Stem Cell Clinic

The First Crispr Medicine Is Now Approved in the US – WIRED

By Stem Cell Medicine

This is a terrible disease, says Samarth Kulkarni, president and CEO of Crispr Therapeutics. Every day feels like a big burden. Patients have this constant specter of mortality hanging over them.

The culprit is abnormal hemoglobin, the protein that carries oxygen through the body. The problem arises from a mutation in the HBB gene. Everyone has two copies of the geneone from each parent. Children born with sickle cell disease inherit a copy of the mutated gene from both parents.

Casgevy uses the Nobel Prizewinning technology Crispr to modify patients cells so that they produce healthy hemoglobin instead. The Crispr system has two parts: a protein that cuts genetic material and a guide molecule that tells it where in the genome to make the cut.

To do this, a patients stem cells are taken out of their bone marrow and edited in a laboratory. Scientists make a single cut in a different gene, called BCL11A, to turn on the production of a fetal form of hemoglobin that typically shuts off shortly after birth. This fetal version compensates for the abnormal adult hemoglobin. The edited cells are then infused back into the patients bloodstream.

A total of 45 patients have received Casgevy in a clinical trial. Of the 31 patients followed for two years, 29 have been free of pain crises for at least a year after receiving a single dose of their own edited cells.

Until now, the only cure for sickle cell has been a stem cell transplant from a closely related donor, but this option is available to only a small fraction of people. Transplants can also involve life-threatening risks and dont always work.

The first commercial patients to get Casgevy likely wont be treated until early next year. It takes a few weeks to collect patients cells, edit them, and perform quality control checks before the cells are ready for infusion. It takes a little bit of time to treat the patients, Kulkarni says. But we dont want to waste any timeand patients dont want to waste any time, because theyve been waiting for this for a while.

Today, the FDA also approved a second type of gene treatment for sickle cell, called Lyfgenia. This therapy does not use Crispr to cut the genome but instead adds a therapeutic gene to cells so they can produce healthy hemoglobin. Made by Bluebird Bio of Somerville, Massachusetts, it also involves modifying patients cells outside the body. In a two-year trial, pain crises were eliminated in 28 out of 32 patients between six and 18 months after treatment with Lyfgenia.

The FDA has put a black box warning on Lyfgeniaan indication of severe safety riskssince some patients who were treated with it have developed blood cancer. The agency says patients receiving it should be monitored for the rest of their lives.

Alexis Thompson, chief of the division of hematology at Childrens Hospital of Philadelphia, says these new gene therapies will be transformative for patients. I can now talk to parents about the possibility of their child perhaps being cured of sickle cell, she says A few years ago, I wouldn't dare have that conversation with a family.

See the article here:
The First Crispr Medicine Is Now Approved in the US - WIRED

Exciting Clinical Trials of New Stem Cell Injection Treatment Shows Promise for Halting Multiple Sclerosis – Good News Network

By Stem Cell Medicine

University of Milano-Biocca credit University press

A collaborative study involving experts in Europe and the US found the treatment of stem cells appears to protect the brains of MS patients from further damage.

In the first-ever clinical trials in humans, the researchers found patients injected with the stem cells exhibited no increase in disability or worsening of symptoms.

The promising study, published in the journal Cell Stem Cell, is hoped to lead to further clinical trials that could provide treatment for progressive MS.

More than two million people live with MS across the globe and, whilst some treatments currently available can reduce the severity and frequency of relapses, two-thirds of patients still transition into a debilitating secondary progressive phase of the disease within 25 to 30 years of diagnosis.

An autoimmune disorder like Lupus, ALS, and Crohns, MS is characterized by the bodys immune system attacking and damaging myelinthe protective sheath of tissue around nerve fibers, disrupting messages sent around the brain and spinal cord.

An immune cell called a microglial can attack the central nervous system in progressive forms of MS, causing chronic inflammation and damage to nerve cells.

Recent scientific advances involving the transplantation of stem cells have raised expectations that therapies could be developed to help ameliorate this damage.

Previous experiments in mice from the Cambridge University unit of the new study team have shown that skin cells reprogrammed to be brain stem cells and transplanted into the nervous system can help to reduce inflammation, and may even be able to help repair damage caused by MS.

The research team behind the latest study, incorporating experts from the UK, US, Switzerland, and Italy, completed a world-first early-stage clinical trial in which neural stem cells were injected into the brains of 15 patients with secondary MS recruited from two Italian hospitals.

Along with the Cambridge unit, teams performed the trials at the University of Milano-Bicocca, the Casa Sollievo della Sofferenza and Santa Maria Terni hospitals in Italy, the Ente Ospedaliero Cantonale hospital in Lugano, Switzerland, and the University of Colorado in the United States.

The transplant patients were followed for 12 months. No deaths or serious adverse events related to the treatment were observed throughout the year. Side effects were mild, transient, and reversible.

All patients had a high degree of disability at the start of the clinical trialfor example, they were wheelchair-boundbut during the 12-month observation period, they showed no increase in disability or worsening of symptoms. None of the patients showed symptoms that would indicate a relapse or signs of clinical progression, suggesting substantial stability of the pathology.

A subgroup of patients was also assessed for changes in the volume of brain tissue associated with disease progression, which found that the larger the dose of injected stem cells, the smaller the reduction in this brain volume over time.

HOPE FOR AUTOIMMUNE DISORDERS: MS Breakthrough: New Genetic Clues to What Triggers Multiple Sclerosis Discovered by Scientists

The researchers speculate that this may be down to the stem cell transplant dampening inflammation.

Professor Stefano Pluchino, a co-leader of the study from the University of Cambridge, admitted that though the research had limitations, the findings were extremely promising.

We desperately need to develop new treatments for secondary progressive MS, and I am cautiously very excited about our findings, which are a step towards developing a cell therapy for treating MS, he said.

OTHER STEM CELL STUDIES: Sound Waves Convert Stem Cells Into Bone in Regenerative Breakthrough

We recognize that our study has limitations: it was only a small study and there may have been confounding effects from the immunosuppressant drugs, for example, but the fact that our treatment was safe and that its effects lasted over the 12 months of the trial means that we can proceed to the next stage of clinical trials.

Professor Angelo Vescovi, another co-leader of the study from the University of Milano-Bicocca, added that it has taken nearly three decades to translate the discovery of brain stem cells into this experiment, which he said will pave the way to broader studies soon to come.

SHARE This Latest In Stem Cell Science with Your Friends

Read more here:
Exciting Clinical Trials of New Stem Cell Injection Treatment Shows Promise for Halting Multiple Sclerosis - Good News Network

Paolo Macchiarini: How ‘Dr. Death’ Scammed The World – All That’s Interesting

By Stem Cell Medicine

In 2011, Dr. Paolo Macchiarini revolutionized transplant science when he successfully placed the world's first synthetic trachea into a man in Sweden but soon, his patients began dying in droves.

In her documentary A Leap of Faith (2014), newscaster Meredith Vieira told the audience: Just imagine a world where any injured or diseased organ or body part you have is simply replaced by a new artificial one, literally manmade in the lab, just for you. This incredible future, Vieira explained, was within grasp thanks to a surgeon named Paolo Macchiarini.

Macchiarini had risen to fame in 2008 when he performed a revolutionary operation on a young mother, replacing her windpipe with a donated trachea lined with stem cells from her bone marrow. This, it seemed, heralded a new age in modern medicine. And Macchiarini became a hero doctor who performed almost two dozen tracheal regeneration procedures.

But Paolo Macchiarini was not what he seemed. Before long, his patients began to suffer from horrific side effects and most of them died. It also soon came to light that the hero doctor had not only embellished much of his resume but that he was a shameless pathological liar in his personal life.

Paolo Macchiarinis dramatic fall from grace, including criminal charges against him and the retractions of many of his research papers, will be covered in Peacocks Dr. Death as well as a new Netflix documentary.

Paolo Macchiarini was born to Italian parents in Switzerland on August 22, 1958. But the rest of his personal and professional biography should be taken with a large grain of salt.

Macchiarini claimed that he had a difficult childhood growing up in Basel and often felt like an outsider. While studying medicine at the University of Pisa, Macchiarini purportedly had a formative experience when his father fell ill and local doctors could find nothing wrong with him. Shortly thereafter, his dad died.

In Macchiarinis telling, he then left Italy to avoid a system that only rewarded those with the right connections. He claimed that he went on to study or work at the University of Alabama at Birmingham, the University of ParisSud, and Hannover Medical School. But Macchiarini would soon exaggerate his experience. He said, for example, that he earned a masters degree in biostatistics in Alabama. However, the university denies this. They say he merely completed a six-month non-surgical fellowship in hematology and oncology.

By 2008, Paolo Macchiarini was working in Spain. And it was there that he suddenly captured the worlds attention.

In June, Macchiarini performed a revolutionary surgery on a 30-year-old mother named Claudia Castillo. Castillo had damage to her airways caused by tuberculosis that caused severe shortness of breath. So Macchiarini took a donor trachea, covered it with stem cells from Castillos bone marrow, and effectively gave her a new windpipe.

We are terribly excited by these results, Macchiarini said at the time, according to The New York Times. Just four days after transplantation the graft was almost indistinguishable from adjacent normal bronchi.

He wasnt the only one who was excited. Word of the surgery quickly spread, and not only was Macchiarini heralded as the next new thing in medicine, but patients lined up to get transplants like Castillo had. In all, The New York Times reports that 20 people in Russia, Spain, Britain, the U.S., and Sweden would receive tracheal regeneration procedures performed by Macchiarini.

Paolo Macchiarinis method seemed like a miracle, and his professional reputation soared. By 2011, he was working in Sweden at the prestigious Karolinska Institute, where he modified his technique by using a plastic windpipe instead of a donors.

But in less than a decade, nearly everything about the doctors personal and professional life was revealed to be a lie.

Paolo Macchiarinis reputation received a double blow in 2016. The first came from a Vanity Fair article that laid out the incredible lies the doctor had told during his relationship with NBC producer Benita Alexander.

Alexander and Macchiarini had met during the filming of Meredith Vieiras documentary on the surgeon and his apparent medical miracles, A Leap of Faith (2014). Vieira had learned about Macchiarini in 2012, and during the making of the subsequent documentary, her producer Alexander and her subject Macchiarini fell in love. By Christmas 2013, they were engaged.

Paolo Macchiarini was well known around the world at that point, and he promised Alexander a star-studded wedding. He told her that he was Pope Francis personal doctor and that not only had the pope suggested they have the wedding at his summer residence, Castel Gandolfo, but hed even offered to officiate.

Indeed, when the couples wedding invitations arrived, Vanity Fair reports that they included potential guests like the Obamas, the Clintons, the Putins, the Sarkozys, Andrea Bocelli, Kofi Annan, Russell Crowe, Elton John, John Legend, Kenny Rogers, Meredith Vieira, and His Holiness Pope Francis.

But as Alexander prepared to move from New York to Europe to be with Macchiarini, she got an unsettling email from a friend. It clearly showed that the pope would be in South America at the same time he was supposed to be officiating her wedding. From there, with the help of a private investigator, Alexander found that almost everything Macchiarini had told her about the wedding was a lie. He didnt even know the pope and he was still married to his wife of 30 years.

Weeks after Vanity Fair exposed Macchiarinis romantic fraud, a three-part expos of the surgeons medical career aired on Swedish television. It showed that his miraculous artificial windpipes were actually doing more harm than good. Almost all of the 20 people who received an experimental trachea from Macchiarini had died. And many suffered horrible, drawn-out deaths.

According to The Guardian, one expert even remarked: If I had the option of a synthetic trachea or a firing squad, Id choose the last option because it would be the least painful form of execution.

Since he was exposed as a fraud, Paolo Macchiarini has faced criminal charges. In June 2022, he was convicted of gross assault for implanting his artificial tracheas into three patients who later died. Macchiarini was sentenced to two-and-a-half years in prison.

Questions about the miracle surgeon still linger, which will be explored in Peacocks Dr. Death and a new Netflix documentary. But it ultimately seems that Paolo Macchiarini was a con artist who scammed both his patients and people close to him.

Were taught from an early age that when something is too good to be true, its not true, a psychopathy expert told Vanity Fair. And yet we ignore the signals Macchiarini is the extreme form of a con man. Hes clearly bright and has accomplishments, but he cant contain himself. Theres a void in his personality that he seems to want to fill by conning more and more people.

After reading about Paolo Macchiarinis dramatic rise and fall, learn the story of Doctor Death Christopher Duntsch. Then, discover the story of serial killer Dr. Harold Shipman.

Go here to read the rest:
Paolo Macchiarini: How 'Dr. Death' Scammed The World - All That's Interesting

7 medical breakthroughs that gave us hope in 2023 – National Geographic

By Stem Cell Medicine

COVID-19 has continued to claim lives in 2023, killing more than 50 thousand patients in the United States alone and bringing the global death toll to almost seven million people. The pandemic has also created an epidemic of survivors who continue to suffer from long COVID. But it wasnt all bad news in 2023.

With more people becoming immune against the virus, the World Health Organization decided, on May 5, that COVID-19 no longer constitutes a public health emergency of international concern. Updated boosters of existing vaccines helped reduce the number of cases, hospitalizations, and deaths, and a new COVID vaccine from Novavax was approved this year.

Aside from COVID-19 vaccines, there were many other interesting and groundbreaking discoveries made this year, some of which are especially notable for their potential impact on health and medicine.

The worlds first CRISPR-based gene therapy was approved by drug regulators in the United Kingdom on November 16, and the U.S. on December 8. It treats sickle cell disease and beta thalassemia, genetic disorders that affect the red blood cells. Hemoglobin, found in red blood cells, carries oxygen around the body. The errors in hemoglobin genes create fragile red blood cells that cause a shortage of oxygen in the body, a condition known as anemia. Patients with sickle cell disease also suffer from infections and severe pain when sickled cells form clots and impede blood flow, while patients with beta thalassemia must receive blood transfusion every three to four weeks.

The newly approved gene therapy, named CASGEVY, corrects faulty hemoglobin genes in a patients bone marrow stem cells so they can produce functioning hemoglobin. A patients stem cells are harvested from their bone marrow, edited in a laboratory, and then infused back into the patient. A single treatment can potentially cure some patients for life.

Two inventors who fine-tuned CRISPR (short for clustered regularly interspaced short palindromic repeats) to work as a precise gene-editing tool, Emmanuelle Charpentier and Jennifer Doudna, were awarded the Nobel Prize in Chemistry just three years ago in 2020.

This is just the first of dozens of potential treatments in development to treat other genetic diseases, cancer, or even infertility.

The U.S. Food and Drug Administration approved the first drug for Alzheimers that targets one underlying cause of the disease. While the drug, Leqembi, isn't a cure or improve symptoms in late-stage disease, after 18 months of treatment it slows declines in memory and thinking by about 30 percent if the medicine is given in the early stage of disease.

Leqembi is a monoclonal antibody that works by targeting amyloid plaques in the brain that are a defining feature of Alzheimers disease. When abnormal levels of a naturally occurring protein, called beta amyloid, clump together to form sticky plaques in brain, they trigger inflammation and damage neuronal connections. Accumulation of amyloid plaques leads to loss of memory and thinking causing Alzheimers disease.

Clinical trials indicate that Leqembi removes amyloid plaques from the brain, which slows the progression of the disease.

Yes, you read that right. Researchers from Japan presented evidence at a scientific conference that it is possible to produce healthy, fertile mice without an egg from a female mouse.

First, eggs were made from the stem cells derived from the skin cells of a male mouse. These eggs were fertilized with sperm of another male and then the fertilized egg was transferred into a female mouse where it grew and matured.

Although just seven out of more than 600 implanted embryos developed into baby mice, the pups grew normally and were fertile as adults.

It is not yet known if the mouse pups will develop exactly like those born through conventional breeding. These findings have not yet been published in a peer reviewed journal and similar preliminary steps have so far failed in humans.

Scientists have produced the first complete brain-wiring diagram of an insect brain. This may not sound impressive but the brain, even that of a fruit fly, contains vast networks of interconnected neurons called the connectome.

Until now, only the brains of a roundworm, a sea squirt, and a marine worm have been completely mapped; each of which contains just a couple of hundred connections.

But a complete map of the connectome of a fruit fly larva reveals it contains more than 3,000 neurons and more than half a million connections between them. Developing this map took an international team of scientists more than five years. Although a fruit fly brain is much simpler than that of humans, the techniques developed will help map more complex brains in the future.

The neural circuits In the fruit fly brain look similar to neural networks used in machine learning. Understanding the similarities and complexities of the fly brain connectome can help to decipher how the human brain works and how neurological diseases develop. It can also lead to the development of new machine learning methods and more efficient artificial intelligence systems.

Scientists show that when pigment-producing cells, called melanocytes, get stuck in an immature state, they fail to develop their blonde, brown, red, or black, hair color. This arrested state leads to graying hairs. New hair grows from follicles, found in the skin, where melanocytes also reside.

The scientists at New York University observed single melanocyte stem cells migrate up and down the individual hair folicle of mice over two years. To their surprise, they found that melanocyte stem cells can switch back and forth from gray immature stem cells to mature colored cells as they traverse up and down during the life cycle of the hair. But as hair ages, the melanocyte stem cells get sluggish after multiple cycles and become trapped near the base of the hair as immature melanocytes. With no pigment being produced, the hair turns gray.

Scientists have found that some bacteria that are frequently found in many gastrointestinal tract tumors directly help cancer cells evade the bodys immune response.

Not only do these bacteria cooperate with tumor cells to promote cancer progression, they also help them spread more rapidly by breaking down anticancer drugs and causing the treatment to fail.

This research suggests that some anticancer drugs are effective because they also kill the tumor dwelling bacteria. Understanding how the tumor's microenvironment affects its survival and progression can open new doors of treating cancer.

A new artificial intelligence (AI) tool can predict pancreatic cancer up to three years before actual diagnosis, by identifying specific patterns of conditions that occurred in patients health records.

Pancreatic cancer is rare but it is the third largest cause of cancer-related deaths. It is so deadly because it is generally detected in the late stages when the disease has already spread to other areas of body.

Symptoms of early stage pancreatic cancer are easily misdiagnosed, but many patients could live longer if the cancer was detected early. That led scientists to train an AI algorithm on the medical records of 6.2 million people from Denmark spanning 41 years to detect the patterns hidden in the records of 24,000 patients who later developed pancreatic cancer.

In the medical records, each disease is recorded with a code. The AI model analyzed the combinations of these disease codes and the timing of their occurrence. By comparing specific sequences of conditions that preceded a diagnosis of pancreatic cancer, the AI model learned to identify those at greatest risk for the disease.

The scientists then tested the AI tool by analyzing the records of nearly 3 million U.S. veterans spanning 21 years. The computer algorithm correctly identified almost 4,000 individuals, up to three years before they were actually diagnosed with pancreatic cancer. The study shows that AI models can be as accurate as genetic testing in predicting the risk of pancreatic cancer. Because pancreatic cancer is so rare, genetic screening is currently recommended only for high risk individuals, or with those with a family history of the disease.

Editor's Note: This story has been updated to include news that the FDA approved gene therapies for sickle cell disease.

Read the original post:
7 medical breakthroughs that gave us hope in 2023 - National Geographic

F.D.A. Approves 2 Sickle Cell Treatments, One Using CRISPR Gene Editing – The New York Times

By Stem Cell Medical Center

On Friday, the Food and Drug Administration approved the first gene editing therapy ever to be used in humans, for sickle cell disease, a debilitating blood disorder caused by a single mutated gene.

The agency also approved a second treatment using conventional gene therapy for sickle cell that does not use gene editing.

For the 100,000 Americans with the disease, most of them Black, the approvals offer hope for finally living without an affliction that causes excruciating pain, organ damage and strokes.

While patients, their families and their doctors welcome the F.D.A.s approvals, getting either therapy will be difficult, and expensive.

It is practically a miracle that this is even possible, said Dr. Stephan Grupp, chief of the cellular therapy and transplant section at Childrens Hospital of Philadelphia. Dr. Grupp, who consults for Vertex, said his medical center was hoping to begin treating sickle cell patients next year.

But, he added, I am very realistic about how hard this is.

The obstacles to treatment are myriad: an extremely limited number of medical centers authorized to provide it; the requirement that each patients cells be edited or have a gene added individually; procedures that are so onerous that not everyone can tolerate them; and a multimillion-dollar price tag and potential insurance obstacles.

As a result, sickle cell experts said, only a small fraction of patients in the United States are expected to receive the new treatment (to say nothing of the millions of sickle cell patients overseas, particularly in Africa, for whom it may be completely out of reach for now). The F.DA. estimates that about 20,000 patients who are 12 and older and have had episodes of debilitating pain will be eligible for the therapies.

The gene editing treatment, called Exa-cel and using the brand name Casgevy, was jointly developed by Vertex Pharmaceuticals of Boston and CRISPR Therapeutics of Switzerland. It uses CRISPR, the Nobel Prize-winning gene editing tool, to snip patients DNA. For a small number of subjects in clinical trials, it corrected the effects of the mutation, which results in red blood cells that are shaped like sickles or crescents that become caught in blood vessels, blocking them.

Casgevy is the first treatment to be approved that uses CRISPR. Patients will also need expensive, intensive medical care and a long hospitalization.

The other treatment, called Lyfgenia and made by Bluebird Bio of Somerville, Mass., uses a common gene therapy method to add a good hemoglobin gene to patients DNA.

Vertex says its price to edit a patients genes will be $2.2 million; for, Bluebird it will be $3.1 million.

But living with the disease is also extremely costly: On average, $1.7 million for those with commercial insurance over a patients lifetime. Patients themselves may pay about $44,000 out of pocket on average over the course of their lives.

For patients and the doctors who treat them, it is tantalizing to think of being free from the complications of sickle cell. So despite the many unknowns, medical centers say they are compiling lists of interested patients who are ready to pursue treatment when it becomes available.

We are talking for the first time about survivorship, said Dr. Sharl Azar, medical director of the comprehensive sickle cell disease treatment center at Massachusetts General Hospital. Patients, said Dr. Azar, who previously consulted for Vertex, are starting to hope they can live into their 70s and 80s rather than dying young.

Treatment will start with hospital visits to collect patients bone marrow stem cells the precursors of red blood cells that are treated to enable the production of healthy blood cells. Stem cells must be released from the marrow into the blood so they can be collected. To release them, doctors inject patients with a drug, plerixafor.

It can take months to get enough stem cells to send to a central facility for treatment. And Vertex has only one gene editing facility in the United States, in Tennessee, and one in Europe, in Scotland. Bluebirds facility is in New Jersey.

After editing a patients cells with CRISPR, technicians do a sequence of quality checks. About 16 weeks after the process begins, the cells will be shipped back to the medical center to be infused into the patient, said Dr. Julie Kanter, director of the adult sickle cell center at the University of Alabama at Birmingham.

At that point, doctors must clear the patients marrow with intensive chemotherapy to make way for the new cells. Patients remain in the hospital for a month or more while their edited stem cells repopulate their marrows, during which time they have no functioning immune system.

That is if they can find a medical center that offers the new therapy. Most hospitals will not be able to offer Casgevy even if they want to. So far, Vertex has authorized only nine centers to provide its treatment. The company says it will eventually authorize about 50.

Bluebird has 27 authorized centers and also plans to add more.

The gene editing treatment is so challenging and requires so many resources that leading medical centers say that even if they are authorized to provide it they would probably only be able to treat a small number of patients a year.

We cant do more than 10 a year, said Dr. Kanter, who has in the past consulted for Vertex and Bluebird Bio.

And, Dr. Kanter said, were really good at it, adding that her medical center had extensive experience treating sickle cell patients and participating in the Bluebird clinical trials.

Others said the same. Five to 10 a year, said Dr. Jean-Antoine Ribeil, clinical director of the Center of Excellence in Sickle Cell Disease at Boston Medical Center, which says it is the largest sickle cell center in New England and is one approved by Vertex to offer its therapy.

Vertex has not revealed how many patients cells it will be able to edit each year, saying only that it is confident it can meet the demand at the time the treatment is introduced.

Nor has Bluebird. But, Dr. Grupp said, Bluebirds gene therapy for thalassemia a genetic disorder in which the body does not make enough hemoglobin gives a hint. Bluebird, he said, has only been able to treat the cells of 50 patients a year since the drug was approved in August 2022. And that is for the entire country, Dr. Grupp said.

Insurance payments pose another obstacle. Before treatment starts, a patients insurer has to agree to pay. That can take months, said Dr. David Jacobsohn, chief of the division of blood and marrow transplantation at Childrens National Hospital in Washington. His medical center is among those authorized to provide the Vertex and the Bluebird treatments.

Most sickle cell patients are insured through Medicaid, noted Dr. John DiPersio, director of the Center for Gene and Cellular Immunotherapy at the Washington University School of Medicine in St. Louis. Dr. DiPersio consults for Vertex and Bluebird.

If every sickle cell patient in Missouri gets treated, the state couldnt afford it, he said.

Another concern involves unknowns about the new therapy. While a panel of F.D.A. experts concluded that the benefits outweighed the risks, doctors remain mindful of unexpected outcomes.

We dont know yet what the long-term effects will be, Dr. DiPersio said. We havent followed patients long enough just a couple of years. And stem cells, he added, will live forever, so if CRISPR or the Bluebird gene therapy does genetic damage, it will remain.

Haja Sandi, a 19-year-old student at Rowan University in New Jersey, hopes to be at the top of the list at the Childrens Hospital of Philadelphia.

She has frequent hospitalizations for pain so intense she has to take morphine. Her symptoms have forced her into remote schooling. There is no way I could do it in person, she said.

Hearing about the Vertex therapy, she contacted the hospital in Philadelphia asking if she could get it.

God willing, I will go forward with it, she said.

The Childrens Hospital of Philadelphia, among others, is hoping to get on Vertexs list of approved centers and is planning to take eligible patients on a first-come-first-served basis.

Still others, like Childrens National Hospital in Washington, will give priority to the sickest patients.

Dr. Azar intends to take a different approach if Massachusetts General is approved. He said he wanted to proceed with extreme caution, starting with just one patient and going through the entire process before accepting more.

He worries that a misstep could sully the treatment for those who could be helped.

Going forward, the therapies will be provided without the extensive support that the companies gave to clinical trial participants. And it will be a test case for using CRISPR gene editing to treat other diseases. CRISPR Therapeutics is now studying gene editing to treat cancer, diabetes, and A.L.S., among others.

It is a blessing and curse that we are going first, Dr. Azar said. Sickle cell disease has never been first for anything.

The people seeking the therapy mostly Black patients often mistrust the health care system, he added.

We want to do this right, Dr. Azar said. We dont want patients to feel like they are guinea pigs.

Continued here:
F.D.A. Approves 2 Sickle Cell Treatments, One Using CRISPR Gene Editing - The New York Times

Mitophagy in human health, ageing and disease – Nature.com

By Stell Cell Research

Palikaras, K., Lionaki, E. & Tavernarakis, N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat. Cell Biol. 20, 10131022 (2018).

Article CAS PubMed Google Scholar

Palikaras, K., Lionaki, E. & Tavernarakis, N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525528 (2015).

Article CAS PubMed Google Scholar

Lpez-Otn, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243278 (2023).

Article PubMed Google Scholar

Lpez-Otn, C. & Kroemer, G. Hallmarks of health. Cell 184, 3363 (2021).

Article PubMed Google Scholar

Esteban-Martnez, L. et al. Programmed mitophagy is essential for the glycolytic switch during cell differentiation. EMBO J. 36, 16881706 (2017).

Article PubMed PubMed Central Google Scholar

Sandoval, H. et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 454, 232235 (2008).

Article CAS PubMed PubMed Central Google Scholar

McWilliams, T. G. et al. mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J. Cell Biol. 214, 333345 (2016).

Article CAS PubMed PubMed Central Google Scholar

Sun, N. et al. Measuring in vivo mitophagy. Mol. Cell 60, 685696 (2015).

Article CAS PubMed PubMed Central Google Scholar

Sekine, S. & Youle, R. J. PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol. BMC Biol. 16, 2 (2018).

Article PubMed PubMed Central Google Scholar

Tereak, P. et al. Regulation of PRKN-independent mitophagy. Autophagy 18, 2439 (2022).

Article PubMed Google Scholar

Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309314 (2015).

Article CAS PubMed PubMed Central Google Scholar

Zhang, T. et al. BNIP3 protein suppresses PINK1 kinase proteolytic cleavage to promote mitophagy. J. Biol. Chem. 291, 2161621629 (2016).

Article CAS PubMed PubMed Central Google Scholar

Lee, Y., Lee, H.-Y., Hanna, R. A. & Gustafsson, . B. Mitochondrial autophagy by Bnip3 involves Drp1-mediated mitochondrial fission and recruitment of parkin in cardiac myocytes. Am. J. Physiol. Heart Circ. Physiol. 301, H1924H1931 (2011).

Article CAS PubMed PubMed Central Google Scholar

Lou, G. et al. Mitophagy and neuroprotection. Trends Mol. Med. 26, 820 (2020).

Article CAS PubMed Google Scholar

Soubannier, V., Rippstein, P., Kaufman, B. A., Shoubridge, E. A. & McBride, H. M. Reconstitution of mitochondria derived vesicle formation demonstrates selective enrichment of oxidized cargo. PloS ONE 7, e52830 (2012).

Article CAS PubMed PubMed Central Google Scholar

Roberts, R. F., Tang, M. Y., Fon, E. A. & Durcan, T. M. Defending the mitochondria: the pathways of mitophagy and mitochondrial-derived vesicles. Int. J. Biochem. Cell Biol. 79, 427436 (2016).

Article CAS PubMed Google Scholar

Soubannier, V. et al. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr. Biol. 22, 135141 (2012).

Article CAS PubMed Google Scholar

McLelland, G.-L., Soubannier, V., Chen, C. X., McBride, H. M. & Fon, E. A. Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J. 33, 282295 (2014).

CAS PubMed PubMed Central Google Scholar

Nicols-vila, J. A. et al. A network of macrophages supports mitochondrial homeostasis in the heart. Cell 183, 94109 (2020).

Article PubMed Google Scholar

Liang, W. et al. Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired. Nat. Commun. 14, 5031 (2023).

Article CAS PubMed PubMed Central Google Scholar

Rosina, M. et al. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue. Cell Metab. 34, 533548 (2022).

Article CAS PubMed PubMed Central Google Scholar

Davis, C. O. et al. Transcellular degradation of axonal mitochondria. Proc. Natl Acad. Sci. USA 111, 96339638 (2014).

Article CAS PubMed PubMed Central Google Scholar

Melentijevic, I. et al. C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress. Nature 542, 367371 (2017).

Hao, T. et al. Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion. Nat. Commun. 14, 4105 (2023).

Article CAS PubMed PubMed Central Google Scholar

Wu, W. et al. FUNDC1 regulates mitochondrial dynamics at the ERmitochondrial contact site under hypoxic conditions. EMBO J. 35, 13681384 (2016).

Article CAS PubMed PubMed Central Google Scholar

Pryde, K. R., Smith, H. L., Chau, K.-Y. & Schapira, A. H. V. PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy. J. Cell Biol. 213, 163171 (2016).

Article CAS PubMed PubMed Central Google Scholar

Oshima, Y. et al. Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination. J. Cell Biol. 220, e202006043 (2021).

Article CAS PubMed PubMed Central Google Scholar

Munson, M. J. et al. GAK and PRKCD are positive regulators of PRKN-independent mitophagy. Nat. Commun. 12, 6101 (2021).

Article CAS PubMed PubMed Central Google Scholar

Gegg, M. E. et al. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum. Mol. Genet. 19, 48614870 (2010).

Article CAS PubMed PubMed Central Google Scholar

Ziviani, E. & Whitworth, A. J. How could parkin-mediated ubiquitination of mitofusin promote mitophagy? Autophagy 6, 660662 (2010).

Article PubMed Google Scholar

Palikaras, K. & Tavernarakis, N. Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp. Gerontol. 56, 182188 (2014).

Article CAS PubMed Google Scholar

Cant, C. & Auwerx, J. PGC-1, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 20, 98105 (2009).

Article PubMed PubMed Central Google Scholar

Malik, N. et al. Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1. Science 380, eabj5559 (2023).

Article CAS PubMed Google Scholar

Lionaki, E., Markaki, M., Palikaras, K. & Tavernarakis, N. Mitochondria, autophagy and age-associated neurodegenerative diseases: new insights into a complex interplay. Biochim. Biophys. Acta 1847, 14121423 (2015).

Article CAS PubMed Google Scholar

Laker, R. C. et al. Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat. Commun. 8, 548 (2017).

Article PubMed PubMed Central Google Scholar

Iorio, R., Celenza, G. & Petricca, S. Mitophagy: molecular mechanisms, new concepts on parkin activation and the emerging role of AMPK/ULK1 axis. Cells 11, 30 (2021).

Article PubMed PubMed Central Google Scholar

DAmico, D. et al. The RNA-binding protein PUM2 impairs mitochondrial dynamics and mitophagy during aging. Mol. Cell 73, 775787 (2019).

Article PubMed PubMed Central Google Scholar

Shin, H. J. et al. Pink1-mediated chondrocytic mitophagy contributes to cartilage degeneration in osteoarthritis. J. Clin. Med. 8, 1849 (2019).

Article CAS PubMed PubMed Central Google Scholar

Kuroda, Y. et al. Parkin enhances mitochondrial biogenesis in proliferating cells. Hum. Mol. Genet. 15, 883895 (2006).

Article CAS PubMed Google Scholar

Egan, B. & Zierath, J. R. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 17, 162184 (2013).

Article CAS PubMed Google Scholar

Gaitanos, G. C., Williams, C., Boobis, L. H. & Brooks, S. Human muscle metabolism during intermittent maximal exercise. J. Appl. Physiol. 75, 712719 (1993).

Article CAS PubMed Google Scholar

Sin, J. et al. Mitophagy is required for mitochondrial biogenesis and myogenic differentiation of C2C12 myoblasts. Autophagy 12, 369380 (2016).

Article CAS PubMed Google Scholar

Hong, X. et al. Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy. Cell Stem Cell 29, 12981314 (2022).

CAS Google Scholar

Leduc-Gaudet, J.-P. et al. Parkin overexpression attenuates sepsis-induced muscle wasting. Cells 9, 1454 (2020).

Article CAS PubMed PubMed Central Google Scholar

Leduc-Gaudet, J.-P. et al. Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice. Oncotarget 6, 1792317937 (2015).

Article PubMed PubMed Central Google Scholar

Garca-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature 529, 3742 (2016).

Article PubMed Google Scholar

Luan, P. et al. Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy. Sci. Transl. Med. 13, eabb0319 (2021).

Article CAS PubMed Google Scholar

Ryu, D. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879888 (2016).

Article CAS PubMed Google Scholar

Fang, E. F. et al. Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci. Rep. 7, 46208 (2017).

Article CAS PubMed PubMed Central Google Scholar

DAmico, D. et al. Urolithin A improves mitochondrial health, reduces cartilage degeneration, and alleviates pain in osteoarthritis. Aging Cell 21, e13662 (2022).

Article PubMed PubMed Central Google Scholar

Choi, S. et al. 31P magnetic resonance spectroscopy assessment of muscle bioenergetics as a predictor of gait speed in the Baltimore Longitudinal Study of Aging. J. Gerontol. A Biol. Sci. Med. Sci. 71, 16381645 (2016).

Link:
Mitophagy in human health, ageing and disease - Nature.com

From immunology to artificial intelligence: revolutionizing latent … – Military Medical Research

By Stell Cell Research

World Health Organization. Global tuberculosis report 2022. Geneva: World Health Organization; 2022. https://www.who.int/teams/global-tuberculosis-programme/tb-reports

Bagcchi S. WHOs global tuberculosis report 2022. Lancet Microbe. 2023;4(1):e20.

Article PubMed Google Scholar

Ernst JD. The immunological life cycle of tuberculosis. Nat Rev Immunol. 2012;12(8):58191.

Article CAS PubMed Google Scholar

Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017;64(2):e1-33.

Article PubMed Google Scholar

Cohen A, Mathiasen VD, Schon T, Wejse C. The global prevalence of latent tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2019;54(3):1900655.

Article PubMed Google Scholar

Khabibullina NF, Kutuzova DM, Burmistrova IA, Lyadova IV. The biological and clinical aspects of a latent tuberculosis infection. Trop Med Infect Dis. 2022;7(3):48.

Article PubMed PubMed Central Google Scholar

Houben RMGJ, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 2016;13(10):e1002152.

Article PubMed PubMed Central Google Scholar

Jilani TN, Avula A, Zafar Gondal A, Siddiqui AH. Active tuberculosis. In: StatPearls. Treasure Island (FL): StatPearls Publishing LLC; 2023.

Ding C, Hu M, Guo W, Hu W, Li X, Wang S, et al. Prevalence trends of latent tuberculosis infection at the global, regional, and country levels from 19902019. Int J Infect Dis. 2022;122:46.

Article PubMed Google Scholar

Kiazyk S, Ball TB. Latent tuberculosis infection: an overview. Can Commun Dis Rep. 2017;43(34):626.

Article CAS PubMed PubMed Central Google Scholar

Luo Y, Xue Y, Song H, Tang G, Liu W, Bai H, et al. Machine learning based on routine laboratory indicators promoting the discrimination between active tuberculosis and latent tuberculosis infection. J Infect. 2022;84(5):64857.

Article PubMed Google Scholar

Estvez O, Anibarro L, Garet E, Pallares , Barcia L, Calvio L, et al. An RNA-seq based machine learning approach identifies latent tuberculosis patients with an active tuberculosis profile. Front Immunol. 2020;11:1470.

Article PubMed PubMed Central Google Scholar

Gong W, Wu X. Differential diagnosis of latent tuberculosis infection and active tuberculosis: a key to a successful tuberculosis control strategy. Front Microbiol. 2021;12(3126):745592.

Article PubMed PubMed Central Google Scholar

Chee CBE, Reves R, Zhang Y, Belknap R. Latent tuberculosis infection: opportunities and challenges. Respirology. 2018;23(10):893900.

Article PubMed Google Scholar

Hauck FR, Neese BH, Panchal AS, El-Amin W. Identification and management of latent tuberculosis infection. Am Fam Physician. 2009;79(10):87986.

PubMed Google Scholar

Gutti G, Arya K, Singh SK. Latent tuberculosis infection (LTBI) and its potential targets: an investigation into dormant phase pathogens. Mini Rev Med Chem. 2019;19(19):162742.

Article CAS PubMed Google Scholar

Yang Z, Rosenthal M, Rosenberg NA, Talarico S, Zhang L, Marrs C, et al. How dormant is Mycobacterium tuberculosis during latency? A study integrating genomics and molecular epidemiology. Infect Genet Evol. 2011;11(5):11647.

Article PubMed PubMed Central Google Scholar

Gordon SV, Eiglmeier K, Garnier T, Brosch R, Parkhill J, Barrell B, et al. Genomics of Mycobacterium bovis. Tuberculosis. 2001;81(12):15763.

Article CAS PubMed Google Scholar

Chen J, Su X, Zhang Y, Wang S, Shao L, Wu J, et al. Novel recombinant RD2- and RD11-encoded Mycobacterium tuberculosis antigens are potential candidates for diagnosis of tuberculosis infections in BCG-vaccinated individuals. Microbes Infect. 2009;11(1011):87685.

Article CAS PubMed Google Scholar

Meier NR, Jacobsen M, Ottenhoff THM, Ritz N. A systematic review on novel Mycobacterium tuberculosis antigens and their discriminatory potential for the diagnosis of latent and active tuberculosis. Front Immunol. 2018;9:2476.

Article PubMed PubMed Central Google Scholar

Ji P, Fan X, Wu K, Lu S. Research progress on the antigens associated with latent infection of Mycobacterium tuberculosis. Zhonghua Wei Sheng Wu Xue He Mian Yi Xue Za Zhi. 2015;35(1):5964 (in Chinese).

CAS Google Scholar

Zellweger JP, Sotgiu G, Corradi M, Durando P. The diagnosis of latent tuberculosis infection (LTBI): currently available tests, future developments, and perspectives to eliminate tuberculosis (TB). Med Lav. 2020;111(3):17083.

PubMed PubMed Central Google Scholar

Crouser ED, White P, Caceres EG, Julian MW, Papp AC, Locke LW, et al. A novel in vitro human granuloma model of sarcoidosis and latent tuberculosis infection. Am J Respir Cell Mol Biol. 2017;57(4):48798.

Article CAS PubMed PubMed Central Google Scholar

Rosser A, Stover C, Pareek M, Mukamolova GV. Resuscitation-promoting factors are important determinants of the pathophysiology in Mycobacterium tuberculosis infection. Crit Rev Microbiol. 2017;43(5):62130.

Article CAS PubMed Google Scholar

Downing KJ, Mischenko VV, Shleeva MO, Young DI, Young M, Kaprelyants AS, et al. Mutants of Mycobacterium tuberculosis lacking three of the five rpf-like genes are defective for growth in vivo and for resuscitation in vitro. Infect Immun. 2005;73(5):303843.

Article CAS PubMed PubMed Central Google Scholar

Arroyo L, Marn D, Franken KLMC, Ottenhoff THM, Barrera LF. Potential of DosR and Rpf antigens from Mycobacterium tuberculosis to discriminate between latent and active tuberculosis in a tuberculosis endemic population of Medellin Colombia. BMC Infect Dis. 2018;18(1):26.

Article PubMed PubMed Central Google Scholar

Zhu W, Plikaytis BB, Shinnick TM. Resuscitation factors from mycobacteria: homologs of Micrococcus luteus proteins. Tuberculosis. 2003;83(4):2619.

Article PubMed Google Scholar

Cohen-Gonsaud M, Barthe P, Bagnris C, Henderson B, Ward J, Roumestand C, et al. The structure of a resuscitation-promoting factor domain from Mycobacterium tuberculosis shows homology to lysozymes. Nat Struct Mol Biol. 2005;12(3):2703.

Article CAS PubMed Google Scholar

Segueni N, Benmerzoug S, Rose S, Gauthier A, Bourigault ML, Reverchon F, et al. Innate myeloid cell TNFR1 mediates first line defence against primary Mycobacterium tuberculosis infection. Sci Rep. 2016;6:22454.

Article CAS PubMed PubMed Central Google Scholar

Koeken V, Verrall AJ, Netea MG, Hill PC, van Crevel R. Trained innate immunity and resistance to Mycobacterium tuberculosis infection. Clin Microbiol Infect. 2019;25(12):146872.

Article CAS PubMed Google Scholar

Cadena AM, Flynn JL, Fortune SM. The importance of first impressions: early events in Mycobacterium tuberculosis infection influence Outcome. MBio. 2016;7(2):e00342-e416.

Article CAS PubMed PubMed Central Google Scholar

McClean CM, Tobin DM. Macrophage form, function, and phenotype in mycobacterial infection: lessons from tuberculosis and other diseases. Pathog Dis. 2016;74(7):ftw068.

Article PubMed PubMed Central Google Scholar

Hmama Z, Pea-Daz S, Joseph S, Av-Gay Y. Immunoevasion and immunosuppression of the macrophage by Mycobacterium tuberculosis. Immunol Rev. 2015;264(1):22032.

Article CAS PubMed Google Scholar

Middleton AM, Chadwick MV, Nicholson AG, Dewar A, Groger RK, Brown EJ, et al. Interaction of Mycobacterium tuberculosis with human respiratory mucosa. Tuberculosis. 2002;82(23):6978.

Article CAS PubMed Google Scholar

Peyron P, Vaubourgeix J, Poquet Y, Levillain F, Botanch C, Bardou F, et al. Foamy macrophages from tuberculous patients granulomas constitute a nutrient-rich reservoir for M tuberculosis persistence. PLoS Pathog. 2008;4(11):e1000204.

Article PubMed PubMed Central Google Scholar

Mattila JT, Ojo OO, Kepka-Lenhart D, Marino S, Kim JH, Eum SY, et al. Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J Immunol. 2013;191(2):77384.

Article CAS PubMed Google Scholar

El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, et al. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol. 2008;9(12):1399406.

Article PubMed PubMed Central Google Scholar

Duque-Correa MA, Kuhl AA, Rodriguez PC, Zedler U, Schommer-Leitner S, Rao M, et al. Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas. Proc Natl Acad Sci U S A. 2014;111(38):E402432.

Article CAS PubMed PubMed Central Google Scholar

Khan A, Hunter RL, Jagannath C. Emerging role of mesenchymal stem cells during tuberculosis: the fifth element in cell mediated immunity. Tuberculosis. 2016;101S:S45-52.

Article PubMed Google Scholar

Keane J, Balcewicz-Sablinska MK, Remold HG, Chupp GL, Meek BB, Fenton MJ, et al. Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis. Infect Immun. 1997;65(1):298304.

Article CAS PubMed PubMed Central Google Scholar

Harding JS, Schreiber HA, Sandor M. Granuloma transplantation: an approach to study Mycobacterium-host interactions. Front Microbiol. 2011;2:245.

Article PubMed PubMed Central Google Scholar

Gaffney E, Murphy D, Walsh A, Connolly S, Basdeo SA, Keane J, et al. Defining the role of neutrophils in the lung during infection: implications for tuberculosis disease. Front Immunol. 2022;13:984293.

Article CAS PubMed PubMed Central Google Scholar

Yang CT, Cambier CJ, Davis JM, Hall CJ, Crosier PS, Ramakrishnan L. Neutrophils exert protection in the early tuberculous granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages. Cell Host Microbe. 2012;12(3):30112.

Article CAS PubMed PubMed Central Google Scholar

Mantegazza AR, Savina A, Vermeulen M, Perez L, Geffner J, Hermine O, et al. NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells. Blood. 2008;112(12):471222.

Article CAS PubMed PubMed Central Google Scholar

Barnes PF, Leedom JM, Chan LS, Wong SF, Shah J, Vachon LA, et al. Predictors of short-term prognosis in patients with pulmonary tuberculosis. J Infect Dis. 1988;158(2):36671.

Article CAS PubMed Google Scholar

Dallenga T, Schaible UE. Neutrophils in tuberculosisfirst line of defence or booster of disease and targets for host-directed therapy?. Pathog Dis. 2016;74(3):ftw012.

Article PubMed Google Scholar

Eruslanov EB, Lyadova IV, Kondratieva TK, Majorov KB, Scheglov IV, Orlova MO, et al. Neutrophil responses to Mycobacterium tuberculosis infection in genetically susceptible and resistant mice. Infect Immun. 2005;73(3):174453.

Article CAS PubMed PubMed Central Google Scholar

Divangahi M, Chen M, Gan H, Desjardins D, Hickman TT, Lee DM, et al. Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair. Nat Immunol. 2009;10(8):899906.

Article CAS PubMed PubMed Central Google Scholar

Ahmad S, Amoudy HA, Thole JE, Young DB, Mustafa AS. Identification of a novel protein antigen encoded by a Mycobacterium tuberculosis-specific RD1 region gene. Scand J Immunol. 1999;49(5):51522.

Article CAS PubMed Google Scholar

Albayrak N, Dirix V, Aerts L, Van Praet A, Godefroid A, Dauby N, et al. Differential expression of maturation and activation markers on NK cells in patients with active and latent tuberculosis. J Leukoc Biol. 2022;111(5):103142.

Article CAS PubMed Google Scholar

Mah AY, Cooper MA. Metabolic regulation of natural killer cell IFN-gamma production. Crit Rev Immunol. 2016;36(2):13147.

Article PubMed PubMed Central Google Scholar

Read the rest here:
From immunology to artificial intelligence: revolutionizing latent ... - Military Medical Research

Investing in healthcare where are the opportunities? – Hargreaves Lansdown

By Stell Cell Research

Key takeaways

The healthcare sector covers the huge range of activities needed to deliver medical care globally. Things like diagnostic tools and the wide selection of pharmaceuticals and medical devices used to treat patients.

Then there are research organisations and insurers. This universe also includes privately-run care facilities, as well as medical distributors and pharmacies.

Past performance isnt a guide to the future. Source: Refinitiv Eikon, 26 November 2023.

The pandemic has been hugely disruptive for the healthcare sector. It caused significant delays in clinical trials pipelines and an unprecedented backlog in patient care. Made even worse by difficulties in the supply chain.

So maybe its no surprise that the sector underperformed at the peak of the pandemic. But it also let certain players demonstrate excellence in science innovation. They led the world's response to the crisis through the development of new treatments, and most importantly the rollout of vaccines in record time.

In 2022 this let the sector keep generating positive returns, while the wider market retreated as the global economy saw high inflation and rising interest rates.

More recently though, those companies that saw a boost from tackling COVID-19, have struggled to replace the revenue from falling sales of these same products. That's seen a lot of the initial outperformance reverse in 2023.

One of the biggest stories coming from the healthcare industry is the boom in next-generation medicines for combating obesity and diabetes. These have the potential to become the biggest category of pharmaceuticals in medical history.

For now, this space is dominated by a handful of trailblazers, but theres a swarm of competitors waiting in the wings. This reflects the growing burden of chronic diseases. Tackling these conditions makes commercial sense and potentially creates long-term revenue streams.

We also see an opportunity in the evolution of new treatment mechanisms that can help or potentially cure serious diseases. Despite huge advances in the standard of care, cancer is still responsible for nearly one in six deaths worldwide and is by far still the busiest area for pharmaceutical research.

Immunotherapy, where the body's own immune system is honed to fight cancerous cells has been a key driver of improved survival rates. But there's room to improve its efficacy and increase the number of people and cancers it can be used on.

Gene therapy and stem cell treatments are other breakthroughs keeping the white coats busy, and they could also have use cases in other disease areas.

But it's not all about new products.

Pursuing approvals in new territories, patient populations, and conditions for medicines that already exist in the market makes perfect sense. This is a concept thats become known as a pipeline in a product.

Information and communication technology could also have a transformational effect on healthcare delivery.

The adoption of telemedicine was accelerated by the need for social distancing during the pandemic. It's now relatively common to have a consultation by video call, and we expect this will stay integral to health services going forward.

Healthcare hasn't escaped the hype around artificial intelligence either. There are opportunities in drug discovery, diagnostics and the delivery of patient care, but this is still early days.

Drug development is lengthy and expensive, with a low success rate. Companies that focus on these need to spend a lot of cash, with no guarantee of a return.

And it's important to keep refilling the hopper as eventually the exclusivity you get for taking the initial risk lapses. This paves the way for generic competitors to enter the market. And there's always the chance competitors will develop more effective treatments.

In the near term, pressure on government finances could keep a lid on the level of expenditure committed to the healthcare sector.

The sector is dependent on the availability of highly-skilled doctors, nurses and research scientists. This can hamper the development and delivery of products and services as well as push up costs.

Healthcare is highly regulated and a crucial political battleground. There's growing pressure to bring down prices. Consolidation in the industry is attracting the eye of the competition authorities. And there arent guarantees that certain medicines will be reimbursed by state or private health insurers.

Safety of clinical trials and marketed medicines is another risk to watch. It can take years after a product launch for side effects to become apparent, and this leaves the sector open to legal claims which can be expensive.

While COVID-19 seems to be well managed for now, we can't rule out the emergence of aggressive or vaccine-resistant strains, which could bring huge disruption to the sector.

The healthcare sector has an impressive long-term growth record. A number of drivers are likely to prolong this trend, not least being population growth and increasing life expectancy.

Meanwhile, there's a need to improve patient access and bridge the gap in healthcare coverage between developed and developing nations.

It's also a sector that has significant barriers to entry, which we see as a key attraction for investors.

In recent years, many of the major breakthroughs in medicine have been made by smaller biotech companies. The winners among them have proved very rewarding for investors. But the challenging economic environment has seen the falling appetites to fund these riskier businesses.

We favour companies with good cash flows and strong balance sheets. This lets them build more diverse development pipelines. And also create the infrastructure needed to commercialise their science, meaning they get more of the profits.

It also allows them to take advantage of the funding gap for smaller industry participants, by cherry-picking companies and assets in spaces they think are attractive.

It's certainly an exciting space to be in, but also a complex one. Its important to make sure you understand what youre investing in before diving in and remember, there are no guarantees.

Investments and any income from them can fall as well as rise in value, so you could get back less than you invest. This isnt personal advice if youre not sure whats right for you, seek advice.

To make sure you dont miss out on our latest share sector reviews, sign up to our Share Insight email. Well send you our latest share research and articles every week, direct to your inbox.

This article is not advice or a recommendation to buy, sell or hold any investment. No view is given on the present or future value or price of any investment, and investors should form their own view on any proposed investment. This article has not been prepared in accordance with legal requirements designed to promote the independence of investment research and is considered a marketing communication. Non-independent research is not subject to FCA rules prohibiting dealing ahead of research, however HL has put controls in place (including dealing restrictions, physical and information barriers) to manage potential conflicts of interest presented by such dealing. Please see our full non-independent research disclosure for more information.

Sign up to receive weekly shares content from HL.

Please correct the following errors before you continue:

Hargreaves Lansdown PLC group companies will usually send you further information by post and/or email about our products and services. If you would prefer not to receive this, please do let us know. We will not sell or trade your personal data.

Excerpt from:
Investing in healthcare where are the opportunities? - Hargreaves Lansdown

Akari Therapeutics Appoints Experienced Life Sciences Entrepreneur Samir R. Patel, M.D. to Board of Directors

By Global News Feed

NEW YORK and BOSTON, Dec. 01, 2023 (GLOBE NEWSWIRE) -- Akari Therapeutics, Plc (Nasdaq: AKTX), a late-stage biotechnology company developing advanced therapies for autoimmune and inflammatory diseases, today announced the appointment of experienced life sciences entrepreneur Samir R. Patel, M.D. to the Akari Board of Directors.

Go here to see the original:
Akari Therapeutics Appoints Experienced Life Sciences Entrepreneur Samir R. Patel, M.D. to Board of Directors

Spectral Medical Announces CFO Departure

By Global News Feed

TORONTO, Dec. 01, 2023 (GLOBE NEWSWIRE) -- Spectral Medical Inc. (“Spectral” or the “Company”) (TSX: EDT), a late-stage theranostic company advancing therapeutic options for sepsis and septic shock, today announced that Blair McInnis has provided notice of his resignation as Chief Financial Officer of the Company, which is effective immediately, to pursue a new opportunity. Mr. McInnis will assist the Company to ensure a smooth transition.

More:
Spectral Medical Announces CFO Departure

→←