SAN DIEGO, Aug. 09, 2022 (GLOBE NEWSWIRE) -- Codex DNA, Inc. (Nasdaq: DNAY), a pioneer in automated benchtop synthetic biology systems, today reported financial results for the second quarter ended June 30, 2022.

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Codex DNA Reports Second Quarter 2022 Financial Results

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- Announced first patient treated in Phase 1/2a clinical trial for CYNK-101 in first-line advanced HER2 positive gastric and gastroesophageal junction (G/GEJ) cancers -

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Celularity Reports Second Quarter 2022 Financial Results and Corporate Update

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OXFORD, United Kingdom, Aug. 09, 2022 (GLOBE NEWSWIRE) -- Vaccitech plc (NASDAQ: VACC) today announced its financial results for the second quarter ended June 30, 2022 and provided an overview of the Company’s recent corporate developments. Vaccitech is a clinical-stage biopharmaceutical company engaged in the discovery and development of novel immunotherapeutics and vaccines for the treatment and prevention of infectious diseases, autoimmunity, and cancer.

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Vaccitech Reports Second Quarter 2022 Financial Results and Recent Corporate Developments

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Biosimulation software and services fuel second quarter growth Biosimulation software and services fuel second quarter growth

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Certara Reports Second Quarter 2022 Financial Results

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EXTON, Pa., Aug. 09, 2022 (GLOBE NEWSWIRE) -- Idera Pharmaceuticals, Inc. (“Idera,” the “Company,” “we,” “us,” or “our”) (Nasdaq: IDRA) today reported its financial and operational results for the second quarter ended June 30, 2022.

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Idera Pharmaceuticals Reports Second Quarter 2022 Financial Results

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Achieved Record Q2 2022 FIRDAPSE® Net Product Revenues of $53.0 Million, a 57.7% YoY Increase

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Catalyst Pharmaceuticals Delivers Strong Second Quarter 2022 Financial Results with Record FIRDAPSE® Revenues and Provides Corporate Update

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SALINAS, Calif., Aug. 09, 2022 (GLOBE NEWSWIRE) -- Lowell Farms Inc. (the “Company”) (CSE: LOWL; OTCQX: LOWLF), a California-born innovator in cannabis cultivation and maker of the legendary brand Lowell Smokes, announces unaudited revenue and operating results for the second quarter (ended June 30, 2022). All figures stated are in US Dollars.

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Lowell Farms Inc. Announces Unaudited Second Quarter 2022 Financial and Operational Results

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SAN DIEGO, Aug. 09, 2022 (GLOBE NEWSWIRE) -- Cidara Therapeutics, Inc. (NASDAQ: CDTX), a biotechnology company developing long-acting therapeutics designed to improve the standard of care for patients facing serious diseases, today reported financial results for the second quarter ended June 30, 2022 and provided an update on its corporate activities and product pipeline.

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Cidara Therapeutics Provides Corporate Update and Reports Second Quarter 2022 Financial Results

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DALLAS, Aug. 09, 2022 (GLOBE NEWSWIRE) -- Taysha Gene Therapies, Inc. (Nasdaq: TSHA), a patient-centric, pivotal-stage gene therapy company focused on developing and commercializing AAV-based gene therapies for the treatment of monogenic diseases of the central nervous system (CNS) in both rare and large patient populations, today announced that it will report its financial results for the second quarter ended June 30, 2022, and host a corporate update conference call and webcast on Thursday, August 11, 2022, at 8:00 AM Eastern Time.

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Taysha Gene Therapies to Release Second Quarter 2022 Financial Results and Host Conference Call and Webcast on August 11

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INSIDE INFORMATION

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Bone Therapeutics to broaden and derisk therapeutic portfolio by acquiring majority participation in Medsenic

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LA JOLLA, Calif., Aug. 09, 2022 (GLOBE NEWSWIRE) -- MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), today announced an abstract entitled “Improvement of Serum Lipid Panel by Tipelukast (MN-001) in Type 2 Diabetes and NAFLD Patients" has been accepted and selected for poster presentation at the International Diabetes Federation (IDF) 2022 Congress to be held December 5 - 8, 2022. MediciNova’s Chief Medical Officer, Kazuko Matsuda, MD PhD MPH, will present the results of the study. Presentation details will be disseminated as they become available.

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MediciNova Announces MN-001 (tipelukast) Abstract regarding Improvement of Serum Lipid Panel in Type 2 Diabetes and NAFLD Patients Accepted for...

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WROC?AW, Poland, Aug. 10, 2022 (GLOBE NEWSWIRE) -- Captor Therapeutics S.A. (WSE:CTX), a biopharmaceutical company dedicated to the development of Targeted Protein Degradation (TPD)-based drugs for the treatment of cancer and autoimmune diseases, today announces that it has selected CPT-6281 as drug candidate for the CT-01 project, which will initially focus on the clinical development of the asset as a TPD treatment against hepatocellular carcinoma (HCC). The announcement of the drug candidate confirms that CPT-6281 is on track to enter the clinical phase in 2023.

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Captor Therapeutics Nominates the Molecular Glue CPT-6281 as Drug Candidate to Enter CTA/IND-Enabling Studies for the Treatment of Hepatocellular...

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The concept of synthesizing small-scale human organs in lab dishes has matured from pure science fiction to legitimate bioscientific reality in recent years. However, the usefulness of organoids as a research tool for studying the digestive system quickly ran into a roadblock, due to the fact that these in-demand tissues remain difficult to create.

Organoids are stem cell-derived three-dimensional tissue cultures that are designed to exhibit detailed characteristics of organs or act as model organs to produce a specific cell type in laboratory conditions. However, when growing organoids, the yield from each batch of starting material can vary massively and can even fail to produce any viable organoids at all. This of course results in severe delays in their production and utilization in pre-clinical experiments that test the efficacy and safety of drugs.

In a recently published paper from Stem Cell Reports, researchers from Cincinnati childrens (OH, USA) have developed a new practice that overcomes the organoid production hurdle. This novel procedure is already being utilized within the medical facility to boost organoid studies. However, because the materials utilized can be frozen and thawed while still producing high-quality organoids, this discovery allows for the shipment of starter materials to other labs anywhere in the world, foreseeably leading to a dramatic increase in the utilization of human gastrointestinal organoids in medical research.

This method can make organoids a more accessible tool, explains the first author Amy Pitstick, manager of the Pluripotent Stem Cell Facility at Cincinnati Childrens. We show that the aggregation approach consistently produces high yields and we have proven that precursor cells can be thawed from cryogenic storage to produce organoids of the small intestine.

Using this approach will make it possible for many research labs to use organoids in their experiments without the time and expense of learning how to grow induced pluripotent stem cells (iPSCs), states corresponding author Chris Mayhew, director of the Pluripotent Stem Cell Facility. The ability to freeze the precursor cells also will allow labs to easily make organoids without having to start each new experiment with complicated and highly variable iPSC differentiation.

Generally, organoid creation begins with the collection of skin or blood cells, which are then transformed in the lab to become induced pluripotent stem cells. To create intestinal organoids, highly skilled lab professionals produce a flat layer of organ precursor cells known as the mid-hindgut endoderm.

Under the correct conditions, early-stage organoids, termed spheroids, autonomously develop into a three-dimensional ball of cells. These are then collected and placed into a growth medium, which supplies the required signals for the cells to develop into the specialized cell types of a human organ.

However, the quantity of spheroids produced in this manner has been unpredictable. The Cincinnati Childrens researchers discovered that they could harvest the unused precursor cell layer and employ a centrifuge to transport cells into hundreds of tiny wells housed on small plastic plates. This causes the creation of 3D cell aggregates, which may then be collected and utilized to produce organoids.

The experiment described in the research paper demonstrates that the spheroids created in this manner had no discernible differences from those that formed naturally. The scientists then stored samples of the progenitor cells in freezers. These cells generated viable spheroids after being frozen and aggregated.

The paper goes on to verify that these spheroids can be consistently grown into mature organoids, which can simulate organ function. In the case of this research, the mature organoids went on to mimic the function of the small intestine, large intestine and the antrum, the portion of the stomach that links to the intestine.

Although this development is a welcome and promising advance in organoid fabrication, years of research will be required to create organoids large enough and complex enough to be utilized as replacement tissue in transplant surgery. However, having access to a large number of readily manufactured organoids offers up numerous possibilities for medical study.

More labs will be able to create patient-specific organoids in order to evaluate drugcombination therapiesfor precision treatment of complex or rare disease states that necessitate personalized care. Scientists also conducting basic research to understand more about the genetic factors and molecular pathways at play in digestive tract diseases will be able to incorporate organoids in their experiments by procuring frozen spheroid precursors.

In his current effort to generate transplantable intestinal tissues, Michael Helmrath, Director of Clinical Translation for the Center for Stem Cell & Organoid Medicine (CuSTOM) at Cincinnati Childrens, has already begun employing materials made from this new method.

This is a great step forward for the field on many fronts, Helmrath says. To be able to reduce the complexity of the process and provide higher yields is beneficial to our work. And to be able to translate the methods to other labs will help move regenerative medicine forward.

Source: https://linkinghub.elsevier.com/retrieve/pii/S2213671122003599

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New milestone organoid synthesis will boost disease and drug development research - RegMedNet

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that targets motor neurons, gradually bereaving patients of their ability to control muscle movements. Scientists discovered more than 50 potential disease-causing genes and linked several cellular pathways to ALS, but the syndromes diverse clinical and genetic nature make it difficult to predict and interfere with disease progression.1

Researchers discovered a T cell population in mice that mirrors ALS-4 disease progression.

In a recent study published in Nature, Laura Campisi, Ivan Marazzi, and colleagues at Icahn School of Medicine at Mount Sinai discovered an immune cell signature in patients with early onset ALS (ALS-4) that mirrors disease progression and may contribute to neuronal death.2 These findings could have significant implications for ALS diagnostics, prognostics, and therapeutics.

Laura Campisi joined Marazzis laboratory wanting to better understand how the body mounts immune responses. She set out to molecularly profile activated immune cells and discovered several immunity regulators, including SENATAXIN (SETX). Because SETX mutations cause ALS-4, Campisi wondered if ALS might join the suite of other neurodegenerative diseases such as narcolepsy, Alzheimers disease, and Parkinsons disease that scientists recently connected to the immune system.3,4,5,6

To test whether the immune system plays a role in ALS-4 disease progression, Campisi turned to a mouse model that carries the most common human SETX mutation.7 She replaced their mutated hematopoietic stem cells (HSCs)progenitors that form immune cellswith wildtype ones and found that they protected against disease. In contrast, replacing healthy HSCs with SETXmutant ones in wildtype mice did not cause disease. This set of experiments showed that mutant HSCs and their progeny contribute to disease, but do not cause disease on their own. This is extremely strong preclinical evidence that forms a basis for pharmaceutically targeting these cells, said David Gate, an assistant professor of neurology at Northwestern University, who was not involved in this study.

Campisi and her colleagues next characterized the immune system in pre-symptomatic mice and discovered an ALS-specific immune cell signature: ALS-4 mice contained more CD8+ T cells in their blood and cerebrospinal fluid (CSF) prior to symptom onset, and this cell population continued to expand as the disease progressed. While Campisis team faced pandemic-related difficulties in recruiting enough ALS-4 patients to confirm these findings, they are now teaming up with clinicians to expand their preclinical trials. We want to follow this [T cell] population in patients to see if they express specific markers that can predict if and when the disease progresses, Campisi said.

My hypothesis is that the T cells are autoreactive, so they are reacting against a cellular antigen.Laura Campisi, Icahn School of Medicine at Mount Sinai

To find what these T cells responded to, Campisi sequenced them and found that nearly all cells expressed the same T cell receptor, suggesting they bind the same antigen. The problem is that it is very difficult to find the antigen. I dont think it is an infection because [the] mice live in a pathogen-free facility. My hypothesis is that the T cells we found are autoreactive, so they are reacting against a cellular antigen, Campisi said.

Given that ALS targets motor neurons, Campisi wondered if the ALS-4 T cells promoted disease progression because they react to and are activated by a protein in the brain. To test this hypothesis, Campisi injected ALS-4mice with brain cancer cells that express neuronal antigens to see if the T cell population would react and confer protection against the cancer type. It was pretty striking: the tumors became so big in wildtype mice that I had to stop the experiment, but the [mutant] mice that were in the same cage were completely fine, their tumor was not growing, Campisi said. In contrast, there was no protection against skin-related cancer cells that she injected as a control. The T cells that infiltrated the ALS-4 mices brain tumors expressed the same T cell receptor as cells found in their CSF. While Gate cautions that cancer cells typically express many newly created neoantigens, Campisis data suggests that the T cell population likely recognizes a brain cell-related antigen.

Campisis challenge now lies in identifying the actual antigen and therapeutically targeting these T cells to slow and restrict the disease course. In ALS, you probably have a defect that starts with neurons, triggering a cascade of events. So, even if you restore what is wrong in neurons, we have to [also] target the other players, Campisi said.

References

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Mutant T Cells That Drive Amyotrophic Lateral Sclerosis (ALS) Progression May React To a Brain Antigen - The Scientist

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Professor Augustinus Baders skincare products contain the patented TFC8 technology, backed by 30 years of science and research - and results have shown an increase by 110% of more elasticity in the skin as well!

Image: Augustinus Bader)

When we hear on the grapevine that celebrities are obsessing over skincare products or with a beauty brand - we too are equally eager to hear the secret behind their gorgeous, glowing skin.

Augustinus Bader, whos earned a cult-beauty status thanks to his rejuvenating skin care products, is the man whom Jennifer Aniston, Kim Kardashian and Victoria Beckham all love too. And its not just celebrities who hail his namesake products as the secret weapon behind nourished and renewed skin, but beauty editors and dermatologists too. Not to mention contain the patented TFC8 technology, which is backed by 30 years of science and research.

And we have a way to you can get 20% off your next order, thanks to the auto-replenish programme! Customers are able to save 20% on each order when they subscribe to regular, customisable, delivery cycles. How cool is that?

Augustinus Bader

Augustinus Bader

Augustinus Bader

And its so simple too!

The skincare formulas are hand crafted by Professor Augustinus Bader in his own laboratory. Hes a globally recognised biomedical scientist, physician and one of the foremost experts in the field of stem cell biology and regenerative medicine. So its no wonder why celebs are quick to reach for his products before hitting the red carpet.

Not to mention his products have received 90 industry awards in just four years - and products have been voted The Greatest Skincare Of All Time.

Best of all? The results of Augustinus Bader products are proven through extensive clinical trials - and who wouldnt want younger looking skin in as little as four weeks?

Based on a 4-week clinical trial, with participants using hero product The Rich Cream: Forehead wrinkles visibly reduced by 37%, crow's feet wrinkles visibly reduced by 54%, crow's feet fine lines visibly reduced by 46% and of those testers, skin felt 92% firmer and 110% more elasticity in the skin - in just 4 weeks!

So what are you waiting for? Give Augustinus Bader products a go and see how your skin can change in four weeks too!

Have you used any of the Augustinus Bader skincare products before? Or are you keen to give them a try and see what they could do for you? Let us know your thoughts in the comments section below.

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Victoria Beckham and Kim Kardashian are fans of Augustinus Baders skincare range - and you can get 20% off - The Mirror

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The procedure recommended by most doctors might not always be a good option, as it could turn a potentially benign situation into a malignant one.

Thomas Seyfried, Ph.D., professor in the biology department at Boston College, is a leading expert and researcher in the field of cancer metabolism and nutritional ketosis. His book, Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer is a foundational textbook on this topic, and in August 2016, he received the Mercola.com Game Changer Award for his work.

Here, we discuss the mechanisms of cancer and the influence of mitochondrial function, which plays a crucial role in the development and treatment of this disease. Hislandmark cancer theory is available as a free PDF.

Many of his views are now encapsulated in his most paper,1Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis, published online December 27, 2018. Hes also published a number of other papers2,3,4on the metabolic underpinnings of cancer.

The paper is a review and hypothesis paper identifying the missing link in Otto Warburgs central theory,Seyfried explains. [Warburg] defined the origin of cancer very accurately back in the 1920s, 30s, 40s and 50s in his work in Germany. Basically, he argued and provided data showing that all cancer cells, regardless of tissue origin, were fermenters. They fermented lactic acid from glucose as a substrate.

Even in the presence of oxygen, these cells were fermenting. This is clearly a defect in oxidative phosphorylation. The problem is that for decades, people said Warburg was wrong mainly because we see a lot of cancer cells take up oxygen and make adenosine triphosphate (ATP) from within the mitochondria People began to question, If cancer cells have normal respiration, why would they want to use glucose as a fermentable fuel?

The whole concept became distorted The cancer cells simply choose to ferment rather than respire. Now, of course, if you look under the electron microscope at majority of cancers, youll see that the mitochondria are defective in a number of different ways. Their structures are abnormal. The numbers are abnormal. There are many abnormalities of mitochondria seen directly under electron microscopy. Clearly, Warburg was not wrong.

Before we delve into the meat of how cancer actually occurs it would be good to review a diagnostic strategy that nearly all of us are offered when confronted with a cancer diagnosis. It is vital to understand that this may not be your best strategy and that for many it would be wise to avoid the biopsy.

Seyfried warns against doing biopsies, as this procedure may actually cause the cancer to spread. A tumor is basically a group of proliferating cells in a particular part of your body. For purposes of diagnosis, a small biopsy sample will often be taken to ascertain whether the tumor is benign or malignant.

The problem is that when you stab into the cancer microenvironment to remove a part of the tissue, it creates a wound in that microenvironment that in turn elicits the invasion by macrophages and other immune cells.

If you already have an acidic microenvironment, you run the risk of causing a fusion hybridization event in that microenvironment between your macrophages and cancer stem cells (as discussed below). This could turn a potentially benign situation into a malignant one, and if the tumor is malignant, stabbing into it could make a bad situation worse.

The question is, what is the value of doing a biopsy in the first place? We take biopsies of breast tissue to get a genomic readout of the different kinds of mutations that might be in the cells. Now, if cancer is not a genetic disease and the mutations are largely irrelevant, then it makes no sense to do that in the first place. If the tumor is benign, why would you want to stab it? If the tumor is malignant, why would you ever want to stab it?

I came to this view by reading so many articles in the literature based on brain cancer, breast cancer, colon cancer, liver cancer showing how needle biopsies have led to the dissemination of these tumor cells, putting these people at risk for metastatic cancer and death,Seyfried says.

In metabolic therapy you would not touch the tumor; you would not disturb the microenvironment. By leaving it alone, you allow the tumor to shrink and go away.

When you start to look at this as a biological problem, many of the things that we do in cancer make no sense. We have, in brain cancer, people say, You have a very low-grade tumor. Lets go in and get it out. What happens is you go in and get it out, and then the following year it turns into a glioblastoma.

How did that happen? Well, you disturbed the microenvironment. You allowed these cells that are marginally aggressive to become highly aggressive. Then you lead to the demise of the patient,Seyfried says.

That happens significantly because its called secondary glioblastoma arising from therapeutic attempt to manage a low-grade tumor. The same thing can happen with all these different organs. You stab breast tumors, you stab colon tumors, you run the risk of spreading the cells

My argument is the following: If the patient has a lump, whether its in the breast, in the colon, lung or wherever or a lesion of some sort, that should be the cue to do metabolic therapy.

Do metabolic therapy first. In all likelihood, it will shrink down and become less aggressive. Then the option becomes, Should we debulk completely rather than doing some sort of a biopsy? We want to reduce the risk, because if we can catch the whole tumor completely, then we dont run the risk of spreading it

In our procedure, you bring the body back into a very high state of metabolic balance, and then you strategically go and degrade the tumors slowly without harming the rest of the body.

Radiation, chemo and the strategies that were using today dont do this. Theyre based on the gene theory of cancer that genetic mutations are causing the cell cycle to grow out of control. Well, this is not the case. Again, a lot of these toxic procedures need to be rethought, reanalyzed in my mind.

In biology, structure determines function. This is an evolutionarily conserved concept. So, how can mitochondria be structurally abnormal in tissue, yet have normal respiration? As Seyfried notes, this doesnt make sense. Confusion has arisen in part because many study cancer in culture, and make profound statements and comments regarding what happens in culture, Seyfried says.

If you look at cancer cells in culture, many of them do take in oxygen and make ATP, but at the same time, theyre fermenting. This was the conundrum. They called it the Warburg Effect. Theyre fermenting, but many people at the same time thought their respiration was normal.

This was the main problem with Warburgs theory. But Warburg clearly said in his papers [that] its not the fact that they take in oxygen; its how much ATP they can generate from oxidative phosphorylation, which is the normal respiratory capacity of the mitochondria.

As explained by Seyfried, if you measure ATP and look at oxygen consumption in tumor cells, it appears theyre making ATP and taking in oxygen, therefore, their respiration is assumed to be normal. However, when you look at the tissues in cancer patients, the mitochondria are abnormal.

What I and Dr. Christos Chinopoulos from Semmelweis University in Budapest, Hungary, who is the world-leading expert on mitochondrial physiology and biochemistry realized [was] that the mitochondria of tumor cells are actually fermenting amino acids, glutamine in particular. Theyre not respiring. Theyre fermenting an alternative fuel, which is glutamine,Seyfried says.

With this understanding, Warburgs theory can be proven correct cancer arises from damage to the mitochondrias ability to produce energy through respiration in their electron transport chain.

The compensatory fermentation involves not only lactic acid fermentation, but also succinic acid fermentation using glutamine as a fermentable fuel. Its been known for decades that glutamine is a main fuel for many different kinds of cancers, but most people thought it was being respired, not fermented.

Seyfried and Chinopoulos discovery confirms that cancer cells in fact have damaged respiration, and to survive, the cancer cells must use fermentation. The two most available fermentable fuels in the cancer microenvironment are glucose and glutamine. Hence, targeting glucose and glutamine is a crucial component of cancer treatment.

Without glucose and glutamine, the cancer cells will starve, as they cannot use ketones. The simplest approach to cancer then is to bring patients into therapeutic ketosis, and then strategically target the availability of glucose and glutamine.

Basically, what were saying [is] that mitochondrial substrate-level phosphorylation is a non-oxidative metabolism mechanism inside the mitochondria that would generate significant amounts of energy without oxidative phosphorylation,Seyfried says.

According to Seyfried, mitochondrial dysfunction is at the heart of nearly every type of cancer. Unfortunately, few oncologists have this understanding and many still believe cancer is the result of genetic defects. However, nuclear transfer experiments clearly show cancer cannot be a genetic disease.

Theres been no rational scientific argument that I have seen, to discredit the multitude of evidence showing that the [genetic] mutations are not the drivers but the effects [of mitochondrial dysfunction],Seyfried says.

As a matter of fact, theres new information now where people are finding so-called genetic drivers of cancer expressed and present in normal cells, normal skin and also esophagus This is another [issue] how you get these so-called driver mutations in normal tissues. Were also finding some cancers that have no mutations, yet, theyre fermenting and growing out of control.

There are a number of new observations coming out that challenge the concept that cancer is a genetic disease. And once you realize that its not a genetic disease, then you have to seriously question the majority of therapies being used to manage the disease. This [helps] explain [why] we have 1,600 people a day dying from cancer in the United States.

Why do we have such an epidemic of suffering and death when we have been studying this disease for decades? Well, if you look at the massive amounts of scientific papers being written on cancer, youll often find that theyre structured around gene defects.

What Im saying is that if cancer is not a genetic disease and the mutations are downstream epiphenomena, why would the field continue to focus on things that are mostly irrelevant to the nature of the disease? What Im saying is very devastating, because Im telling the majority of the people in the field that theyre basically wasting their time

I think we can drop the death rate of this disease by about 50% in 10 years if cancer is treated as a mitochondrial metabolic disease, targeting fermentable fuels rather than using toxic therapies that are focused on downstream effects.

Radiation is designed to stop DNA replication. DNA replication requires energy. If you pull the plug on their fermentable fuels, theyre not going to be able to replicate anyway All of the things that were doing to treat cancer is basically approaching the disease from a misunderstanding of the biology

We know viruses can cause cancer. We know radiation causes cancer. We know carcinogens cause cancer. We know intermittent hypoxia causes cancer. We know systemic inflammation causes cancer. We know just getting older puts you at risk for more cancer.

We know there are inherited mutations in the genome that can cause cancer. But how are all these things linked through a common pathophysiological mechanism? The common pathophysiological mechanism is damaged through the structure and function of the mitochondria.

Every one of the issues including inherited mutations, damage the respiration of a particular population of cells in a tissue. You look at the breast cancer gene (BRCA 1), for example. People will say, Cancer must be a genetic disease because you inherit a mutation that causes the disease.

You only get the disease if that mutation disrupts the function of the mitochondria. Fifty percent of women who carry the mutation never get cancer or breast cancer because the mutation, for some reason, did not damage the mitochondria in that person.

So, to summarize, the true origin of cancer is damage to the respiratory function of the mitochondria, triggering compensatory fermentation, which is run by oncogenes. Oncogenes play a role by facilitating the entry of glucose and glutamine into the cell to replace oxidative phosphorylation.

Seyfried also has a very different view on the biology of metastasis (the spread of cancer). He explains:

Weve looked at cancer stem cells in a number of our preclinical models These guys grow like crazy in place. The tumor just keeps expanding, but it doesnt spread. It doesnt spread into the bloodstream or metastasize to various organs.

We discovered a very unusual cancer 20 years ago. It took us 10 to 15 years to figure out what it was. You can put a few of these cells anywhere in the mouses body and within three to four weeks, this mouse is full of metastatic cancer. It made the cover of the International Journal of Cancer, when we published this back in 2008, but we had worked on the problem for years.

We couldnt figure out what it was that made these cells so incredibly metastatic. We found out that once we identified the biology of the cell, it turned out [it has] many characteristics in common with the macrophage, which is one of the most powerful immune cells in our body.

We said, Wow. Is this unique only to this kind of cell or do metastatic cancers in humans also express characteristics of macrophages? We looked and we found that almost every major cancer that metastasizes has characteristics of macrophages. Then we said, Well, how could this possibly happen? Is it coming from the macrophage?

A number of scientists have all clearly shown that there is some fusion hybridization character going on. In other words, macrophages, our wound-healing cells, they come into a microenvironment where you might find many proliferating neoplastic stem cells, but they dont have the capacity to metastasize.

Its only when the macrophages fuse with these stem cells that you have a dysregulated energy metabolism coming in this hybrid cell. This hybrid cell now has characteristics of both stem cells and macrophages.

The stem cell is not genetically equipped to enter and exit tissue. The macrophage, as a normal cell of your body, is genetically equipped to enter and exit tissue and live in the bloodstream. Theyre very strongly immunosuppressive. These are all characteristics of metastatic cancer.

According to Seyfried, metastatic cancer cells are essentially a hybrid, a mix of an immune system cell and a dysregulated stem cell, the latter of which could originate from a disorganized epithelial cell or something similar. In short, its a hybrid cell with macrophage characteristics.

Macrophages are essential for wound healing and part of our primary defense system against bacterial infections. They live both in the bloodstream and in tissues, and can go anywhere in the body. When an injury or infection occurs, they immediately move in to protect the tissue.

The metastatic cancer cell has many of those same properties,Seyfried explains,But the energy and the function of the cell is completely dysregulated, so it proliferates like crazy but has the capacity to move and spread through the body, so its a corrupted macrophage. We call it a rogue macrophage.

Like macrophages, metastatic cancer cells can also survive in hypoxic environments, which is why most angiogenic therapies are ineffective against metastatic cancer.

So, what do these metastatic hybrid cells need to survive? Both macrophages and immune cells are major glutamine consumers, and according to Seyfried, you can effectively kill metastatic cells by targeting glutamine.

However, it must be done in such a way so as to not harm the normal macrophages and the normal immune cells. In other words, it must be strategic. For this reason, Seyfried developed a press-pulse therapy for cancer, which allows the patient to maintain normal immune system function, while at the same time targeting the corrupted immune cells the macrophage fusion hybrid metastatic cells as well as inflammation.

The therapies we are using to attempt to kill these [metastatic] cells put us at risk for having the cells survive and kill us. You can control these cells for a short period of time, but they can hunker down and enter into some sort of a slightly dormant state, but they reappear.

People say, Oh, these tumor cells are so nifty and smart they can come back at you. The problem is youve never really challenged them on their very existence, which is they depend on fermentation to survive. If you dont target their fermentation, theyre going to continue to survive and come back at you.

Many of the therapies that we use radiation, chemo and some of these other procedures are not really going after the heart of the problem. That oftentimes puts you at risk for the recurrence of the disease. Your body is already seriously weakened by the toxic treatments. And in the battle, you lose. If you are fortunate enough to survive your body is still beat up.

You have now put your [body] at risk for other kinds of maladies Why are we using such toxic therapies to kill a cell when we know what its weaknesses are? These are the paradigm changes that will have to occur as we move into the new era of managing cancer in a logical way.

To properly address cancer, then, you need to clean up the microenvironment, because the microenvironment will strategically kill cells that are dependent on fermentation while enhancing cells that arent. At the same time, the microenvironment will also reduce inflammation.

You also have to be very careful not to kill your normal and healthy immune cells, because they need glutamine too,Seyfried says. What we find is that when we strategically attack the tumor this way, it turns out that our immune cells are paralyzed.

The cancer cells are killed, but the normal immune cells are paralyzed. Theyre not dying, theyre just not doing their job. What we do is we back off the therapy a little; allow the normal immune cells to regain their biological capacity, pick up dead corpses, heal the microenvironment, and then we go after the cancer cells again.

Its a graded response, knowing the biology of the normal cells and the abnormal biology of the tumor cells. This is a beautiful strategy. Once people know how you can play one group of cells off another, and how you can strategically kill one group of cells without harming the other cells, it really becomes a precision mechanism for eliminating tumor cells without harming the rest of the body.

You dont need to be poisoned and irradiated. You just have to know how to use these procedures to strategically kill the cells. Protecting normal macrophages is part of the strategic process. Killing the corrupted ones is part of the strategic process. Again, you have to put all of these together in a very logical path. Otherwise, youre not going to get the level of success that we should be getting.

This strategy is what Seyfried calls press-pulse treatment, and essentially involves restricting the fermentable fuels glucose and glutamine in a cyclical fashion to avoid causing damage to normal cells and tissues. Glucose is effectively restricted through a ketogenic diet. Restricting glutamine is slightly trickier.

The press-pulse strategy was developed from the concept of press-pulse in the field of the paleobiology. A press was some chronic stress on populations, killing off large numbers, but not everything, because some organisms can adapt to stress. The pulse refers to some catastrophic event.

The simultaneous occurrence of these two unlikely events led to the mass extinction of almost all organisms that existed on the planet. This was a cyclic event over many hundreds of millions of years. The geological records show evidence for this press-pulse extinction phenomenon.

What we simply did was take that concept and say, Lets chronically stress the tumor cells. They need glucose. You can probably kill a significant number of tumor cells by just stressing their glucose. Thats the press. The press is different ways to lower blood sugar. You put that chronic stress on top of the population either by restricted ketogenic diets [or] therapeutic fasting. There are a lot of ways that you can do this.

Also, emotional stress reduction. People are freaked out because they have cancer, therefore their corticoid steroids are elevated, which elevates blood sugar. Using various forms of stress management, moderate exercise all of these will lower blood sugar and contribute to a chronic press and stress on the cancer cells.

However, youre not going to kill all cancer cells if you just take away glucose. Because the other fuel thats keeping the beast alive is the glutamine. We have to pulse, because we cant use a press for glutamine targeting, because then youre going to kill your normal immune cells or impair them, and they are needed for the eventual resolution of the disease.

What were going to do is were going to pulse various drugs. We dont have a diet system that will target glutamine. Glutamine is everywhere. Its the most abundant amino acid in your body But you have to use [the drugs] very strategically; otherwise they can harm our normal immune system and then be counterproductive

I think that once we understand how we can target effectively glutamine without harming our normal immune cells this is the strategy that will make most of these other therapies obsolete Its cost-effective and non-toxic and it will work very well.

But were still at the very beginning of this. We need to continue to develop the doses, timing and scheduling of those drugs that are most effective in targeting glutamine that can be done without harming the rest of the cells in our body.

If you would like to support Dr. Seyfrieds research, please consider making a donation to the Foundation For Metabolic Cancer Therapies. The donation tag is on the top row of the of the foundationsite. This Foundation is dedicated to supporting Dr. Seyfrieds studies using metabolic therapy for cancer management with 100% of the donated funds going directly to research on metabolic therapy for cancer.

Originally published July 31, 2022 on Mercola.com

Views expressed in this article are the opinions of the author and do not necessarily reflect the views of The Epoch Times. Epoch Health welcomes professional discussion and friendly debate. To submit an opinion piece, please follow these guidelines and submit through our form here.

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Why Glucose Restrictions Are Essential in Treating Cancer - The Epoch Times

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Raising the dead sounds like science fiction, but a team of medical scientists at Yale University have managed to achieve just thatat least on a cellular level. They successfully revived cells from pigs that were dead for an hour, as a Nature study published August 3 reports. While the study authors emphasize the technology is ages away from being used on people, the work could eventually help keep human tissues alive longer, increasing the supply of viable organs for transplants.

These cells are functioning hours after they should not be, said Nenad Sestan, a professor of neuroscience and comparative medicine at Yale and lead author of the study, in a news briefing per CNN. And what this tells us is that the demise of cells can be halted. And their functionality restored in multiple vital organs. Even one hour after death.

Sestan and his colleagues received 100 pigs from a local breeder. They placed the pigs on ventilators and shocked the animals hearts to induce cardiac arrest. An hour after confirmed death, the Yale scientists used two systems to pump blood back into the bodiesan ECMO machine removed carbon dioxide and added oxygenated blood to one group, while another device, called OrganEx, pumped artificial blood back into the other. That fluid entered the blood vessels of the dead pigs, where synthetic forms of hemoglobin and other molecules protected cells from degradation and stopped blood clots.

After six hours, the researchers recorded signs of oxygen recirculating into the pigs tissues. A heart scan confirmed signs of electrical activity in the heart of pigs on the OrganEx machine, though those organs did not fully restart. Elsewhere, there were signs of business as usual, too: The livers of the deceased pigs resumed production of a protein called albumin. Additionally, the cells of other vital organs were responsive to glucose, suggesting the pigs metabolic processes were working again.

The experiment is not the first time scientists have tried to redefine life and death. In the early 20th century, there were attempts to reboot the brains of deceased monkeys. And in 2019, neuroscientists reanimated the brains of decapitated pigs four hours after they died in a slaughterhouse.

Studies such as these raise questions about what it means to be dead. We presume death is a thing, it is a state of being, Nita Farahany, a Duke law professor who studies ethical, legal and social implications of emerging technologies, told The New York Times. Are there forms of death that are reversible? Or not?

The findings also call into question who is considered legally dead, especially as medicine adapts to make cardiac death one day reversible. People tend to focus on brain death, but theres not much consensus on when cardiac death occurs, Arthur Caplan, a bioethicist at New York University told Nature News. This paper brings that home in an important way.

Ethical challenges abound if technology such as this were applied to people. In 2016 Indias medical research council, citing ethical concerns, blocked a planned clinical trial that aimed to revive brain-dead people to a minimally conscious state using a mix of stem cells and other techniques.

While the current study showed no signs of brain activity in the pigs, the researchers observed the heads, necks, and torsos moved. If brain activity was restored, there is no telling how functional or conscious the pigs would be, making it one of a slew of ethical questions scientists will need to answer as they breach this murky area of science.

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Heart failure in obesity: insights from proteomics in patients treated with or without weight-loss surgery | International Journal of Obesity -...

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Research led by Muhammad Riaz, PhD, Jinkyu Park, PhD, and Lorenzo Sewanan, MD, PhD, from the Qyang and Campbell laboratories at Yale, provides a mechanism to identify abnormalities linked with a hereditary cardiac condition, hypertrophic cardiomyopathy (HCM), in which walls of the left ventricle become abnormally thick and often stiff. The findings appear in the journal Circulation.

Patients with familial HCM have an increased risk of sudden death, heart failure, and arrhythmias. HCM is the most common inherited cardiac disease, affecting one in 500 people. The disease is thought to be caused by mutations that regulate cardiac muscle contraction, compromising the hearts ability to pump blood. However, the mechanisms behind the disease are poorly understood.

For this multi-model study, the researchers used stem cell approaches to understand the mechanisms that drive inherited HCM. The technology, induced pluripotent stem cells (iPSCs), can accelerate insights into the genetic causes of disease and the development of new treatments using the patients own cells.

This is a humbling experience that a patients disease phenotypes teach researchers fundamental basic knowledge that sets the stage for innovative new therapies. Furthermore, our research has established a great model to assist many physicians at Yale School of Medicine and Yale New Haven Hospital to unravel mechanistic insights into disease progression using the patients own iPSCs and engineered tissues, said Yibing Qyang, PhD, associate professor of medicine (cardiology) and of pathology.

We wanted to understand the disease mechanism and find a new therapeutic strategy, Park said.

Probing the heart disorders mechanismThe concept originated with an 18-month-old patient who suffered from familial HCM. Through a collaboration with Daniel Jacoby, MD, adjunct associate professor of cardiovascular medicine and an expert on HCM, who provided medical care for this patient, Park and the team used stem cell technologies to address a fundamental question, the disease mechanisms behind HCM. They collected 10 cc of the patients blood and introduced stem cell factors into the blood cells to generate self-renewable iPSCs. By applying cardiac knowledge, they coaxed iPSCs into patients own cardiomyocytes (heart cells) for cardiac disease studies. We discovered a general mechanism which explains the disease progression, said Park.

Next, they engineered heart tissues that resembled the early-onset disease scenario of the young patient. The disease was a severe presentation at the age of 18 months, which suggested that the disease started at the fetal/neonatal stage.

The next phase of the study was to recreate a 3-D model that was used to mimic the progression of the disease, including mechanical properties such as contraction and force production of that muscle, to understand how much force is compromised if the mutation is present. This was performed in collaboration with Stuart Campbell, PhD, and Sewanan from Yales Department of Biomedical Engineering. Coupled with computational modeling for muscle contraction, the authors developed robust systems that allowed them to examine the biomechanical properties of the tissue at three-dimensional levels.

Finally, using advanced gene editing technologies, the research team modified these mutations. They discovered that after the mutations were corrected, the disease was reversed. These insights about sarcomeric protein mutations could lead to novel therapeutics for HCM and other diseases. The interaction between mutations could also suggest that the same biomechanical mechanism exists in other conditions such as ischemic heart disease.

Our research has established a great model to assist many physicians at Yale School of Medicine and Yale New Haven Hospital to unravel mechanistic insights into disease progression using the patients own iPSCs and engineered tissues.

Yibing Qyang, PhDWe can apply these findings to cardiac conditions associated with hypertension, diabetes, or aging, said Riaz.

Applying the findings to heart diseaseOne of the fundamental challenges was that we needed to generate iPSCs from the patients family, Riaz added. Using this technology, Park was able to recreate primary cells from the cells of a patient with HCM, a process which takes over a month. Riaz and Park used stem cells to identify the vital role of pathological tissue remodeling, which is caused by sarcomeric hypertrophic cardiomyopathy mutations.

We are hopeful that our findings will be replicated in the scientific community, said Riaz. This is an example of bed to bench research, where scientists extract materials from clinics and conduct the experiment in the laboratory and then discover new methods to treat patients.

The authors also noted that RNA sequencing could be used as a guide to characterize the disease at a molecular level. Scientists may be able to identify more targeted drugs by examining the biomechanical properties of the tissue. We can now screen multiple drugs to see whether any of those drugs are able to rescue the phenotype, they said.

Riaz, now an associate research scientist in the Qyang lab, began as a cancer researcher. He earned a PhD from the Erasmus University Medical Center, based in Rotterdam, Netherlands. He later studied genetic disorders in skeletal muscle disease before joining the lab in 2017.

Park, also from the Qyang lab, graduated from Seoul National University, South Korea in 2013. He completed postdoctoral research at the University of Missouri where he focused on vascular biology and emerging areas in stem cell technology.

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Yale University: Uncovering New Approaches to a Common Inherited Heart Disorder | India Education - India Education Diary

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Immediate cord clamping (ICC), within a few seconds after birth, became routine in the latter half of the 20th century, as part of a tranche of medical birth-related interventions that collectively, undoubtedly improved maternal and neonatal survival and outcomes [1]. The trend to ICC (within 15-20 seconds after birth) was partly driven by some early studies suggesting that the most benefit in terms of blood volume is achieved within this time frame [2], and that deferred cord clamping (DCC) increased rates of polycythemia and jaundice [1]. It may also have been partly driven by increased rates of operative deliveries and consequent pressure to minimize surgical times, as well as the increased availability and effectiveness of neonatal resuscitation. Furthermore, ICC was proposed as a means to reduce the risk of maternal exposure to fetal blood group antigens at a time (before RhD immunoprophylaxis) when hemolytic disease of the fetus and newborn was far more common than it is now.

Formal evidence that ICC was beneficial was never sought, and recent research summarized in systematic reviews [3-6] has suggested that it may be harmful when compared with DCC for various intervals from 30 seconds until when the cord stops pulsating (defined in some studies as physiological cord clamping). ICC before the onset of breathing exposes the newborn baby to a period of significantly restricted cardiac function, whereas DCC until after the onset of breathing (which often does not occur until late in the first minute after birth) may mean that the expanding pulmonary circulation is able to fill with blood from the placenta, rather than by reverse flow across the ductus arteriosus [7]. This may improve left ventricular preload and stabilize pressures and flows in major vessels [7].

In addition, when cord clamping is deferred, babies may receive a transfusion of blood from the umbilical cord and placenta. A recent systematic review demonstrated that DCC in preterm babies improves peak hematocrit in the first week by 2.7% (95% confidence intervals (CI) 1.88-3.52) and reduced the proportion of babies receiving any subsequent blood transfusion (RD: -0.07, 95%CI -0.11 to -0.04) [6]. Some studies have found a weight increase in the first two minutes after birth when the cord is not clamped, supporting the hypothesis of placental transfusion [8]. Yet, recent evidence shows that placental transfusion may not always occur (Conference abstract: Vijayaselvi R, Abraham A, Kumar M, Kuruvilla A, Mathews J, Duley L. Measuring Umbilical Flow and Placental Transfusion for Preterm Births: Weighing Babies at 33-36 Weeks Gestation with Cord Intact. 1st Congress of Joint European Neonatal Societies; 2015).

The relative roles of cardiovascular stabilization at birth versus placental transfusion in improving outcomes have not been established. Understanding the contributions of these two mechanisms has significant implications for research and practice: for example, if the size of placental transfusion is more important, then prescribing a top-up transfusion soon after birth for babies with lower than average hemoglobin (who are known to be at higher risk of various adverse outcomes) [9] may be justified, especially for the babies for whom DCC has been precluded by maternal or fetal conditions. These include significant maternal bleeding, and monochorionic twins, where deferred cord clamping in the first twin could lead to one twin losing blood to the other. However, if it is the effects on improving cardiovascular stability in the first minutes (with consequential benefits for cardiorespiratory function and reducing severity of illness during the subsequent neonatal intensive care unit (NICU) stay), regardless of the magnitude of transfusion, then early top-up transfusion is unlikely to be helpful.

Observational studies suggest that exposure to blood transfusion itself is harmful to preterm babies, increasing the risk of adverse outcomes [10]. However, this suggestion has not been supported by the small number (to date) of randomized controlled trials of blood (red cell) transfusion thresholds [11-14]. It is unlikely to be the means by which DCC reduced deaths in the largest trial to date of deferred cord clamping in preterm babies, the Australian Placental Transfusion Study (APTS), and in the most recent systematic review on this, because neither showed a difference in rates of other adverse outcomes [6,15].

Another possibility is that it is the umbilical cord blood stem cells received by the baby are the main reason for the observed benefits to both survival and reduced requirement for later blood transfusion [16]. Umbilical cord blood has been demonstrated to be such a good contributor to hematopoiesis that it is a recognized stem cell resource for pediatric and adult hematopoietic stem cell transplant [17]. In addition, umbilical cord blood is a potential regenerative and immunomodulatory agent for a variety of clinical conditions [18], so in this case, the extent of placental transfusion would be critical to the improvement of outcomes, and transfusion with adult red cells would not suffice. There are no established methods to quantify the contribution of umbilical cord stem cells to placental transfusion. However, a larger volume of placental transfusion results in the baby receiving more nucleated cells [19], including more umbilical cord stem cells.

Discerning whether these effects (initial enhanced cardiovascular stability leading to early and sustained reduction in severity of illness or volume of placental transfusion) appear to be the main driver of improved outcomes is likely to contribute to practice change, as well as to informing the design of future research studies into methods to improve outcomes of high-risk newborn babies and reduce their transfusion dependence.

The causal mechanisms of reduced transfusion requirements found in DCC relative to ICC are yet to be resolved. The aim of the study is to address the question; In preterm infants (P) does DCC (I) compared to ICC (C) reduce dependence on red cell transfusion via enhanced cardiovascular stability (mediator 1, M1) or via an increased volume of placental transfusion (M2).

The study is a nested retrospective study, called the Transfusions in the APTS Newborns Study (TITANS) (study registration: ACTRN12620000195954), of the cohort of babies who were enrolled and randomly assigned to ICC or DCC in the Australian and New Zealand (NZ) sites for APTS (study registration: ACTRN12610000633088). This design has been developed to take advantage of the comprehensive dataset already collected for APTS, and because there is currently no suitable prospective study that could address the same research questions in such a large group of participants.

Babies had been considered eligible for APTS if obstetricians or maternal-fetal medicine specialists anticipated that delivery would occur before 30 weeks of gestation. Exclusion criteria included fetal hemolytic disease, hydrops fetalis, twin-twin transfusion, genetic syndromes, and potentially lethal malformations. Further details are available in the original APTS publication [15]. In the present TITANS analysis, we will also exclude any baby with a diagnosis of hemolytic anemia or aplastic/hypoplastic anemia.

There were 1401 babies enrolled for APTS from the 13 Australian and 5 NZ hospital sites [15]. APTS data was provided to the TITANS team on 31 July, 2020. It is planned to collect additional data from Australian and NZ APTS sites using a customised, secure web-based database application (REDCap) [20], which is maintained by the University of Sydney, Sydney, Australia. Data will be obtained from source documents (patient hospital records and laboratory reports) using the electronic data collection application from each study site. The individual participant data collected will correspond to the minimum data required to answer the research questions. Baby identification (ID) and other babies details from APTS will be used to re-identify participants and link them to hospital records. Identified data will be collected, in order to allow linkage between the data newly collected from patient records and hospital laboratories and the existing APTS dataset. The data will be checked with respect to range, internal consistency, consistency with published reports and missing items. After data cleaning and analysis, data will be stored in re-identifiable form, with each participants data being identified with the same study numbering system as used for the APTS study.

We will combine the data already extracted, stored and cleaned from APTS with the additional data obtained from study sites for each participating baby, to determine which factors are most influential in reducing transfusion requirements. The specific objectives are, after adjustment for prior risk factors (listed below), to determine:

1.Whether the effect of the intervention (cord clamping) on the outcome (blood transfusions) is mediated by placental transfusion (measured by hematocrit (Hct)) as seen in Figure 1 (a, c) following the causal path X M1 Y, where X is the intervention, ICC or DCC, Y is the outcome, mediator M1 is placental transfusion, and M2 is initial severity of illness stability

2.Whether the effect of the intervention (cord clamping) on the outcome (blood transfusions) is mediated by initial severity of illness (respiratory support, sampling line yes/no and total duration number, blood pressure, cumulative blood sample volume) as seen in Figure 1 (b, c) following the causal path X M2 Y

3.Whether the effect of cord clamping intervention on the outcome (blood transfusions) is driven by multiple mediators (placental transfusion and initial severity of illness) as seen in Figure 1 (c)

4.Whether cording clamping intervention (ICC or DCC) has a direct effect on the outcome after accounting for the mediators as seen in all panels of Figure 1: X Y.

The protocol was approved by the Northern Sydney Local Health District Human Research Ethics Committee in November 2019 (Version 3.0, Reference 2019/ETH12819), the Mater Misericordiae Ltd Human Research Ethics Committee (Version 1.0, Reference HREC/MML/56247), the Mercy Health Human Research Ethics Committee (Version 2.0, Reference 2020-078), and the Southern Health and Disability Ethics Committee (Version 1.0, Reference 19/STH/195). The ethics committees have granted a waiver of consent. The study is conducted in accordance with the National Health and Medical Research Council Statement on Ethical Conduct in Research Involving Humans.

Intervention

The intervention consisted of either immediate or delayed cord clamping (as assigned in APTS). Immediate clamping was defined as clamping the cord within 10 seconds of delivery. Delayed clamping was defined as clamping the cord at least 60 seconds after delivery, with the infant held as low as possible, below the introitus or placenta, and with no palpation of the cord. Variations in the protocol were allowed if they would aid the mother, baby, or both. If the baby was non-vigorous (heart rate <100 beats per minute, low muscle tone, or lack of breathing, or crying), clinicians were allowed to break protocol using their discretion. Cord milking was not part of the protocol for either intervention. Further details may be sourced from the original APTS publication [15].

Outcomes

The primary outcome is the proportion of babies receiving red cell transfusion (for restoration of hemoglobin or blood volume). The secondary outcomes are number of transfusions per baby, cumulative transfusion volume (mL/kg) per baby, and primary reasons for each transfusion.

Putative Mediators

M1: Indicators of placental transfusion to be assessed will be hematocrit (on admission, highest on the first day, highest in the first week collected before any postnatal transfusion).

M2: Indicators of initial severity of illness to be assessed will be cumulative blood sample volume collected throughout hospital stay (number of blood tests multiplied by hospitals usual sample volume for each type of test), sampling line (umbilical arterial line or peripheral arterial line) - yes/no and total duration, mechanical ventilation or inspired O2, and blood pressure.

Sensitivity Analyses (For the Primary Outcome Analysis Only)

Sensitivity analyses will adjust for the following variables: gender, birth <27 weeks vs. 27 weeks, method of delivery (vaginal versus cesarean), intraventricular hemorrhage (IVH) (yes/no and grade III/IV yes/no), surgery for patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), and sodium in the first 24 hours of life. We will also test model assumptions relating to sequential ignorability and post-randomization confounding (discussed further in the data analysis plan).

Potential Confounders (Covariates)

The following covariates may be used for adjustment in the analysis: gestational age at randomization before birth and any oral iron supplement pre-transfusion.

Timing of Assessments

Putative mediating variables will only be analyzed if they have been measured before the outcome and will be excluded if there is not adequate time and date information available. If the multiple mediator model is applied, careful consideration of timing information will be evaluated. If there is insufficient empirical information to conclude the causal ordering of mediators (M1 causes M2), we will adjust our analytic approach (as discussed in the analysis plan) and discuss any limitations.

Data Analysis Plan

The analysis will include all babies who were initially randomized in the APTS trial for whom we were able to obtain the relevant data and be based on intention-to-treat. All statistical analyses will be conducted in R version 4.1.3 (2022-03-10; R Foundation for Statistical Computing, Vienna, Austria). Descriptive characteristics for continuous data will be presented as means or medians, as appropriate, and categorical data will be presented as frequencies and percentages.

A model-based inference approach will be applied to estimate the average causal mediation effect (ACME), average direct effect (ADE), and the average total effect as recommended [23-25]. This approach will be applied with the R mediation package [26]. We will initially fit two models, one model with mediation as the dependent variable and intervention as the independent variable (mediator model), and a second model with the outcome as the dependent variable, and both mediation and intervention as independent variables (outcome model). To account for the clustering of multiples, estimates will be calculated with generalized estimating equations with a compound symmetric correlation structure to account for within subject correlations. Depending on the outcome (binary, count, skew) these will be modelled with the appropriate family and link functions.

A counterfactual framework will be applied to the mediator and outcome models to simulate the values of the mediator and outcome to estimate the potential values of the mediator. This process is used to estimate the ACME, ADE, and average total effects; 95%CI will be estimated with 1000 bootstrap simulations.

We will apply single mediator models on both placental transfusion variables and initial severity of illness variables if mediators are statistically independent, as seen in Table 1. Independence will be tested using linear regression and any appropriate link functions. If both mediators are not statistically independent, we will investigate the possibility of multiple mediator models, which require an expanded framework for analysis [21]. Here we assume that initial severity of illness is causally related to placental transfusion. For this process, we will use the method developed by Imai and Yamamoto [21] to estimate the ACME and ADE. Following this, 95%CI will be estimated with 1000 bootstrap simulations. If theoretical and empirical timing data and sensitivity analyses suggest that M1 and M2 have non-causal correlation and may be affected by an unmeasured latent mediator, we will adjust our approach to estimate interventional direct and path-specific indirect effects [27,28].

Sensitivity analyses have been limited to a set of biologically plausible and clinically meaningful groups that will be explored by including them for adjustment with covariates, and with the introduction of interaction terms if appropriate. Missing data will be described, reasons for missing data will be explored, and the impact of missing data on conclusions about the treatment effect on the primary outcome will also be explored where possible (e.g., using sensitivity analyses and multiple imputation techniques).

Methodological Assumptions

The causal mediation approach assumes sequential ignorability: that the treatment effect on the outcome is not confounding and that the mediator effect on the outcome is not confounded. As treatment was randomly allocated to neonates, we will assume that the treatment-mediator relationship is not confounded. However, the mediator itself has not been randomized. Thus, unknown confounders may be driving a spurious effect in the mediator-outcome relationship. We will employ additional sensitivity analyses to estimate whether any mediation effects are sensitive to the violation of the assumption of sequential ignorability. To test the possibility of unmeasured confounders we will examine the correlation between residuals in the mediator model and the outcome model. If there is no correlation this would suggest there is no unmeasured confounding, if there is correlation between the residuals, an unmeasured mediator may be affecting both the measured mediator and the outcome. We will apply the method developed by Imai et al. andTingley et al. [23,26] that uses sensitivity analyses to evaluate if the ACME estimate is sensitive to unmeasured confounding.

Post-randomization confounders are dependent on the treatment allocated, affect both mediator and outcome, and can corrupt the mediation estimate. In the context of the present trial, it is possible that non-adherence to the intervention is a post-randomization confounder. We are analyzing our data based on intention to treat principles; however, a sensitivity analysis based on the actual time of cord clamping to assess the influence of non-adherence with the treatment protocol on our estimates may be performed.

Blood transfusions of neonates have been associated with a number of serious adverse outcomes [29]. Nevertheless, there are few evidence-based methods to reduce transfusion exposure [30]. The APTS study found that DCC was associated with a statistically significant reduced need for red cell transfusions by about 10% compared to ICC [15]. However, the mechanism remains unclear.

The study will, at a minimum, provide further information that should increase clinicians understanding of the pathways by which DCC (or other methods to accomplish placental transfusion) results in beneficial patient outcomes. Since one of the main barriers to implementation is lack of understanding about the mechanisms by which such a simple practice change should have such dramatic effects, this should improve adherence to recommendations to defer cord clamping for most babies, thereby reducing mortality and transfusion incidence.

By elaborating on the mechanisms, it may also provide good evidence for how other routine neonatal intensive care practices and interventions affect likelihood of needing to transfuse. Better understanding of these effects may lead to other testable hypotheses or improvements in other aspects of practice, further reducing transfusion exposure and improving other outcomes.

Potential limitations of the study include the dependence on some routinely collected clinical data, which were not collected at the time by the original study according to predefined research definitions. However, we have no reason to think that potential problems of data quality would have been influenced by study group allocation and so do not anticipate that this will be a source of bias.

Originally posted here:
Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort - Cureus

Cardiac Stem Cells Comments Off on Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort – Cureus | August 10th, 2022