Category Archives: Cell Medicine

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.

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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)

Family, friends and positive attitudes helped Katherine Haug through months of failed attempts at ridding her body of cancer. Then a passionate doctor with an experimental treatment gave the wife, mother and grandmother a big reason to smile.

Last November, Manali Kamdar, MD, informed the longtime Buena Vista resident that her cancer was in remission. Go live your life, and Ill see you in a year, Kamdar told her. The news was profound, not just for the people standing in Kamdars office that fall day, but for the thousands of patients who will find themselves on Haugs path in the future.

Did you know: Patients at the University of Colorado Anschutz Medical Campus have access to potentially life-saving therapies often years before the treatments are approved for general use? At any given time, 1,400-plus active clinical trials are taking place on campus, transforming healthcare. Find research studies here.

This is not just about me. Its not just about Ron, Haug said of her husband of 47 years. Its about everybody.

Haug was diagnosed with large B-cell lymphoma (LBCL) in January 2019, when scans showed two large masses, one in her spleen and one in the parietal peritoneum, the tissue that lines the abdominal wall. The standard immunochemotherapy treatment (R-CHOP), which succeeds nearly 60% of the time, failed.

The tumor in the peritoneal area disappeared after the second R-CHOP treatment, said Haug, who had six rounds in total. But the one in the spleen was the one that was kind of cranky and didnt want to go away.

Her oncologist near her Buena Vista home of 40 years sent Haug down the mountain to Kamdar at the University of Colorado Anschutz Medical Campus. There, Haug found herself with an option:

She could undergo the standard and often-brutal second-line treatment of intensive chemotherapy followed by stem-cell transplant. Or she could roll the dice and join a randomized clinical trial comparing that therapy to lisocabtagene maraleucel (liso-cel), an investigational chimeric antigen receptor (CAR) T-cell therapy.

Haug decided to gamble.

Although she had never heard of CAR T-cell therapy, a rising star in cancer research deemed the 2018 Advance of the Year by the American Society for Clinical Oncology, Haug sensed Kamdars excitement about the treatment, which was not yet an option for patients in Haugs situation. She joined the study, deciding, among other reasons, to be part of something bigger than myself.

Today, thanks in part to Haug and the 183 other participants in the global phase-3 trial that involved 47 sites, the liso-cel CAR T-cell therapy is now approved as a second-line treatment for relapsed or refractory large B cell lymphoma (LBCL).

To Kamdar, lead author of the study published in June in The Lancet, approval represents a win for patients and for science.

Without the CAR T-cell option, nearly 70% of patients like Haug who failed R-CHOP would succumb to their disease, said Kamdar, an associate professor of hematology at the University of Colorado School of Medicine and a member of the CU Cancer Center. Its amazing to see how quickly we are moving forward in advancing patient care and improving patient outcomes.

In the most recent assessments of the ongoing randomized study called TRANSFORM, survival rates were significantly higher in the CAR T group compared with the standard therapy group. Median event-free survival was 10.1 months versus 2.3 months, and median progression-free survival (disease doesnt get worse) was 14.8 months versus 5.7 months.

Potential CAR T-cell therapy side effects can include cytokine release syndrome, an over-aggressive immune system response that causes fever, nausea, fatigue and body aches. Neurological issues, such as speech problems, tremors, delirium and seizures, also can occur. But of the CAR T-related toxicities seen in the study, all were low-grade and completely reversible, said Kamdar, clinical director of lymphoma services.

The breakthrough outpatient therapy also involves less time in the hospital than the traditional stem-cell transplant a winning point for Haug. I told Dr. Kamdar, I cant sit for 15 days in the hospital.

The dice rolled in Haugs favor, and she was randomly assigned to the trial's CAR T arm. After undergoing tests for study approval, she and her husband packed up and traveled over 140 miles to Aurora to begin the therapy.

The process begins with leukapheresis, where blood is drawn via a large, centrifuge-like machine that extracts T cells before returning the remaining blood to the patient. Thats about four hours and 20 minutes laying with your arm straight out, and you cant move, Haug said. It wasnt painful. It was just one of those things.

A nurse monitors injection of the genetically modified CAR T cells.

Cells are then modified in the lab where they are genetically engineered to become fighter cells, and millions of copies are created. Then they are injected back into the patient, and an observation period begins. The couple had to be near the hospital for 30 days, made easy by the nonprofit Brents Place program, Haug said. They give you a place to stay, and it was within walking distance of the hospital.

Patients are carefully monitored during that month for progress and side effects. I was fortunate, Haug said. My numbers just got better and better, and I never experienced any significant side effects.

The Haugs, who recently moved to Kansas to be closer to family, are grateful for finding Kamdar and the trial.

Shes obviously very good at what she does, but yet shes very human, Haug said. She wants it to work, and she wants it to work for everybody, not just me. And I think that attitude bears a lot of merit. Going through cancer, you have to have, I think, not only a good sense of humor but great confidence in who you are going to. If you dont, you need to find somebody else.

I cant thank her enough, Ron Haug said of Kamdar, adding that hes proud of his wife for taking part in the trial that can make cancer treatment a little easier on other patients in the future. The Haugs also hope the Food and Drug Administration approval will make CAR T-cell therapy more accessible and affordable for everyone.

That would make me feel like maybe I accomplished something good in my life, Katherine Haug said, to which her husband quickly responded: You did.

As the therapy highlighted in this article exemplifies, doctors at CU Anschutz continually pursue new treatments that save lives without debilitating their patients. Patient Katherine Haug offered other top strategies for staying as mentally and physically healthy as possible during a cancer journey.

We laughed a lot, with each other and at each other, she said of her and her main supporter: husband Ron Haug.

One time, a family member looked horrified after saying: Well, Id better get out of your hair, when Haug was bald from chemotherapy. No need to get out of my hair; I dont have any! she responded, busting out laughing, along with her husband.

You do have to have a real positive aura around you because otherwise it would be too hard, said Haug, who even cut ties with toxic friends after being diagnosed.

The Haugs found and relied on support all along, from friends, family (especially their daughter) and nurses, who overwhelmed her husband, he said, with their kindness and compassion.

"You have to keep your body moving," Haug said, adding that a friend and breast-cancer survivor shared the advice with her when she was diagnosed. "No matter how bad you feel, try to at least go for a walk," her friend told her.

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Rolling the Dice: Gamble Pays Off For Cancer Patient in CAR T-Cell Clinical Trial - University of Colorado Anschutz Medical Campus

image:The new study shows that boosting neurogenesis increases the number of newly formed neurons involved in storing and retrieving memories (arrows) in the hippocampus of mice with AD. view more

Credit: 2022 Mishra et al. Originally published in Journal of Experimental Medicine. https://doi.org/10.1084/jem.20220391

Researchers at the University of Illinois Chicago have discovered that increasing the production of new neurons in mice with Alzheimers disease (AD) rescues the animals memory defects. The study, to be published August 19 in the Journal of Experimental Medicine (JEM), shows that new neurons can incorporate into the neural circuits that store memories and restore their normal function, suggesting that boosting neuron production could be a viable strategy to treat AD patients.

New neurons are produced from neural stem cells via a process known as neurogenesis. Previous studies have shown that neurogenesis is impaired in both AD patients and laboratory mice carrying genetic mutations linked to AD, particularly in a region of the brain called the hippocampus that is crucial for memory acquisition and retrieval.

However, the role of newly formed neurons in memory formation, and whether defects in neurogenesis contribute to the cognitive impairments associated with AD, is unclear, says Professor Orly Lazarov of the Department of Anatomy and Cell Biology in the University of Illinois Chicago College of Medicine.

In the new JEM study, Lazarov and colleagues boosted neurogenesis in AD mice by genetically enhancing the survival of neuronal stem cells. The researchers deleted Bax, a gene that plays a major role in neuronal stem cell death, ultimately leading to the maturation of more new neurons. Increasing the production of new neurons in this way restored the animals performance in two different tests measuring spatial recognition and contextual memory.

By fluorescently labeling neurons activated during memory acquisition and retrieval, the researchers determined that, in the brains of healthy mice, the neural circuits involved in storing memories include many newly formed neurons alongside older, more mature neurons. These memory-stowing circuits contain fewer new neurons in AD mice, but the integration of newly formed neurons was restored when neurogenesis was increased.

Further analyses of the neurons forming the memory-storing circuits revealed that boosting neurogenesis also increases the number of dendritic spines, which are structures in synapses known to be critical for memory formation, and restores a normal pattern of neuronal gene expression.

Lazarov and colleagues confirmed the importance of newly formed neurons for memory formation by specifically inactivating them in the brains of AD mice. This reversed the benefits of boosting neurogenesis, preventing any improvement in the animals memory.

Our study is the first to show that impairments in hippocampal neurogenesis play a role in the memory deficits associated with AD by decreasing the availability of immature neurons for memory formation, Lazarov says. Taken together, our results suggest that augmenting neurogenesis may be of therapeutic value in AD patients.

Mishra et al. 2022. J. Exp. Med. https://rupress.org/jem/article-lookup/doi/10.1084/jem.20220391?PR

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About Journal of Experimental Medicine

Journal of Experimental Medicine (JEM) publishes peer-reviewed research on immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions on research manuscripts are made through collaborative consultation between professional scientific editors and the academic editorial board. Established in 1896, JEM is published by Rockefeller University Press, a department of The Rockefeller University in New York. For more information, visit jem.org.

Visit our Newsroom, and sign up for a weekly preview of articles to be published. Embargoed media alerts are for journalists only.

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Journal of Experimental Medicine

Experimental study

Animals

Augmenting neurogenesis rescues memory impairments in Alzheimers disease by restoring the memory-storing neurons

19-Aug-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Boosting neuron formation restores memory in mice with Alzheimer's disease - EurekAlert

The image shows an irradiated Drosophila embryo, where p53 activity (green) is reduced in neuronal precursors (red). All nuclei are labeled in blue.

John Abrams, Ph.D.

DALLAS August 18, 2022 A gene thats well known for its role in turning on tumor-suppressing genes when cells become stressed also keeps potential tumor-driving genes turned off, UTSouthwestern researchers report in a new study. The findings, published in Developmental Cell, provide new insight into the gene, known as p53, which is mutated in most human cancers.

"If we truly want to understand how cells move from normal to malignant states, understanding p53 and what happens when it becomes disabled is critical, said study leader John Abrams, Ph.D., Professor of Cell Biology and a member of theHarold C. Simmons Comprehensive Cancer Center at UTSW. Our study suggests that when this gene becomes mutated, certain genes and programs that should otherwise be silent become reactivated.

The p53 gene has long been a focus of cancer research because of how often its mutated in malignant tumors, covering more than half of all human cancers. Studies over the past several decades have shown that this gene appears to activate a variety of downstream genes when cells become stressed from factors that damage their DNA, such as genotoxic chemicals or ionizing radiation. These genes subsequently kick off a cascade that stops genes from proliferating a hallmark of cancer by causing cells to go into an inactive stage called senescence or inducing a type of cellular suicide called apoptosis.

Mutations that disable p53 prevent this cascade, allowing cells to begin multiplying out of control. However, explained Dr. Abrams, when researchers individually disabled cellular programs known to be activated by p53, the gene appeared to still suppress tumor development, suggesting that stress-induced gene activation isnt its only job. Previous research by the Abrams labshowed that p53 can also suppress gene activity but how it accomplishes both activation and suppression wasnt understood.

The new study builds on a2020 report from the Abrams lab. Together, the two papers suggest that beyond turning on genes when cells are stressed, p53 appears to have a second role in which it acts directly on other genes to keep them turned off. Notably, these include many not currently known to contribute to cancer, such as transposons, or jumping genes DNA sequences that can move around the genome and genes associated with meiosis, a type of cell division that halves the number of chromosomes to produce sperm and eggs.

Further experiments in the new study showed that p53 accomplishes simultaneous gene activation and inactivation by producing a set of different proteins, or isoforms. By individually deleting specific p53 protein isoforms in their model system the quintessential lab model Drosophila melanogaster, or fruit fly Dr. Abrams and his colleagues demonstrated that previously silent gene programs became activated.

Dr. Abrams said the work has two important implications for developing new cancer treatments. First, ongoing efforts to discover drugs that can replace p53 activity when it becomes impaired by mutations should not only focus on p53s role as a gene activator but also replicate its role as a gene silencer. Secondly, genes that healthy p53 keeps inactivated may play currently unrecognized roles in promoting cancer, Dr. Abrams explained. His lab is currently investigating whether transposons that become reactivated when p53 is disabled could function as oncogenes, making them potential targets for cancer therapies.

Other researchers who contributed to this research include Annika Wylie, Amanda E. Jones, and Simanti Das of UTSW; and Wan-Jin Lu of Stanford University School of Medicine.

This study was supported by grants from the National Institutes of Health (5T32CA124334, R01GM115682, R01CA222579), the Cancer Prevention and Research Institute of Texas (RP160157, RP170086), and the SCCC Translational Pilot Program.

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in more than 80 specialtiesto more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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UTSW study finds p53 gene plays second role in suppressing genes tied to cancer - UT Southwestern