Category Archives: Cell Medicine

Experiments from the UNC School of Medicine lab of Nobel Prize-winning scientist Aziz Sancar, MD, PhD, show how a common molecular tool for DNA labeling also has anticancer properties worthy of further investigation, especially for brain cancers.

CHAPEL HILL, NC Scientists at the UNC School of Medicine have made the surprising discovery that a molecule called EdU, which is commonly used in laboratory experiments to label DNA, is in fact recognized by human cells as DNA damage, triggering a runaway process of DNA repair that is eventually fatal to affected cells, including cancer cells.

The discovery, published in the Proceedings of the National Academy of Sciences, points to the possibility of using EdU as the basis for a cancer treatment, given its toxicity and its selectivity for cells that divide fast.

The unexpected properties of EdU suggest it would be worthwhile to conduct further studies of its potential, particularly against brain cancers, said study senior author Aziz Sancar, MD, PhD, the Sarah Graham Kenan Professor of Biochemistry and Biophysics at the UNC School of Medicine and member of the UNC Lineberger Comprehensive Cancer Center. We want to stress that this is a basic but important scientific discovery. The scientific community has much work ahead to figure out if EdU could actually become a weapon against cancer.

EdU (5-ethynyl-2-deoxyuridine) is essentially a popular scientific tool first synthesized in 2008 as an analog, or chemical mimic, of the DNA building block thymidine which represents the letter T in the DNA code of adenine (A), cytosine (C), guanine (G) and thymine (T). Scientists add EdU to cells in lab experiments to replace the thymidine in DNA. Unlike other thymidine analogs, it has a convenient chemical handle to which fluorescent probe molecules will bond tightly. It thus can be used relatively easily and efficiently to label and track DNA, for example in studies of the DNA replication process during cell division.

Since 2008, scientists have used EdU as a tool in this way, as published in thousands of studies. Sancar, who won the 2015 Nobel Prize for Chemistry for his seminal work on DNA repair, is one such scientist. When his lab began using EdU, his team unexpectedly observed that EdU-labeled DNA triggered a DNA repair response even when it wasnt exposed to DNA-damaging agents, such as ultraviolet light.

That was quite a shock, Sancar said. So we decided to explore it further.

Following up on the strange observation, the team discovered that EdU, for reasons that are still unclear, alters DNA in a way that provokes a repair response called nucleotide excision repair. This process involves the removal of a short stretch of damaged DNA and re-synthesis of a replacement strand. This is the mechanism that repairs most damage from ultraviolet light, cigarette smoke, and DNA-altering chemo drugs. The researchers mapped EdU-induced excision repair at high resolution and found that it occurs across the genome, and it apparently occurs again and again, since each new repair strand includes EdU and thus provokes the repair response anew.

It had been known that EdU is moderately toxic to cells, though the mechanism of its toxicity had been a mystery. The teams findings strongly suggest that EdU kills cells by inducing a runaway process of futile excision repair, which ultimately leads the cell to terminate itself through a programmed cell-death process called apoptosis.

That discovery was interesting in its own right, Sancar said, because it suggested that researchers using EdU to label DNA need to take into account its triggering of runaway excision repair.

As we speak, hundreds and maybe thousands of researchers use EdU to study DNA replication and cell proliferation in lab experiments without knowing that human cells detect it as DNA damage, Sancar said.

Sancar and colleagues also realized that EdUs properties might make it the basis for an effective brain cancer drug because EdU becomes incorporated into DNA only in cells that are actively dividing, whereas, in the brain, most healthy cells are non-dividing. Thus, in principle, EdU could kill fast-dividing cancerous brain cells while sparing non-dividing, healthy brain cells.

Sancar and his team hope to pursue follow-up collaborations with other researchers to investigate EdUs properties as an anticancer agent.

Prior studies have already found evidence that EdU kills cancer cells, including brain cancer cells, but strangely, no one has ever followed up on those results, Sancar said.

Nucleotide excision repair removes thymidine analog 5-ethynyl-2-deoxyuridine from the mammalian genome was co-authored by Li Wang, Xuemei Cao, Yanyan Yang, Cansu Kose, Hiroaki Kawara, Laura Lindsey-Boltz, Christopher Selby, and Aziz Sancar. Funding was provided by the National Institutes of Health (GM118102, ES02755).

Media contact: Mark Derewicz, UNC School of Medicine, 919-923-0959

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Scientists Discover Surprise Anticancer Properties of Common Lab Molecule | Newsroom - UNC Health and UNC School of Medicine

1. There was no difference in median overall survival between minimal follow-up and CT-based follow-up groups.

2. Disease-free survival was not significantly different between minimal follow-up and CT-based follow-up groups.

Evidence Rating Level: 1 (Excellent)

Study Rundown: For patients with non-small-cell lung cancer (NSCLC) who meet the guidelines, the standard of care is to receive surgical resection of their tumour(s). Regardless, there is a high risk of recurrent disease and lung cancer is the primary cause of death in this population. This randomized controlled study aimed to compare the outcomes between CT-based surveillance and minimal follow-up measures post-surgical resection of NSCLC tumours. The primary outcome of interest was overall survival (OS) and secondary outcomes included disease-free survival. In the minimal follow-up group, 44.9% of patients died, compared to 42.0% of those in the CT-based group. There was no significant difference between the groups for median OS; 8.5 years for the minimal follow-up group and 10.3 years for the CT-based group. There was similarly no difference statistically between the groups for disease-free survival. There were 404 recurrences, second primary cancers, or deaths in the minimal follow-up group, compared to 440 in the CT-based group. Limitations to this study include the high proportion of patients who had stage I and I NSCLC that contributed to less OS events and reduced power of the study. Additionally, the study excluded patients who had received wedge resections, so applications of the results from this study should be considered cautiously in those patient groups. Overall, the results from this study provide evidence that the inclusion of CT scan for follow-up post surgical intervention for non-small-cell lung cancer does not improve overall survival as compared to minimal follow-up strategies that include chest x-ray.

Click to read the study in The Lancet Oncology

Relevant Reading: Let us not underestimate the long-term risk of SPLC after surgical resection of NSCLC

In-Depth [ randomized controlled trial]: This open-label, phase 3, randomized controlled trial was conducted out of 122 healthcare centres in France. The study enrolled 1,775 adult patients to receive one of two follow-up options; 888 were allocated to the minimal follow-up group, consisting of chest x-ray, and 887 were allocated to receive CT-based follow-up, which included chest x-rays, thoraco-abdominal contrast-enhanced CT scan, and fibre-optic bronchoscopy. Patients had received their surgical resections within the previous 8 weeks of enrollment. The median OS for patients in the minimal follow-up group was 8.5 years (95% confidence interval (CI), 7.4-9.6 years) compared to 10.3 years (95% CI, 8.1 not reached) for patients in the CT-based group (hazard ratio (HR) 0.95, 95% CI, 0.83-1.10). There were also no differences between 3- and 5-year OS rates between the groups. Three year OS for the minimal follow-up group was 77.2% (95% CI, 74.5-80) vs 76.1% (95% CI, 73.3-78.9) for the CT-based group. The median OS after 5 years for the minimal follow-up group was 66.8% (95% CI, 63.7-69.0) vs 65.8% (95% CI, 62.6-68.9) for the CT-based group. There was no significant difference between groups for disease-free survival; 4.9 years (95% CI, 4.3-not reached) in the CT-based group compared to median not reached (95% CI not reached-not reached) in the minimal follow-up group (adjusted HR 1.14; 95% CI, 0.99-1.30).

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Overall survival is similar for patients receiving CT-based or minimal follow-up after surgical resection of non-small-cell lung cancer - 2 Minute...

Researchers at Oregon State Universitys Carlson College of Veterinary Medicine are moving forward with developing a specialized antibody treatment for dogs with cancer, thanks to a recent grant from the National Science Foundation.

The research team plans for this treatment to be a gentler, more targeted and effective option for addressing canine cancer, just as immunotherapeutics are used in human cancer patients.

Its not a drug like chemotherapy where its a toxin. Youre actually recruiting the bodys natural immune response for clearing out transformed cells for instance, a tumor and then it kills them, said Dan Mourich, senior OSU research associate and the molecular biologist on the research team.

Currently, veterinarians can use radiation, chemotherapy and surgery to tackle canine cancer, but these typically involve frequent trips to veterinary hospitals where the dog must be sedated, and can take a physical and emotional toll on both pets and owners, Mourich said.

In contrast, the OSU therapy will be administered daily in the home as a small subcutaneous injection, similar to how pet owners with diabetic animals inject them with insulin.

The research team includes Dr. Chris Cebra, camelid expert and the chair of the clinical sciences department in OSUs veterinary college; former OSU professor and clinical veterinary oncologist Dr. Shay Bracha, who recently joined the Ohio State University Veterinary Medical Center; and Carl Ruby, veterinary pharmacology instructor at OSU.

The treatment was developed with help from some unlikely collaborators: the llamas and alpacas that OSU owns, which are both members of the camelid family. Researchers injected them with a protein found in canine tumors, which provoked the alpacas immune system to respond by creating a specific antibody.

The researchers then screened a genetic library of the resultant antibodies to determine which were most effective at binding and blocking tumors from interacting with that protein on dogs cytotoxic killer T-cells, the cells responsible for fighting cancer.

Killer T-cells are essentially the smallest scalpel you can have, Mourich said. They identify the cancer cell, remove that cell and leave healthy tissue alone. Theyre so precise that you can utilize them to go and eliminate all the little pieces of tumor around the body.

Camelids can produce a specialized smaller type of antibodies referred to as nanobodies.

Their smaller structure allows nanobodies to penetrate tissues that arent accessible to larger antibodies, and also makes them easier to produce and store for long periods of time, which reduces the overall cost.

The $250,000 grant from the National Science Foundation Partnership for Innovation will allow the researchers to develop their clinical candidate and establish a production method for the treatment, after which they can hold a clinical trial to test its effectiveness.

The efficacy of immune-based therapeutics has already been tested in the human clinic for cancer and other diseases, but were not going to take human drugs and try to adapt them to the dog, Mourich said. Were going to make the dog drug that does the same thing.

Read this article:
NSF Grant to Aid OSU Researchers Developing Treatment for Canine Cancer - The Corvallis Advocate

When fat accumulates in the liver, the immune system may assault the organ. A new study from Weill Cornell Medicine researchers identifies the molecule that trips these defenses, a discovery that helps to explain the dynamics underlying liver damage that can accompany type 2 diabetes and obesity.

In a study published Aug. 19 in Science Immunology, researchers mimicked these human metabolic diseases by genetically altering mice or feeding them a high-fat, high-sugar diet. They then examined changes within the arm of the rodents immune system that mounts defenses tailored to specific threats. When misdirected back on the body, this immune response, which involves B and T cells, damages the organs and tissues it is meant to protect.

For the longest time, people have been wondering how T and B cells learn to attack liver cells, which are under increased metabolic stress due to a high fat high sugar diet, said lead investigator Dr. Laura Santambrogio, who is a professor of radiation oncology and of physiology and biophysics, and associate director for precision immunology at the Englander Institute for Precision Medicine at Weill Cornell Medicine. We have identified one protein probably the first of many that is produced by stressed liver cells and then recognized by both B and T cells as a target.

Back row from left to right: Madhur Shetty; Marcus DaSilva Goncalves; Laura Santambrogio; Lorenzo Galluzzi; Aitziber Buqu. Front row from left to right: Jaspreet Osan; Shakti Ramsamooj; Cristina Clement; Takahiro Yamazaki

The activation of the immune system further aggravates the damage already occurring within this organ in people who have these metabolic conditions, she said.

In type 2 diabetes or obesity, the liver stores an excessive amount of fat, which can stress cells, leading to a condition known as nonalcoholic steatohepatitis, commonly called fatty liver disease. The stress leads to inflammation, a nonspecific immune response that, while meant to protect, can harm tissue over time. Researchers now also have evidence that B and T cells activity contributes, too.

B cells produce proteins called antibodies that neutralize an invader by latching onto a specific part of it. Likewise, T cells destroy infected cells after recognizing partial sequences of a target protein. Sometimes, as happens in autoimmune diseases, these cells turn on the body by recognizing self proteins.

Dr. Santambrogio and her colleagues, including Dr. Lorenzo Galluzzi, assistant professor of cell biology in radiation oncology at Weill Cornell Medicine and Dr. Marcus Goncalves, assistant professor of medicine at Weill Cornell Medicine and an endocrinologist at NewYork-Presbyterian/Weill Cornell Medical Center, as well as researchers from Dr. Lawrence Sterns group at the University of Massachusetts Medical School, wanted to know what molecule within liver cells became their target.

Examining the activity of another type of immune cell, called dendritic cells, led them to a protein, called PDIA3, that they found activates both B and T cells. When under stress, cells make more PDIA3, which travels to their surfaces, where it becomes easier for the immune system to attack.

While these experiments were done in mice, a similar dynamic appears to be at play in humans. The researchers found elevated levels of antibodies for PDIA3 antibodies in blood samples from people with type 2 diabetes, as well as in autoimmune conditions affecting the liver and its bile ducts.

Unlike in autoimmune conditions, however, improving ones diet and losing weight can reverse this liver condition. The connection with diet and a decrease in fatty liver disease was already well established, Dr. Santambrogio said.

We have added a new piece to the puzzle, she said, by showing how the immune system starts to attack the liver.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosurespublic to ensure transparency. For this information, see profiles for Dr. Lorenzo Galluzzi and Dr. Marcus Goncalves.

More here:
Researchers Identify the Target of Immune Attacks on Liver Cells in Metabolic Disorders - Weill Cornell Medicine Newsroom

Announcer:Welcome to CU Anschutz 360, a podcast about the CU Anschutz Medical Campus.

Today's installment focuses on a promising breakthrough therapy for patients with large B-cell lymphoma, an aggressive subtype of lymphoma. In a clinical trial for relapsed patients, or patients who didn't respond to treatment initially, CAR T-cell therapy with lisocabtagene maraleucel, or liso-cel, showed significant improvement in keeping patients in remission when compared to the standard of care, which consisted of chemotherapy followed by stem-cell transplantation.

Our guest is Dr. Manali Kamdar, associate professor and clinical director of the lymphoma program in the Division of Hematology at the University of Colorado School of Medicine and a member of the CU Cancer Center. Dr. Kamdar led this groundbreaking study, which was a phase III global clinical trial known as TRANSFORM.

Co-hosting our discussion today are Dr. Thomas Flaig, CU Anschutz's vice chancellor of research, and Chris Casey, director of digital storytelling in the Office of Communications.

Manali Kamdar:Hi everyone. My name's Manali Kamdar. I am an associate professor and the clinical director of the lymphoma program within the Division of Hematology. I am a member of the CU Cancer Center. Looking forward to talking to you today.

Chris Casey:Terrific. And thanks for being here both Dr. Flaig and Dr. Kamdar. Dr. Kamdar, could you start us off by just giving a broad overview of lymphoma?

Manali Kamdar:Sure. So lymphoma is the most common blood cancer. It accounts for the fifth-most common cancer in the United States, so that makes up for about 80,000 patients in the United States. And lymphoma is not really one disease it's made up of nearly 85 different subtypes. So to really understand how to manage lymphomas, it's really important to understand what subtype of lymphoma because the management is very nuanced.

Just to briefly talk about the subtypes, they're primarily divided into aggressive lymphomas and non-aggressive lymphomas. And then the others, where there is a mix of non-aggressive going into aggressive. The current unmet need within the world of aggressive lymphomas is the fact that whenever we have a patient with aggressive lymphoma the frontline therapy is always intensive chemotherapy.

The good news is that we can actually cure at least 40 to 50% of patients, which basically makes the remainder either respond initially to relapse later, or not respond at all. So, that's an unmet need where we need to do better. And in patients with non-aggressive lymphomas, it's basically living with a chronic disease wherein therapies work but, so far whatever we have, these therapies don't have as much of a durability. So, we want to make sure that in these patients, if we are treating it as a chronic disease, we hope to give them treatments that are efficacious, durable, as well as less toxic. So, these are some of the unmet needs within lymphomas as a whole.

Thomas Flaig:Yeah, so it's great to have you here today, by the way. And I've been looking forward to this conversation since we first started talking about it.

So, I'm an oncologist by training. I treat urologic cancers, but, from my perspective in that realm, lymphomas are incredibly complicated. And the therapies are incredibly difficult at times. Or I would say intense the therapies we give people. CAR T therapy is something that's been introduced. It's been used in a variety of hematologic tumors. What we're going to talk about today is your work in CAR T therapy in lymphoma. Can you just say a few words though, for the audience, just in general, about CAR T therapies. What is it? How's it being used now?

Manali Kamdar:Absolutely. And may I digress, you are probably one of the best urological oncologists I've seen. I've referred so many patients to you. And we have co-shared a lot of patients.

But coming back to the topic of CAR T-cell therapy. It has been, in my opinion, the most promising breakthrough in the world of hematologic malignancies, particularly lymphomas. Historically, we have had patients who would have succumbed to their disease. And I would say within the subtype of aggressive lymphomas, about 40 to 50% of patients, would've succumbed to their cancer. So, as you can imagine, there is certainly a lot of promise within this treatment.

So, to really cut it down into non-medical terms, what is CAR T? So, as a way of background, we all have what we call fighter cells within our immunity, or our immune system, which have the ability to recognize foreign antigens, such as cancer, as an enemy. And we can identify certain proteins on these cancer cells as foreign, and basically kill it. In patients with lymphoma, the issue is that the ability to recognize these proteins on the cancer cells as foreign is lost by the patient's own fighter cells.

There are many fighter cells such as T cells, NK cells, macrophages. CAR T-cell therapy is basically a therapy which typically manipulates this inability to fight off cancer. So, what CAR T-cell therapy is, is that we take patients' own cells, we take them to the lab. And we isolate their fighter cells, which are T-cells. Now, we know that these T cells have lost the ability to fight off cancer, which is lymphoma. So, we genetically engineer them in such a way that we make them super-fighter cells. Basically, fighter cells will unleash on them, which can now recognize lymphoma cells as foreign.

This manufacturing takes about 3 to 4 weeks with the existing FDA approved constructs. Once we get the cell product back, we then give patients low-dose chemotherapy for 3 days, not to kill cancer, but basically to make space in the marrow so that these CARs can hone in on the marrow. The product is then infused and then, subsequently, the idea is that these T-cell or CAR T-cell, which are your super-fighter cells unleash upon the enemy here, the lymphoma cell, and destroy it. And that is the mechanism of how CAR T-cell therapy works.

Thomas Flaig:Yeah, I think one of the really striking things about this as I've kind of watched this, and it's not used in solid organs like prostate cancer, and colon cancer, has been this idea that it's an individual product. We talk about manufacturing, but it's essentially taking their cells, making these changes and re-infusing them in.

Manali Kamdar:Absolutely. I think it's one of the most phenomenal advances in science. And, I will have to say, some of the early work happened nearly three decades ago, but those CAR T constructs were preliminary because we could make them efficacious, but we couldn't make them last in the system. The idea is when we infuse these CARs they give memory to the existing T cells of the patients as well, and make them fighter cells and thus, wait off cancer forever. Over the last 4 1/2 years, there has been a lot of work with CAR T-cell therapy constructs. And I will have to say the leadership at the CU Cancer Center within the University of Colorado has been exceptionally supportive in helping us open some of the key clinical trials within patients for aggressive, large B-cell lymphoma, as well as for non-aggressive B-cell lymphoma. And I will have to say that I'm very proud that most of these clinical trials have been positive studies, thus leading to FDA approval.

What does it mean to really get on a clinical trial with CAR T? That basically means that our patients who enrolled on the trial had the ability to get this product at least 4 1/2 years before the FDA approved it. So, that is where we got an edge for our patients to be able to first tackle cancer. Number two, be in remission. And most of our patients are still in remission. Thus, basically, getting the advantage of the therapies through the clinical trials.

Thomas Flaig:So, maybe we could just shift gears a little bit with that great background on this complex topic and, frankly, a complex disease. And so, when the CAR T therapy, or any new therapies come into practice, they're typically integrated in the later stages of the disease, where there's fewer therapeutic options. And then, as we gain experience and learn about efficacy, we move things forward, and care for patients. So, there's recently an article in which you were the lead author looking at the use of CAR T therapy in specific lymphomas, which had, I think, a major impact. We'd like to hear more about that, if you could tell us?

Manali Kamdar:Absolutely. We are so pumped about the positive results from this trial. That again, as way of background, as Dr. Flaig just mentioned, CAR T-cell therapy previously has been FDA approved for patients with aggressive, large-cell lymphoma who have failed two lines of treatment. What that means is patients who have failed chemotherapy after chemotherapy, or patients who have failed an autotransplant. An autotransplant is basically chemo times seven. That's the intensity of the autotransplant.

So, clearly, if a product works for patients who have failed an autotransplant, intuitively within the world of science, we'd like to move it forward. As a result, the next advance was to really test the current standard of care for relapsed aggressive, large B-cell lymphoma is that we give patients more chemotherapy. And, if they respond, then we take them to an autotransplant. Unfortunately, patients with high-risk, large B-cell lymphoma who have relapsed, although the intention is to take them to an autotransplant, only about a quarter are able to successfully go through the procedure. As a result, most of these patients will succumb to their disease. Or get CAR T in the third-line setting.

So clearly, the next advance was to prove and find out if CAR T can take over autotransplant in the second-line setting. And this is where I will have to say, again, thanks to the leadership within University of Colorado and the Division of Hematology, we opened a clinical trial here, which was called the TRANSFORM study. The TRANSFORM study uses a CAR T construct called lisocabtagene maraleucel. And this construct was compared head-to-head with an autotransplant in patients with high-risk, relapsed, large B-cell lymphoma in the second-line setting.

They enrolled a total of 232 patients over 47 global sites. And I'm, again, very proud to say that we ended up being the largest site in terms of patient enrollment. And our patients, we enrolled a total of about 11 patients on this study. And these patients were high-risk, large B-cell lymphoma, which had come back very quickly after getting initial chemotherapy. And most of our patients, although it was a randomized phase III study, our patients were randomized to CAR T. And these patients ended up getting CAR T in the second-line setting.

The primary endpoint of this study was what we call event-free survival. And at a median follow up of six months, the study was positive. The primary endpoint was met. And the event-free survival was statistically significant and superior on the CAR T arm versus patients who got an autotransplant. Event-free survival was 10 months on the CAR T arm versus only two months on the autotransplant arm. There were many other endpoints within this study that were also positive: meaning complete response rate was higher. Patients were able to remain progression free for a longer period of time. And most impressive, and striking here was the side-effect profile.

As you can imagine, with patients who get an autotransplant because they get high-dose chemotherapy, they do encounter infections, low blood counts, need for blood transfusion. And they're just very, very tired. On the CAR T study, they found that the incidence of the side-effect profile of the toxicities were actually comparable to patients who went through an autotransplant. But there are certain unique toxicities that patients who go through CAR T can actually experience. And these unique toxicities are not chemo-like toxicities. They really happen because these immune cells unleash on the cancer cells, they kill the cancer cells, and that releases substances called cytokines.

So, there is a syndrome called cytokine-release syndrome, which constitutes low blood pressure, shortness of breath, fevers. Patient could also have neurological toxicities. And I will have to say, as compared to the other FDA approved molecule, the molecule here that was tested within this clinical trial, which is lisocabtagene maraleucel, was exceptionally well tolerated. Some of our patients could actually get this therapy outpatient. And we look at side effects in terms of grade. And whenever we look at a clinical trial experimental product, we look at how many patients had high-grade toxicities. And I'm, again, super pumped to say that they absolutely had no high-grade toxicities with regards to cytokine-release syndrome and neurological toxicity. So grade 4 or grade 5 side effects were zero on this clinical trial which is, again, exceptional and impressive.

At the end of the day, this trial was presented at one of our premier meetings called the American Society of Hematology meeting last year. And I got the opportunity to represent these 47 global sites on behalf of the University of Colorado. And it was just fantastic very well received. And on the 24th of June, we finally found that the FDA reviewed the data, and accepted this as the new standard over autotransplant in patients with second-line relapse, large B-cell lymphoma. So for patients who now have a high-risk relapse, DLBCL, or large B-cell lymphoma, autotransplant is no longer the standard of care. Thanks to all the effort here of the team, as well as all the exceptional resources that were available at the University of Colorado, we led this trial, we championed it. And, at this point, the FDA has approved it.

Chris Casey:That's fantastic. Dr. Kamdar, and you mentioned the resources that are available here. Can you expound on that as far as what resources you took advantage of on the CU Anschutz campus to enable the research, for example, the CAR T cells reprogrammed here on the campus.

Manali Kamdar:So, within the context of a company-sponsored trial, like the TRANSFORM study, I will say it takes a village. And the village here will constitute my team, my clinical trials team. And it's just so many people, including transfusion medicine doctors, nurses, nurse practitioners, physician assistants, data coordinators. The list just goes on and on, besides just the medical providers like MDs, and DOs, who take care of patients. So, it just is impossible without this large team.

CAR T-cell therapy is resource intensive. And that's why most of the times CAR T-cell therapy gets offered at an academic site like ours, which is experienced and has dealt with many, many trials like this in the past as well. To piggyback on what resources here are currently available, I will have to say that within this world of CAR T everything's looking great. But we are still not at 100% cure. And that's what we aim for. As a result, with that one, single-minded focus, the University of Colorado, the Gates Biomanufacturing Facility, GBF, here has championed the idea of making CARs that are even more efficacious than the existing product.

The first instance of this was what we call the UCD19 trial. And the UCD19 trial has so far enrolled about 10 to 11 patients.

We're actually now moving a step further because we now also know that cancers can outsmart us and what can we do to outsmart them. So at this point, we develop CARs against one antigen called CD-19, and the cancers develop resistance against them by becoming CD-19 negative. As a result, the CAR can no longer recognize cancer as foreign. So how do we trick them? We basically now are trying to make products with two antigens on it, and the GBF as well as the University of Colorado campus have been exceptionally helpful. And the team that they have put in place is just so astute that we are now making what we call Bicistronic CARs, which attack two antigens, naming UCD 19/22.

So we have now opened this clinical trial called UCD 19/22 and we have so far enrolled two patients on it. We await their responses, but the hope is that if we do find good efficacy, as well as excellent toxicity profile, the hope is that patients who go through the routine FDA CARs, if they were to fail, which can happen in 40% of patients, we are also going to be now enrolling them on the 19/22 CARs as well.

And this is just the beginning. I think, the idea of cell therapy continues to evolve. And, at this point, we have some excellent scientists, clinicians on campus, not to mention Dr. Terry Fry. Under his leadership, the idea is to really continue to develop more novel products. Like I said, there are just simply three goals here: a cure, make sure that the novel therapy is durable, and make sure that it is not toxic to our patients. I think our patients have had chemotherapy far too long enough that it's time to move on beyond chemo.

Thomas Flaig:So often in oncology, we see therapeutic advances with better efficacy. So, it works better against the cancer. And the downside is there's a lot more toxicity for our patients. That's been the traditional paradigm. You can talk to a patient say, "I can do better and try to control your cancer, but there's been more side effects."

One of the things I just want to bring out about the article we're talking about. And the thing here is that you did not see terrible toxicity with this. You actually saw, compared to the standard, really acceptable toxicity. And so, to me, someone that's been in oncology for 15 or 20 years, that's been a big change. And just I think a very welcome change.

Manali Kamdar:Absolutely. And I think it's really important. Like I do believe that what's the point in killing cancer if the end result is making a patient wheelchair bound? If I can give that patient a good quality of life along with curing the cancer, that's where the true impact lies.

And I will have to say, within the world of cell therapy, that's exactly what we are shooting for. In fact, within the TRANSFORM study, there was what we call a quality-of-life analysis, or a patient-reported outcome analysis. And it did show that lisocabtagene maraleucel was way superior to an autotransplant from a quality-of-life or patient-reported outcome standpoint. So, absolutely, I agree with you that it's important to now start focusing on treatments that are not just efficacious, but also less toxic.

Chris Casey:And I can tell just by the way you talk about patients, Dr. Kamdar, that you probably develop quite a rapport with your patients. The fact that you enroll patients in clinical trials where potentially a novel therapy can emerge, could you just speak to what you think of your patients? Or how that conversation goes with your patients? And what you think of patients when they volunteer to go into this?

Manali Kamdar:At the cost of sounding sappy, I truly believe that my patients are my extended family. And I would do everything to give them the best product. Then, whether it's on a trial, whether it's FDA approved, it's always going to be a conversation. It's never a one-way street. And I think it's a relationship that develops over time. And because we are doing so well in lymphomas, the relationship with our patients is actually long-lasting. I see so many patients. I joined the University of Colorado in 2015, and I'm seeing a lot of patients since 2015, doing absolutely well. This is, of course, thanks to novel therapeutics and clinical trials, which, at the campus level, have worked. And therefore, our patients have gotten the benefit.

But to really talk about patients and their ability to trust in a clinical trial, I want to reiterate that I am in awe of the fact that they have the courage to participate in a clinical trial that's number one. The reason they have that courage is because we, as physicians, as providers, definitely want to help them understand where they are in their patient journey. Where is their cancer? What are their options? And what is the possibility of a response? Or even better with the clinical trial enrollment?

I want to also underscore that we do not do clinical trials, wherein patients get a placebo, or a sugar pill. That is unethical within the world of lymphoma, especially if patients have relapsed lymphoma. Also, there are many, many patients who initially could be averse to getting on a clinical trial because they feel like they're a guinea pig. But I do want to let you know that clinical trials are very robustly taken care of. We have eyes from the FDA every time we open a clinical trial.

And there are different phases of a clinical trial. Phase I is when it's never been tested in human beings. It's the first time that we are actually testing the molecule that's looking exceptionally promising in a lab. Phase II is when we actually find that it's not that toxic, we now want to see if it's efficacious. That's when it's been tested in human beings, but now we want to enroll a larger cohort and see if it's efficacious. And then phase III, like the TRANSFORM study which was positive, finally, compares it to the existing standard.

So, of course, this is something that takes time, that takes a lot of energy, both from the standpoint of a patient, as well as the provider. But that is what really keeps us going on campus here. And I, again, have to say hats off to the patients that they are so open to understanding where they are in their patient journey. And then, very open to also accepting of this possible new therapeutic that eventually has led to FDA approval.

Chris Casey:This is pretty amazing work that's been done. And Dr. Kamdar, like you say, a big team effort. And as you say, Dr. Flaig, very complex. Do you have any final thoughts about Dr. Kamdar's work into this lymphoma?

Thomas Flaig:Well, I'd just like to personally say that the work you've been doing here, the leadership you've shown in this trial, I think, is just really outstanding. And at the center of all this, as you've said, and I've watched you as you put in your practice, are the patients the patients in the trial, the future patients that will benefit from those who have volunteered to be in a trial.

I think it's a great conversation. It's such an exciting topic. I don't know if there's anything that we didn't touch on today in terms of the future of where CAR Ts are going, or next steps that you'd like to add to the conversation?

Manali Kamdar:I think the future is bursting with just so many new things that are coming down the pike. We hope to continue the winning streak. And we hope to offer exceptional treatments to our patients. Like you said, and I completely second that, the center or the core of our aim is just improving patient outcomes. And that is where the entire focus of the campus is. All these thousands of providers at whatever level they are working, that is the focus of care. So, I couldn't be more proud to be associated with this campus, with my team. And I really, really hope that we continue our journey with finding many, many more novel treatments.

Chris Casey:Well, thank you, Dr. Kamdar for sharing your story into this area of research, and the fantastic success you've had, and where you see things going. Thank you for your time. And also thank you, Dr. Flaig.

Manali Kamdar:Thank you so much for having us.

Outro:CU Anschutz 360 is produced by the University of Colorado CU Anschutz Medical Campus. Story editing and production by Chris Casey, Matt Hastings and Kelsey Peters. Digital design by Sarah Adams and Jenny Merchant.

Special thanks to the rest of the Office of Communications team for support and edits. Special thanks to Denver band Splitstep for our theme music featuring School of Medicine student Matt Golub, class of '22, Daniel Carillo and Kevin McKinnon.

We'd also like to thank our guests this week, Manali Kamdar and Tom Flaig, for co-hosting. You can read about the latest stories on our campus at news.cuanschutz.edu.

This is CU Anschutz 360.

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Why Is CAR T-Cell Therapy One of the Most Phenomenal Advances in Science? - University of Colorado Anschutz Medical Campus

SUZHOU, China, Aug. 21, 2022 /PRNewswire/ -- On August 19, 2022, Porton Advanced Solutions (Porton Advanced) announced the completion of its Series B financing round with over US$80Million. Current round of financing was led by China Merchants Groups' healthcare PE fund Merchant Health, along with its sister fund China Merchants Capital, China Merchants Securities Investments. In addition, a number of renowned venture and private equity firms participated in the current round of financing, including Fosun Health Capital, Gortune Investment and SDICTK. Apart from the new investors, current Porton Advanced shareholders, Porton Pharma Solutions, CS Capital, HM Capital, Ruilian Investment and Momentum Venture, also participated in the current round. Porton Advanced will use the proceeds to continue its business expansion into different markets, with investment in core manufacturing infrastructures and in global commercial operations. Such expansion would put Porton Advanced in a great position to become a global end-to-end gene and cell therapy (GCT) CDMO platform to help bring cutting edge therapies to patients.

Focusing solely on gene and cell therapy CDMO services, Porton Advanced has rapidly established an integrated CDMO platform providing a spectrum of services covering plasmids, cell therapy, gene therapy, oncolytic virus, nucleic acid therapy and microbial vectors used for gene therapy (MVGTs). Current operational footprint includes a 40,000sqft R&D and GMP production facility already in operation for over two years, which successfully delivered a number of plasmids, viruses and cell batches to our sponsors. A 160,000sqft facility for commercial production will be operational in the end of 2022/early 2023. By then, Porton Advanced will have over 200,000sqft of PD, AD, and GMP manufacturing facility dedicated for gene and cell therapy. In total, Porton Advanced will have 10 GMP viral vector production lines, 10 GMP cell therapy production lines and hundreds of clean rooms. Such a scale and footprint would allow Porton Advanced to significantly upgrade its AAV, oncolytic virus and mRNA CDMO capacity and capability which in turn empower our sponsors and support the GCT industry.

Current round of financing will help Porton Advanced to further improve the development and manufacturing capacity in both China and overseas, with the aim of establishing a global end-to-end gene and cell therapy CDMO platform. Through its efforts to accelerate the development of GCT therapeutics, Porton Advanced intends to become a top player that help drive the transformation of medicine.

Dr. Wang Yangzhou, CEO of Porton Advanced, said, "we are very pleased and grateful for the recognition and trust by China Merchants Health and all the other new and current capital partners. With a talented and passionate team, proprietary technologies, state of the art production lines and equipment, as well as track records from both Porton Advanced and from our parent company, Porton Pharma Solutions, we will work hand in hand with our sponsors and partners to reach more milestones in the GCT field. In the coming months, we will continue to improve and optimize our internal quality and program management systems, enhance our ability to operate at overseas and domestic markets, and continue to provide best possible CDMO services to our customers with our open, innovative and reliable platforms, so that best medicine would reach the public sooner."

Representing the current consortium of investors, the lead investor China Merchants Health, expressed its great confidence in the GCT field and said that, "the cell and gene therapy holds great promises for patients as well as for long-term commercial success. Porton Advanced is a leading cell and gene therapy CDMO service provider with a very experienced, internationally oriented management and technical team. China Merchants Health is pleased to lead in this round of financing and looks forward to working with Porton Advanced to unlock the great benefit of GCT by serving global cell and gene therapy companies, and promote the development of the cell and gene therapy industry for the benefits of patients everywhere."

About Porton Advanced SolutionsEstablished in Suzhou Industrial Park in December 2018, by its parent company Porton Pharma Solutions Ltd. (Stock Code: 300363), Porton Advanced has built a CDMO platform integrating plasmid, cell therapy, gene therapy, oncolytic virus, nucleic acid therapy and microbial vectors used for gene therapy (MVGTs), providing end-to-end services from cell banking, process development and analytical development, cGMP production to final Fill and Finish , investigator-initiated clinical trials (IIT), investigational new drugs (IND), clinical trials to commercial production. Porton Advanced is dedicated to support sponsors advance their GCT drug development and market launches.

Porton Advanced focuses solely on gene and cell therapy services. Built on the professional experience of its cohort of world-class professionals, as well as on the successes of its parent company, Porton Advanced insists on "Customer First" and the tenet of "Compliance, Expertise, Focus, Open Collaboration". With its key focus on protecting IP for its sponsors, through its comprehensive project management and quality systems, Porton Advanced strives to bring gene and cell therapy products to the clinic and the market through its quality CDMO services, and help bring the best medicine to the public sooner.

About Porton Pharma SolutionsWith over 5000 customer-centric employees, and operations and commercial offices across the US, EU and China, Porton Pharma Solutions Ltd. provides global pharmaceutical companies with innovative, reliable and end-to-end process R&D and manufacturing services across small molecule APIs, dosage forms and biologics. We are committed to being the most open, innovative and reliable pharmaceutical service platform in the world and enabling public's early access to good medicines.

About China Merchants HealthChina Merchants Health Care Holdings Company Limited ("China Merchants Health"), is the major health care investment platform of China Merchants GroupThe vision of the China Merchants Health Fund is "Empowering better Health care in the new Digital Era", and its mission is "Lead with Technology, build better healthcare value chain ". Focusing on key & Core Technologies , China Merchants Health is committed to driving the transformation of health-care sector and health care ecosystem through investment and operational empowerment.

About China Merchants CapitalChina Merchants Capital Investment Co., Ltd (hereinafter referred to as "China Merchants Capital" or "CMC") specializes in alternative investment and asset management, and seeks opportunities across seven key sectors: green technology; healthcare; transportation, infrastructure and logistics; TMT; advanced manufacturing; real estate; financial services and fintech. At the end of 2021, China Merchants Capital manages 44 RMB funds and 8 Foreign Currency funds. Its total AUM exceeds 300 billion RMB, in which RMB AUM totals over 230 billion yuan, and foreign currency AUM totals over 70 billion yuan.

About China Merchants Securities InvestmentChina Merchants Securities Investment Co., Ltd. is a wholly-owned alternative investment subsidiary of China Merchants Securities, with a registered capital of CNY7.1 billion, mainly engaged in equity investment and financial product investment. Focusing on national policies and industrial layout, it is committed to providing financial services covering the whole industry chain for its investees. It has invested in more than 20 leading companies in the medical market.

About Fosun Health CapitalFosun Health Capital is a majority-owned subsidiary of Shanghai Fosun PharmaceuticalGroupCo., Ltd.. It acts as the general partner of a number of RMB-denominated funds that focus on the healthcare sector, including incubation angel funds, venture capital funds and growth private equity funds. These funds invest in various healthcare sectors, including biopharmaceuticals, advanced medical equipment, in vitro diagnostics, life sciences, and treatment technologies, and leverage various exit options to achieve capital appreciation subsequently. Taking advantage of Fosun's global R&D advantages and industrial layout, Fosun Health Capital performs effective value-add and nurture growth to its portfolio companies throughout their entire life cycle.

About Gortune InvestmentGORTUNE PRIVATE EQUITY FUND MANAGEMENT CO.,LTD. is the only private equity investment platform controlled by GORTUNE INVESTMENT CO., LTD. The key investment directions include life sciences, new energy, pan-consumption, agriculture and other fields. It is committed to long-term wealth management for investors.

About SDICTKSDICTK Trust aims to serving the real economy, cultivates high-quality equity projects with professional investment and research capabilities, and empowers invested enterprises at multiple levels with its core strengths, such as industry-financing combination. Such efforts have won advantages for the active transition of the trust company!

About CS CapitalCS Capital ("CSC") is one of the largest private equity investment firms headquartered in Beijing with over RMB 100bn of AUM from a diversified investor base. Riding on the need for advances in technology, tech-enabled services, smart devices, and next-generation communication networks in China's NEV and healthcare industries, CSC invests in companies with attractive prospects for growth driven by anticipated emerging trends and proven technological advantages and has generated strong returns for its LPs over a ten-year period.

About HM CapitalHM Capital is a healthcare -focused investment firmcommitted to building an investment platform with a global view and local execution. Through the investment mode of dual-currency and multi-strategy, we aim to help early and growth-stage healthcare companies achieve accelerated development by leveraging the ecosystems of HM Healthcare Management Services. We work closely with fast-growing, innovative healthcare companies to harness the power of breakthroughs in sciences and technologies globally, and create value for the leading entrepreneurs through empowerment by sharing our global business and resource network.

About Ruilian InvestmentRuilian InvestmentHainan Hongde Ruilian Consulting Management Co., Ltd. is a wholly-owned subsidiary of Huashan Ruilian Fund Management Co., Ltd. With accumulated AUM over RMB 15 billion, Ruilian Investment focus its investments on healthcare, advanced manufacturing and consumer goods.

About Momentum VentureMomentum Venture is a venture capital focused on innovative teams in the field of life and health, dedicated to mining and cultivating revolutionary and disruptive technologies. The fund's investors include listed companies, government guidance funds, market-oriented fund of funds, and high-net-worth individuals. Working closely with the industry, we provide our portfolio companies with resources to accelerate their development and promote the industrialization of science and technology.

SOURCE Porton Advanced Solutions

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Porton Advanced Solutions completes a Series B financing round to expand its end-to-end Gene and Cell Therapy CDMO Platforms - PR Newswire

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Dublin, Aug. 17, 2022 (GLOBE NEWSWIRE) -- The "Cell Analysis Global Market - Forecast to 2029" report has been added to ResearchAndMarkets.com's offering.

According to analysis, the cell analysis global market is expected to grow at a low single digit CAGR from 2022 to 2029 to reach $38,020.6 million by 2029. The rising incidence of infectious and non-infectious diseases and demand for early detection, diagnosis & treatment, increasing government and private funding towards cell based research, increasing advancements in cell imaging technologies to reduce the cost & time during the drug discovery process are driving the cell analysis market.

The market for cell analysis is segmented based on technique, product, application, end-user and geography. The cell analysis techniques global market is segmented into PCR, Sequencing, Microfluidics and Microarrays, Spectrometry, Microscopy, Cytometry, High Content Analysis, Electrophoresis and Others. Among the techniques, the PCR segment accounted for the largest revenue in 2022. The Sequencing segment is expected to grow at a double digit CAGR from 2022 to 2029.

The cell analysis products market is mainly segmented into consumables, instruments, software and services. Among these, consumables segment commanded the largest revenue in 2022 and is expected to grow at a low single digit CAGR from 2022 to 2029. The software and services segment is expected to grow at a mid single digit CAGR from 2022 to 2029.

The consumables market is further sub-segmented into reagents, assay kits, microplates and others. Among the consumables sub-segments, the assay kits held the largest revenue in 2022. Reagents sub-segment is the fastest growing segment with a mid single digit CAGR from 2022 to 2029.

The application market is categorized based on processes, field, and by therapeutic area. In the process of application, the market is segmented into cellular processes, signal transduction pathways, circulating tumor cells, single-cell analysis, epigenetic target analysis, subpopulation characterization, and drug and candidate screening.

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Based on field of application, the market is further segmented into forensic, therapeutics, cell imaging, biomarker research, genomic analysis, stem cell analysis, and diagnostics. Diagnostics held the largest revenue of in 2022. Stem cell analysis is the fastest-growing segment at a mid single digit from 2022 to 2029.

The end-users market is segmented into hospitals & diagnostic laboratories, academic and research institutes, contract research organizations (CROs), pharmaceuticals and biotechnology companies, cell banks, and others.

Market DynamicsDrivers and Opportunities

Rising Incidence of Infectious and Non-Infectious Diseases and Demand for Early Detection, Diagnosis & Treatment

Increasing Government and Private Funding

Increasing Advancements in Cell Imaging Technologies Reduce the Cost and Time Consumption for the Drug Discovery Process

Growing Focus on Personalized Medicine

Introduction of Advanced Technologies in Cell Analysis

Increasing Merger and Acquisition Activities in Cell Analysis

Restraints & Threats

Lack of Skilled Personnel to Use Advanced Cell Analysis Instruments

Expensive Cell Analysis Instruments

Maintaining Consistency, Reproducibility of Assays and Lack of Standardization

Availability of Alternative Technologies

Stringent Regulatory Framework Limits Advancements in Cellular Analysis Market

Key Topics Covered:

1 Executive Summary

2 Introduction

3 Market Analysis

4 Cell Analysis Global Market, Based on Techniques

5 Cell Analysis Global Market, Based on Products

6 Cell Analysis Global Market, Based on Application

7 Cell Analysis Global Market, Based on End-Users

8 Regional Market Analysis

9 Competitive Landscape

10 Major Player Profiles

Companies Mentioned

10X Genomics

1CellBio

Abbexa Ltd

Abbott Laboratories, Inc.

Abcam Plc.

Abnova Corporation

ABP Biosciences LLC

Adaptive Biotechnologies Corp.

Agilent Technologies Inc. (U.S.)

Aigenpulse

Akadeum Life Sciences

Akoya Biosciences, Inc.

Alit Lifesciences Co., Ltd

Altona Diagnostics GmbH

Analytik Jena AG (CyBio AG)

ArrayGen Technologies Pvt Ltd (India)

Art Robbins Instruments LLC (U.S.)

Aviva Bioscience (U.S.)

Axion Biosystems (CytoSMART Technologies B.V.) (U.S.)

Azenta Life Sciences (Brooks life sciences)

Becton Dickinson and Company

BennuBio Inc.

Berry Genomics Co., Ltd

BGI Group

Bico (Cellenion)

Bio View Ltd.

BioAgilytix Labs, LLC (Cambridge Biomedical Inc.)

Biochrom Ltd.

Biofluidica

BioinGentech

Bioneer Corporation

Bio-Rad Laboratories Inc.

Bioron GmbH

BioSkryb, Inc.

Bio-Techne Corporation

Biotium

bitBiome, Inc.

Blue-Ray Biotech

Brand GMBH

Bruker Corporation

Carl Zeiss AG

Etaluma Inc

Eurofins Scientific

Fluent BioSciences

Fluidigm Corporation

Fluxion Biosciences

GC biotech B.V.

Genomatix AG

GenXPro GmbH

Hamilton Company

Hausser Scientific

Helena Laboratories Corporation

Herolab GmbH

Hettich Lab Technology

HighQu GmbH

Horiba, Ltd

Illumina Inc.

Immunai

IncellDx

Inscopix

Insightful Science

IsoPlexis

Jasco Analytical Instruments

JEOL Ltd

Keyence Corporation

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Cell Analysis Global Market Report 2022: Growing Focus on Personalized Medicine & Introduction of Advanced Technologies in Cell Analysis Presents...

NEEDHAM, Mass.--(BUSINESS WIRE)-- Invicro LLC (Invicro), a global, industry-leading imaging CRO, and a subsidiary of REALM IDx, Inc., today announced the publication of the paper Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimers disease1 in Science Translational Medicine.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20220818005136/en/

Figure 1: Mean PET images demonstrating AD patients have widespread increases in sigma 1 receptor, along with regional decreases in mitochondrial complex I and SV2A. (Graphic: Business Wire)

The study provides novel in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in patients with early-stage Alzheimers Disease (AD) and highlights the potential value of mitochondrial imaging in longitudinal studies of AD.

Invicros research and novel biomarkers are significant for the progression of clinical trials in AD and neurodegenerative disorders, and we are delighted to see this important work published in Science Translational Medicine, said Dr. Roger Gunn, CSO, Neuroscience, for Invicro. This work further extends Invicros repertoire of biomarkers for use in AD clinical trials.

Position emission tomography and magnetic resonance imaging markers were utilized to show that cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of AD. Compared to controls, AD patients had widespread increases in sigma 1 receptor, along with regional decreases in mitochondrial complex I, SV2A, brain volume and cerebral blood flow. Furthermore, significant reductions in mitochondrial density were seen in AD patients over a 1218-month period, indicating this biomarker may be suitable for use in early-stage trials of novel disease-modifying treatment for this devastating disease.

This study was led by Professor Paul Matthews of the UK Dementia Research Institute and Imperial College London as part of the multi-arm, pre-competitive consortium, Molecular Imaging of Neurodegenerative Disease Mitochondria Associated Proteins and Synapses (MIND MAPS) AD cohort. The MIND MAPS consortium was developed and is headed by Dr. Eugenii Rabiner, EVP for Translational Imaging at Invicro.

MIND MAPS is an important industry-academic collaboration that is bringing together experts from across the globe. It was developed with the aim of characterizing imaging biomarkers of the neurodegenerative process to address important problems in the development of novel medication for neurodegenerative disease, said Dr. Rabiner. Together, we have shown that mitochondrial and cellular stress biomarkers open the promise of better monitoring of the therapeutic potential of these drugs.

Science Translational Medicine is the leading weekly online journal publishing translational research at the intersection of science, engineering and medicine. The goal of Science Translational Medicine is to promote human health by providing a forum for communicating the latest research advances from biomedical, translational and clinical researchers from all established and emerging disciplines relevant to medicine. Science Translational Medicine published Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimers disease on August 17, 2022.

About Invicro

Headquartered in Needham, MA, Invicro, a subsidiary of REALM IDx, was founded in 2008 with the mission of improving the role and function of imaging in translational drug discovery and development across all therapeutic areas. Today, Invicros multi-disciplinary team provides solutions to pharmaceutical and biotech companies across all stages of the drug development pipeline (preclinical through Phase 0-IV), all imaging modalities and all therapeutic areas, including neurology, oncology and systemic and rare diseases. Invicros quantitative biomarker services, advanced analytics and AI tools, and clinical operational services are backed by Invicros industry-leading software informatics platforms, VivoQuant and iPACS, as well as their pioneering IQ-Analytics Platform, which includes AmyloidIQ, TauIQ and DaTIQ.

Invicro operates out of nine global laboratories, clinics and sites within the United States in Massachusetts, Michigan, California, Connecticut and globally in the United Kingdom, India, Japan and China. For more information visit http://www.invicro.com

View source version on businesswire.com: https://www.businesswire.com/news/home/20220818005136/en/

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Cell Stress and Mitochondrial Dysfunction Found in Early Alzheimers Disease Patients, Findings Published in Science Translational Medicine - BioSpace

Scientists at Weill Cornell Medicine in New York say that stress-induced circadian clock disruptions may influence weight gain.

A study published in June showed that mice with artificially increased stress levels and interrupted hormone releases experienced an increase in fat cell growth. Its results appear in Cell Reports.

The second study, published in August, found that fat cell precursors commit to becoming fat cells only within a few hours at night. This work appears in the Proceedings of the National Academies of Sciences (PNAS).

Mary Teruel, PhD, associate professor of biochemistry at Weill Cornell Medicine, was the senior author of both studies.

A lot of forces are working against a healthy metabolism when we are out of circadian rhythm, Dr. Teruel said in a press release. The more we understand, the more likely we will be able to do something about it.

In the Cell Reports study, Dr. Teruel and her team implanted pellets with glucocorticoids, a type of stress-related hormone, in mice. This was to mimic the effects of chronic stress or Cushings disease.

Cushings disease triggers elevated levels of cortisol, the bodys stress hormone.

The pellets released glucocorticoids under the skin of the mice at a steady rate over three weeks. The researchers also observed control mice with typical daily stress hormone fluctuations.

Although all the mice ate the same healthy diet, the mice with pellets ended up weighing over 9% more than the control mice.

The researchers observed whether the weight gain was from fat expansion and found that the brown and white fat of the pellet mice had more than doubled. Their insulin levels spiked as well.

To the teams surprise, the metabolic disturbances kept blood glucose levels low. Further, the disruptions prevented fat from accumulating in the blood or liver.

When the researchers removed the pellets, these changes reversed immediately.

Dr. Teruel explained to MNT: We saw this in our paper, basically, once we stopped flattening the corticoids, [the mice] started reversing [the fat mass gain] and the hyperinsulinemia went away so that increased insulin that seems to be causing the fat mass gains that went away when the restored rhythm.

She added that this study indicates that chronic stress can make weight gain more likely, even with a healthy, low fat diet.

If you stress the animals at the wrong time, it has a dramatic effect. The mice arent eating differently, but a big shift in metabolism causes weight gain, Dr. Teruel said in the release.

Dr. Teruels research team hopes that their findings lead to developing drugs that could help reset circadian rhythms to help people with obesity.

We dont know enough [yet], but one would think cortisol receptor antagonists or [] things that restore the cortisol rhythms would probably help a lot.

Dr. Mary Teruel

Experts understand that flaws in circadian clock genes can alter cell differentiation in fat, immune, skin, and muscle cells.

The PNAS study revealed that even though differentiation happens over a few days, differentiation commitment happens within only a few hours. The findings also show that daily bursts of cell differentiation seem to be limited to evening phases when people are normally resting.

The decision to become a fat cell happens rapidly over 4 hours. It is like a switch, Dr. Teruel said.

Medical News Today discussed this with Dr. Mir Ali, bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, California.

Dr. Ali explained how fat cells come to be: Fat cells form from [an] adipocyte progenitor cell or a type of cell that has not differentiated into its final form. The form it takes [to become] a fat cell depends on the hormonal and chemical stimulation it receives.

In the study, Dr. Teruel and her partners used fluorescent markers to observe daily fluctuations of fat cell production.

The researchers attached a red fluorescent protein to a protein that regulates circadian clock genes. They also attached a yellow fluorescent protein to peroxisome proliferator-activated receptor gamma (PPARG), a protein that controls fat cell production.

They discovered that during the rest period of the day, a certain circadian protein CCAAT enhancer binding protein alpha induces a rapid increase in the protein that regulates fat cell production.

The researchers also found that when PPARG levels hit a certain threshold, individual fat precursor cells irreversibly commit to differentiate within only a few hours, which is much faster than the rest phase and the overall multiday differentiation process.

Dr. Teruel and her team believe that working with this time window may open therapeutic strategies to use timed treatment relative to the [circadian] clock to promote tissue regeneration.

Dr. Ali said: These studies are interesting in that they show the timing and length of stimulation affect the formation and growth of fat cells. The implications of this are that if we can find a way to safely influence the cell to grow or not grow, it may affect obesity in humans.

However, he believed that more extensive research is needed to make the studies findings applicable to humans.

Dr. Teruel told MNT that she and her co-authors were just trying to work on basic mechanisms [] Right now, we need to show this is really a mechanism that happens []

The researchers do plan to replicate the studies with people. We are looking at protein ribbons and humans using saliva samples, Dr. Teruel shared with MNT. Were planning to do those kinds of experiments.

Their main objective, she said, is to figure out ways to restore circadian [rhythms].

Dr. Teruel mentioned that currently known strategies, such as meditation and regular sleep in the dark may help.

She expressed hope that there could be some pharmacological ways [to] fix this in the future as well.

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Stress can throw off circadian rhythms and lead to weight gain - Medical News Today

August 16, 2022

Without a steady supply of oxygen from the blood, processes leading to cell death in mammals begin within minutes. Recent studies have shown that cells can still recover even hours after interrupting blood flow. But such recovery has so far only been demonstrated in isolated organs.

An NIH-funded team of researchers led by Dr. Nenad Sestan at Yale School of Medicine developed a system to promote cellular recovery and preserve tissue integrity in the intact body after loss of blood flow. The system, called OrganEx, is based on the teams previous work restoring circulation and cell function in a pig brain that was removed after the animals death.

OrganEx uses a device like the heart-lung machines that take over the functions of the heart and lungs during surgery. The device pumps a mix of the pigs own blood and a protective fluid throughout the bodys blood vessels in a process called perfusion. This fluid contains oxygen and a synthetic form of hemoglobinthe oxygen-carrying protein in red blood cells. It also contains electrolytes and compounds designed to protect cells and prevent blood clots.

The researchers tested OrganEx in pigs undergoing cardiac arrest. Perfusion of pigs began one hour after cardiac arrest and continued for another six hours. Results appeared in Nature on August 3, 2022.

OrganEx was able to circulate the fluid throughout the body and deliver adequate oxygen to tissues. It also prevented electrolyte imbalances that normally occur when blood flow stops. The researchers compared OrganEx with a conventional heart-lung perfusion machine that pumped the pigs own blood back through its body.

OrganEx perfusion for six hours preserved cell and tissue integrity and reduced cell death in various organs. These included the brain, heart, liver, and kidneys. In the brain, OrganEx preserved all three major cell types: neurons, astrocytes, and microglia. Cells in the heart, liver, and kidneys had less damage than corresponding cells after treatment with the standard device.

The researchers also found signs of restored organ function in the perfused pigs. They observed glucose uptake in brain, heart, and kidneys. They found electrical activity and contraction in the heart, and protein synthesis in the liver and brain. Several organs activated genes associated with cellular repair processes and preventing cell death.

These findings suggest the potential for organs to recover up to an hour after blood flow stops. OrganEx technology could leverage this potential to prolong the life of human donor organs. This could make more organs available for transplants. It might also help damaged organs to recover following heart attacks or strokes. Yet the researchers stress that further research will be needed. It remains to be seen how much organ function can be recovered and how long it can be maintained. Because of the ethical implications of brain recovery after death, this and future work will continue to require rigorous ethical review.

There are numerous potential applications of this exciting new technology, says study co-author Dr. Stephen Latham, director of the Yale Interdisciplinary Center for Bioethics.However, we need to maintain careful oversight of all future studies, particularly any that include perfusion of the brain.

by Brian Doctrow, Ph.D.

References:Cellular recovery after prolonged warm ischaemia of the whole body. Andrijevic D, Vrselja Z, Lysyy T, Zhang S, Skarica M, Spajic A, Dellal D, Thorn SL, Duckrow RB, Ma S, Duy PQ, Isiktas AU, Liang D, Li M, Kim SK, Daniele SG, Banu K, Perincheri S, Menon MC, Huttner A, Sheth KN, Gobeske KT, Tietjen GT, Zaveri HP, Latham SR, Sinusas AJ,Sestan N. Nature. 2022 Aug 3. doi: 10.1038/s41586-022-05016-1. Online ahead of print. PMID:35922506.

Funding:NIHs National Institute of Mental Health (NIMH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of General Medical Sciences (NIGMS), and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Schmidt Futures.

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Restoring cell and organ function after the heart stops - National Institutes of Health (.gov)