockage of veins and a marked reduction of platelets, which are an important part of the blood clotting system. VITT was first identified in the UK by Professor Marie Scully (UCL Institute of Cardiovascular Science), also a Consultant Haematologist at UCLH, and Dr Will Lester from University Hospitals Birmingham NHS Foundation Trust.

The new research paper, published in the New England Journal of Medicine (NEJM), reports on the first 220 cases of definite and probable VITT in the UK.

The paper is based on cases of VITT presented by 182 consultant haematologists from 96 NHS Trusts, and builds on understanding about the condition outlined in an April 2021 NEJM paper led by Professor Scully which reported on 23 early cases of VITT.

Meanwhile, a study led by Dr Richard Perry (UCL Queen Square Institute of Neurology and UCLH) published in the Lancet earlier this month provided the most detailed observations so far of cases of cerebral venous thrombosis (CVT) caused by VITT. CVT is the commonest and severest manifestation of VITT.

In the latest paper, researchers found that the overall mortality rate of those presenting to hospitals with definite or probable VITT was 23%.

Almost all patients experienced the condition between five and 30 days after their first vaccination. There was no difference in incidence between the sexes, and no prior medical condition was seen more often than expected for the general population.

The chances of death increased significantly the lower the platelet count and the greater the activation of the blood clotting system, increasing to 73% in patients with a very low platelet count and intracranial haemorrhage following blood clots in the brain.

41% of patients had no previous medical diagnoses and 85% were less than 60 years old. Overall incidence in individuals under 50 was estimated to be 1 in 50,000 – consistent with reports from other countries.

Researchers said the optimal treatment was still uncertain, but that treatment approaches were being continually refined in real time. For instance, the introduction of the use of plasma exchange in the most severe cases has led to survival rates that were significantly better than would be predicted based on baseline characteristics.

In addition, the research provides further evidence that non-heparin-based blood thinners should be used to tackle blood clotting in cases of VITT, and that use of intravenous immunoglobin was associated with better outcomes.

Professor Scully said: “As a new condition we are still learning about how best to diagnose and manage VITT, but as time goes on, we have been able to refine our treatment approaches and improve rates of survival and chance of recovery. This continuous learning in real time has been made possible thanks to collaboration between colleagues across the UK.”

Dr Sue Pavord at Oxford University Hospitals (OUH) NHS Foundation Trust, lead author of the latest study, said: “We have worked relentlessly to understand and manage this new condition, so that the hugely successful vaccine roll out can continue, which is the most viable solution to the global pandemic.”


Blood clot. Credit: Anne Weston, Francis Crick Institute. CC BY-NC 4.0. Source: Wellcome Collection.

Link to paper:

Provided by UCL

Potential New Therapeutic Approach For Chronic Inflammatory Bowel Diseases (Medicine)

FAU research team identify messenger substance protecting cells in the intestine

Why people suffer from chronic inflammatory bowel diseases (IBD) such as ulcerative colitis is only partially understood. However, it is known that the bacteria of the intestinal flora and dysfunction in the immune system play an important role. In patients with IBD, an increased number of cells in the intestinal wall, known as epithelial cells, die. Bacteria then pass from the interior of the intestine into the damaged intestinal wall, causing inflammation and further cell death. The epithelial barrier, the barrier between the intestinal contents and the intestinal wall also becomes more permeable. With increasing cell death, the disease also progresses as more bacteria settle in the damaged intestinal wall – a vicious circle. A research team led by Prof. Dr. Christoph Becker from FAU has now found a mechanism that could prevent cell death, break the vicious circle and potentially be used as a therapy for inflammatory bowel diseases. The results have now been published in the renowned journal Nature Cell Biology.

In mice and tissues of ulcerative colitis patients, researchers found that a messenger substance called prostaglandin E2 can protect epithelial cells from a special form of cell death, necroptosis. Prostaglandins are hormone-like messenger substances that have various effects in the organism. Researchers have found that prostaglandins such as prostaglandin E2 are released in the body during inflammation. However, it is not yet fully understood how prostaglandins regulate inflammatory processes.

In recent years, the researchers have already shown that the incorrect regulation of necroptosis leads to cell death and thus to holes in the intestinal barrier. Prostaglandin E2 prevents this by binding to EP4 receptors on the epithelial cells. The more of these receptors are activated, the fewer cells die, according to the FAU team from the Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology – at Universitätsklinikum Erlangen. Patients with high levels of EP4 on the cell surface show a milder course of disease than patients with low levels of EP4.

The activation of the receptors by prostaglandin E2 thus counteracts the progression of intestinal inflammation. Together with colleagues in Canada, the research team tested an artificially produced molecule that can activate the EP4 receptor, like prostaglandin E2. Treatment with this molecule could prevent excessive cell death in the intestinal barrier and block bacteria from penetrating it. These findings offer a promising new therapy approach for ulcerative colitis and other chronic inflammatory bowel diseases.

Featured image: Microscopic image of a cultured intestinal epithelial cell with cell death programme activated (red). Pores form in the cell membrane (green) causing the cell to die. The nucleus is shown in blue. © FAU

Further information

Patankar, J.V., Müller, T.M., Kantham, S. et al. E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis. Nat Cell Biol 23, 796–807 (2021).

Provided by Friedrich-Alexander-Universität Erlangen-Nürnberg

Adoptive Cell Therapy Plus Checkpoint Inhibitors Show Promise in Non-small cell Lung Cancer (Medicine)

Immunotherapy has become an important tool in the treatment of lung cancer, especially checkpoint inhibitors that block certain immune checkpoints to allow immune cells to recognize and kill cancer cells. Several checkpoint inhibitors targeting PD-1 and PD-L1 have been approved for the treatment of non-small cell lung cancer. However, many patients do not respond well to this therapy creating a need for alternative treatment options.

Researchers in Moffitt Cancer Center’s Lung Cancer Center of Excellence believe a combination of checkpoint inhibitors with adoptive cell therapy could be the answer for these patients. Results of their investigator-initiated phase 1 clinical trial evaluating the checkpoint inhibitor nivolumab in combination with tumor infiltrating lymphocyte (TIL) therapy were published today in Nature Medicine.

Non-small cell lung cancer tumors are often categorized as a “cold” tumor, meaning the tumor has not been infiltrated with immune cells making it hard to mount a response to immunotherapy.

“These results really give hope to adding cell therapy to the armamentarium for treatment of lung cancer. The TILs give the immune system a boost by providing more T cells to mount an attack, and the checkpoint inhibitor prevents the tumor from inactivating the T cells that infiltrate the tumor,” said Eric Haura, M.D., associate center director of Clinical Science at Moffitt.

Twenty non-small cell lung cancer patients were enrolled in the pilot study. Each patient had one or more of their tumors removed. Those tumors were sent to the lab where each was dissected to remove the immune cells that had penetrated. These cells, called tumor infiltrating lymphocytes, were then cultured and expanded to be reinfused into the patient.

Before TIL therapy, each patient was treated with nivolumab. If the patient experienced disease progression after checkpoint inhibitory therapy, they were infused with their personalized TIL therapy followed by nivolumab maintenance therapy.

The researchers were able to successfully expand TILs for 95% of patients, and 16 out of 20 patients received the TIL infusion because their disease progressed after initial nivolumab therapy. The treatment combination resulted in promising anti-tumor activity, with 11 out of 16 patients experiencing tumor regression. Two patients had complete tumor responses that were ongoing after 18 months, and two patients had either a partial response or maintained clinical remission.

After treatment, the researchers performed additional studies and confirmed that the patients had T cells that were reactive to multiple different tumor specific proteins, including proteins with genetic mutations.

“Our data indicate that TIL can mediate effective tumor responses in subtypes that are not sensitive to traditional immune checkpoint targeted therapy. Therefore, we believe TIL may extend the scope and impact of immunotherapy into wider populations,” said Ben Creelan, M.D., associate member of the Department of Thoracic Oncology at Moffitt.

A new study is being developed to improve the TIL production and expand testing in oncogene- driven lung cancer patients whose tumors progressed on targeted agents. Ongoing work from the current study is determining why some patients respond best and why some tumors progress despite initial responses from TIL.

Reference: Benjamin C. Creelan et al, Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial, Nature Medicine (2021). DOI: 10.1038/s41591-021-01462-y

Provided by H. Lee Moffitt Cancer Center & Research Institute

Ultrasound Remotely Triggers Immune Cells to Attack Tumors in Mice Without Toxic Side Effects (Medicine)

Bioengineers at the University of California San Diego have developed a cancer immunotherapy that pairs ultrasound with cancer-killing immune cells to destroy malignant tumors while sparing normal tissue.

The new experimental therapy significantly slowed down the growth of solid cancerous tumors in mice.

The team, led by the labs of UC San Diego bioengineering professor Peter Yingxiao Wang and bioengineering professor emeritus Shu Chien, detailed their work in a paper published Aug. 12 in Nature Biomedical Engineering.

The work addresses a longstanding problem in the field of cancer immunotherapy: how to make chimeric antigen receptor (CAR) T-cell therapy safe and effective at treating solid tumors.  

CAR T-cell therapy is a promising new approach to treat cancer. It involves collecting a patient’s T cells and genetically engineering them to express special receptors, called CAR, on their surface that recognize specific antigens on cancer cells. The resulting CAR T cells are then infused back into the patient to find and attack cells that have the cancer antigens on their surface.

This therapy has worked well for the treatment of some blood cancers and lymphoma, but not against solid tumors. That’s because many of the target antigens on these tumors are also expressed on normal tissues and organs. This can cause toxic side effects that can kills cells—these effects are known as on-target, off-tumor toxicity.

“CAR T cells are so potent that they may also attack normal tissues that are expressing the target antigens at low levels,” said first author Yiqian (Shirley) Wu, a project scientist in Wang’s lab.

“The problem with standard CAR T cells is that they are always on—they are always expressing the CAR protein, so you cannot control their activation,” explained Wu.

To combat this issue, the team took standard CAR T cells and re-engineered them so that they only express the CAR protein when ultrasound energy is applied. This allowed the researchers to choose where and when the genes of CAR T cells get switched on.

“We use ultrasound to successfully control CAR T cells directly in vivo for cancer immunotherapy,” said Wang, who is a faculty member of the Institute of Engineering in Medicine and the Center for Nano-ImmunoEngineering, both at UC San Diego. What’s exciting about the use of ultrasound, noted Wang, is that it can penetrate tens of centimeters beneath the skin, so this type of therapy has the potential to non-invasively treat tumors that are buried deep inside the body.

The team’s approach involves injecting the re-engineered CAR T cells into tumors in mice and then placing a small ultrasound transducer on an area of the skin that’s on top of the tumor to activate the CAR T cells. The transducer uses what’s called focused ultrasound beams to focus or concentrate short pulses of ultrasound energy at the tumor. This causes the tumor to heat up moderately—in this case, to a temperature of 43 degrees Celsius (109 degrees Fahrenheit)—without affecting the surrounding tissue. The CAR T cells in this study are equipped with a gene that produces the CAR protein only when exposed to heat. As a result, the CAR T cells only switch on where ultrasound is applied.

The researchers put their CAR T cells to the test against standard CAR T cells. In mice that were treated with the new CAR T cells, only the tumors that were exposed to ultrasound were attacked, while other tissues in the body were left alone. But in mice that were treated with the standard CAR T cells, all tumors and tissue expressing the target antigen were attacked.

“This shows our CAR T-cell therapy is not only effective, but also safer,” said Wu. “It has minimal on-target, off-tumor side effects.”

The work is still in the early stages. The team will be performing more preclinical tests and toxicity studies before it can reach clinical trials.

Paper: “Control of the activity of CAR-T cells within tumours via focused ultrasound.” Co-authors include Yahan Liu, Ziliang Huang, Xin Wang, Jiayi Li, Linshan Zhu, Molly Allen, Yijia Pan, Robert Bussell, Aaron Jacobson, Thomas Liu and Shu Chien, UC San Diego; Zhen Jin, Shanghai Jiao Tong University, China; and Praopim Limsakul, Prince of Songkla University, Thailand.

This work was supported in part by the National Institutes of Health (grants HL121365, GM125379, GM126016, CA204704 and CA209629).

Disclosure: Peter Yingxiao Wang is scientific co-founder of and has financial interest in Cell E&G Inc. and in Acoustic Cell Therapy Inc., a company that aims to license the technology for further development. These financial interests do not affect the design, conduct or reporting of this research.

Reference: Wu, Y. et al, Control of the activity of CAR-T cells within tumours via focused ultrasound, Nat Biomed Eng (2021).

Provided by University of California – San Diego

Novel Nanotechnology Found To Enhance Fight Against Colorectal Cancer and Melanoma (Medicine)

A first-of-its-kind nanotherapeutic delivery system demonstrated remarkable efficacy against both early-stage and difficult-to-treat late-stage metastatic tumors.

University of Arizona Health Sciences researchers recently completed a study that has the potential to improve cancer treatment for colorectal cancer and melanoma by using nanotechnology to deliver chemotherapy in a way that makes it more effective against aggressive tumors. The findings were published today in Nature Nanotechnology.

“I’ve always been interested in harnessing the intrinsic immunity to fight against cancer,” said Jianqin Lu, BPharm, PhD, assistant professor of pharmaceutics and pharmacokinetics in the UArizona College of Pharmacy’s Department of Pharmacology and Toxicology and associate member of the UArizona Cancer Center. “To do this in a safe and effective way, nanotechnology comes into play because of its ability to improve drug movement and therapeutic efficacy, as well as the potential to reduce systemic toxicities. My hope is that these innovative nanotherapeutics and therapeutic regimens eventually will help cancer patients combat cancers more effectively and safely.”

Immunotherapies help boost the immune system’s ability to fight off cancer cells. Immune checkpoints are regulators of the immune system, which are pivotal in preventing the body from attacking healthy cells indiscriminately. Some types of cancer circumvent these checkpoints, allowing cancerous cells to avoid detection and continue to spread. Immune checkpoint blockade (ICB) is a newer therapy that can essentially “release the brakes” on the immune system and help the body fight back. 

ICB therapies are effective for some types of cancer, but they don’t work for every patient. For example, only approximately 4% of patients with colorectal cancer, the second leading cause of cancer-related deaths in U.S., will respond to ICB therapy, Dr. Lu said.

Recent research has focused on ways to enhance the power of ICB therapies by combining them with chemotherapeutic agents such as camptothecin. Though camptothecin is potent, it is also unstable, has poor solubility in water and can have serious side effects for healthy cells.

Dr. Lu and the research team created the first nanotherapeutic platform of its kind to overcome these hurdles. Using a nanotechnology delivery method, researchers enhanced camptothecin’s ability to synergize with ICB therapies, making them more effective against aggressive tumors. 

“To render a more effective ICB therapy, we have developed a nanotherapeutic platform that can switch the tumors from ‘immune-cold’ to ‘immune-hot,’” said Dr. Lu, who is also a member of the BIO5 Institute and the Southwest Environmental Health Sciences Center. “As a result, this nanotherapeutic platform was able to increase the effectiveness of the ICB therapy to eradicate a large portion of early-stage colorectal cancer tumors while concurrently activating the body’s memory immunity, preventing tumor recurrence.”   

The team attached camptothecin to sphingomyelin, a naturally occuring lipid found on the surface of cells. The combination of the two molecules into a nanovesicle called camptothesome stabilized camptothecin, improving its efficacy and diminishing systemic toxicities. The nanotech delivery method also improved the tumor uptake of the camptothesome in a rodent model, where it deeply penetrated the tumour with efficient release of the chemotherapy.

Dr. Lu and the research team then created a way to load an immune checkpoint inhibitor targeting one of the key checkpoints, indoleamine 2,3-dioxygenase (IDO1), inside of the camptothesomes. When combined with inhibitors targeting other immune checkpoints known as PD-L1 and PD-1, this nanotherapeutic strategy eliminated a significant portion of clinically difficult-to-treat late-stage metastatic colorectal cancer and melanoma tumors, paving the pathway for further studies.   

The researchers note that their nanotechnology platform can be used to deliver a range of cancer therapeutics, and it has a significant head start in the drug development pipeline as it is derived from sphingomyelin, a lipid that is already approved by the U.S. Food and Drug Administration.

Dr. Lu hopes to collaborate with oncologists at the UArizona Cancer Center to further optimize the nanotherapeutic system to make it suitable for an early phase clinical trial.

Co-authors include: Aaron James Scott, MD, associate professor in the UArizona College of Medicine – Tucson and member of the UArizona Cancer Center; and from the Department of Pharmacology and Toxicology, Zhiren Wang, PhD, a postdoctoral research associate; Weiguo Han, PhD, an assistant research professor; former PharmD student Nicholas Little; and former undergraduate students, Jiawei Chen, Kevin Tyler Lambesis, Kimberly Thi Le.

This research was supported in part by the National Institute of Environmental Health Sciences (P30 ES006694), a division of the National Institutes of Health, the National Cancer Institute (R01CA092596 and P30 CA023074), also a division of the National Institutes of Health, and the UArizona BIO5 Institute and Arizona’s Technology and Research Initiative Fund.

Reference: Wang, Z., Little, N., Chen, J. et al. Immunogenic camptothesome nanovesicles comprising sphingomyelin-derived camptothecin bilayers for safe and synergistic cancer immunochemotherapy. Nat. Nanotechnol. (2021).

Provided by University of Arizona Health Sciences

UCI Study Finds Targeting Mitochondria Shows Promise in Treating Obesity (Medicine)

Molecule that changes the shape of mitochondria corrects obesity

 A team of University of California, Irvine, scientists have discovered a novel pharmacological approach to attenuate the mitochondrial dysfunction that drives diet-induced obesity. The results of their study were published recently in the journal, EMBO Molecular Medicine.

Consuming a high-fat diet can lead to obesity and metabolic disorders such as diabetes and fatty liver. Palmitate, a fat abundant in a Western diet, triggers metabolic dysfunction by causing excessive mitochondrial fission within cells. Mitochondria play a crucial role in a cell’s energy production, but also coordinate cell stress responses. Too much mitochondrial fission impairs their function, undermining metabolism and increasing toxic by-products associated with insulin resistance in some tissue types.

“Elegant genetic studies in mice show that maintaining mitochondrial networks in a fused state can overcome high fat diet-induced obesity. Our study uses a small molecule to re-shape mitochondria in multiple tissues simultaneously, reversing obesity and correcting metabolic disease even though mice continue to consume the unhealthy diet,” said senior author Aimee Edinger, UCI Chancellor’s Fellow and professor of developmental & cell biology.

In their new study, Professor Edinger and her team utilized their patented water-soluble, orally bioavailable, synthetic sphingolipid SH-BC-893 to inhibit endolysosomal trafficking proteins required for mitochondrial fission. The study was conducted using in vitro experiments and a high-fat diet-induced obesity mouse model. The researchers observed that SH-BC-893 prevented mitochondrial dysfunction in the liver, brain, and white adipose tissue of mice consuming a Western diet. As a result, circulating levels of critical metabolic hormones, leptin and adiponectin, were normalized leading to weight loss, improved glucose handling, and reversal of fatty liver disease despite continued access to high-fat food.

“Imbalances in the hormones leptin and adiponectin that accompany obesity create an uphill battle for people trying to lose weight. Having too much leptin can increase appetite while too little adiponectin activity is linked to many metabolic diseases. How or why is not really clear, but the state of the mitochondria may be an important link between these hormones and obesity,” said Elizabeth Selwan, a former graduate student researcher in UCI’s Department of Developmental and Cell Biology and co-lead author of the study.

The study’s findings suggest that SH-BC-893 could be a promising therapy for managing diet-induced obesity. The authors found the drug to be safe and effective in the mouse model and plan on further investigating the compound for possible use in human patients. 

“This compound works through a novel mode of action – if it is safe and effective in humans, it would offer a new weight loss strategy that could also be combined with other treatments,” said Professor Edinger.

Researchers who contributed to this work were: Vaishali Jayashankar, Amandine Verlande, Maggie Goodson, Kazumi Eckenstein, Giedre Milinkeviciute, Brianna Hoover, Angela Fleischman, Karina Cramer and Selma Masri from the University of California, Irvine; Sarah Hancock and Nigel Turner from the University of New South Wales; and Bin Chen and Stephen Hanessian from the Université de Montréal. 

The study was supported by the University of California, Irvine, the National Institutes of Health, UCI Beall Applied Innovation, the National Health and Medical Research Council of Australia, the Concern Foundation for Cancer Research, the V Foundation for Cancer Research, and the U.S. Department of Education.  

The study, “Drug-like sphingolipid SH-BC-893 opposes ceramide-induced mitochondrial fission and corrects diet-induced obesity”, EMBO Mol Med (2021)13:e13086

Provided by University of Columbia Irvine

Researchers Identify New Gene Variants That Cause Hypertension in Pregnant Women (Medicine)

An international study, led by researchers from Queen Mary University of London and St Bartholomew’s Hospital, has found a unique pair of gene variants that causes sudden onset high blood pressure in pregnant women.null

The research in the UK was funded by the National Institute of Health Research, their EME program in partnership with the Medical Research Council, the British Heart Foundation and Barts Charity.

Hypertension (high blood pressure) affects 30% of adults. Most cases are caused by a combination of inherited and acquired factors that require long-term treatment to prevent the complications of stroke and heart attacks.

For one in ten people with hypertension, a specific cause can be found and removed. The most common cause is a tiny benign nodule in one of the adrenals. These are glands near the kidneys that produce steroid hormones. The hormone aldosterone stimulates the kidneys to retain salt and hence increase blood pressure. As a result the condition known as primary aldosteronism typically leads to a type of hypertension which is resistant to conventional drugs, and is linked to an increased risk of stroke and heart attacks compared to other patients with hypertension.

Over the years, a research team at Queen Mary University of London and St Bartholomew’s Hospital has found a number of gene variants which cause the production of high levels of aldosterone from small adrenal nodules. Their latest study, published today in the journal Nature Genetics, is the discovery of a new type of primary aldosteronism caused by the coincidence of a unique pair of new variants which always occur together. The patients are predominantly women, who present with sudden onset of high blood pressure and low blood potassium in the early months of a pregnancy.

In partnership with Professor Christina Zennaro, Inserm Research Director at the Paris Cardiovascular Research Center, and colleagues in Paris, it emerged that the new variants switch on a receptor molecule in the adrenal cells which recognizes the pregnancy hormone Human Chorionic Gonadotropin (HCG), the same as is measured in routine pregnancy testing—and that the receptor molecule triggers a surge of aldosterone production.

Professor Morris Brown, Professor of Endocrine Hypertension at Queen Mary University of London said: “What was particularly satisfying is that recognition of the cause of hypertension in these women enabled them to complete a successful pregnancy, and that afterwards they were completely cured of hypertension by a procedure to remove the adrenal nodule, and were able to stop all their drugs.”

Reference: Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause, Nature Genetics (2021). DOI: 10.1038/s41588-021-00906-y ,

Provided by Queen Mary, University of London