Fibrosis is the thickening of various tissues caused by the deposition of fibrillar extracellular matrix (ECM) in tissues and organs as part of the bodys wound healing response to various forms of damage. When accompanied by chronic inflammation, fibrosis can go into overdrive and produce excess scar tissue that can no longer be degraded. This process causes many diseases in multiple organs, including lung fibrosis induced by smoking or asbestos, liver fibrosis induced by alcohol abuse, and heart fibrosis often following heart attacks. Fibrosis can also occur in the bone marrow, the spongy tissue inside some bones that houses blood-producing hematopoietic stem cells (HSCs) and can lead to scarring and the disruption of normal functions.

Chronic blood cancers known as myeloproliferative neoplasms (MPNs) are one example, in which patients can develop fibrotic bone marrow, or myelofibrosis, that disrupts the normal production of blood cells. Monocytes, a type of white blood cell belonging to the group of myeloid cells, are overproduced from HSCs in neoplasms and contribute to the inflammation in the bone marrow environment, or niche. However, how the fibrotic bone marrow niche itself impacts the function of monocytes and inflammation in the bone marrow was unknown.

Now, a collaborative team from Penn, Harvard, the Dana-Farber Cancer Institute (DFCI), and Brigham and Womens Hospital has created a programmable hydrogel-based in vitro model mimicking healthy and fibrotic human bone marrow. Combining this system with mouse in vivo models of myelofibrosis, the researchers demonstrated that monocytes decide whether to enter a pro-inflammatory state and go on to differentiate into inflammatory dendritic cells based on specific mechanical properties of the bone marrow niche with its densely packed ECM molecules. Importantly, the team found a drug that could tone down these pathological mechanical effects on monocytes, reducing their numbers as well as the numbers of inflammatory myeloid cells in mice with myelofibrosis. The findings are published in Nature Materials.

We found that stiff and more elastic slow-relaxing artificial ECMs induced immature monocytes to differentiate into monocytes with a pro-inflammatory program strongly resembling that of monocytes in myelofibrosis patients, and the monocytes to differentiate further into inflammatory dendritic cells, says co-first author Kyle Vining, who recently joined Penn.More viscous fast-relaxing artificial ECMs suppressed this myelofibrosis-like effect on monocytes. This opened up the possibility of a mechanical checkpoint that could be disrupted in myelofibrotic bone marrow and also may be at play in other fibrotic diseases. Vining will be appointedassistant professor of preventive and restorative sciences in theSchool of Dental Medicine and the Department of Materials Sciences in theSchool of Engineering and Applied Science, pending approval by Penn Dental Medicines personnel committees and the Provosts office.

Vining worked on the study as a postdoctoral fellow at Harvard in the lab of David Mooney. Our study shows that the differentiation state of monocytes, which are key players in the immune system, is highly regulated by mechanical changes in the ECM they encounter, says Mooney, who co-led the study with DFCI researcher Kai Wucherpfennig. Specifically, the ECMs viscoelasticity has been a historically under-appreciated aspect of its mechanical properties that we find correlates strongly between our in vitro and the in vivo models and human disease. It turns out that myelofibrosis is a mechano-related disease that could be treated by interfering with the mechanical signaling in bone marrow cells.

Mooney is also the Robert P. Pinkas Family Professor of Bioengineering at Harvard and leads the Wyss Institutes Immuno-Materials Platform. Wucherpfennig is director of DFCIs Center for Cancer Immunotherapy Research, professor of neurobiology at Brigham and Harvard Medical School, and an associate member of the Broad Institute of MIT and Harvard. Mooney, together with co-senior author F. Stephen Hodi, also heads the Immuno-engineering to Improve Immunotherapy (i3) Center, which aims to create new biomaterials-based approaches to enhance immune responses against tumors. The new study follows the Centers road map. Hodi is director of the Melanoma Center and The Center for Immuno-Oncology at DFCI and professor of medicine at Harvard Medical School.

The mechanical properties of most biological materials are determined by their viscoelastic characteristics. Unlike purely elastic substances like a vibrating quartz, which store elastic energy when mechanically stressed and quickly recover to their original state once the stress is removed, slow-relaxing viscoelastic substances also have a viscous component. Like the viscosity of honey, this allows them to dissipate stress under mechanical strain by rapid stress relaxation. Viscous materials are thus fast-relaxing materials in contrast to slow-relaxing purely elastic materials.

The team developed an alginate-based hydrogel system that mimics the viscoelasticity of natural ECM and allowed them to tune the elasticity independent from other physical and biochemical properties. By tweaking the balance between elastic and viscous properties in these artificial ECMs, they could recapitulate the viscoelasticity of healthy and scarred fibrotic bone marrow, whose elasticity is increased by excess ECM fibers. Human monocytes placed into these artificial ECMs constantly push and pull at them and in turn respond to the materials mechanical characteristics.

Next, the team investigated how the mechanical characteristics of stiff and elastic hydrogels compared to those in actual bone marrow affected by myelofibrosis. They took advantage of a mouse model in which an activating mutation in a gene known as Jak2 causes MPN, pro-inflammatory signaling in the bone marrow, and development of myelofibrosis, similar to the disease process in human patients with MPN. When they investigated the mechanical properties of bone marrow in the animals femur bones, using a nanoindentation probe, the researchers measured a higher stiffness than in non-fibrotic bone marrow. Importantly, we found that the pathologic grading of myelofibrosis in the animal model was significantly correlated with changes in viscoelasticity, said co-first author Anna Marneth, who spearheaded the experiments in the mouse model as a postdoctoral fellow working with Ann Mullally, a principal investigator at Brigham and DFCI, and another senior author on the study.

An important question was whether monocytes response to the mechanical impact of the fibrotic bone marrow niche could be therapeutically targeted. The researchers focused on an isoform of the phosphoinositide 3-kinase (PI3K)-gamma protein, which is specifically expressed in monocytes and closely related immune cells. PI3K-gamma is known for regulating the assembly of a cell-stiffening filamentous cytoskeleton below the cell surface that expands in response to mechanical stress, which the team also observed in monocytes encountering a fibrotic ECM. When they added a drug that inhibits PI3K-gamma to stiff elastic artificial ECMs, it toned down their pro-inflammatory response and, when given as an oral treatment to myelofibrosis mice, significantly lowered the number of monocytes and dendritic cells in their bone marrow.

This research opens new avenues for modifying immune cell function in fibrotic diseases that are currently difficult to treat. The results are also highly relevant to human cancers with a highly fibrotic microenvironment, such as pancreatic cancer, says Wucherpfennig.

Adapted from a press release written by Benjamin Boettner of the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Other authors on the study are Harvards Kwasi Adu-Berchie, Joshua M. Grolman, Christina M. Tringides, Yutong Liu, Waihay J. Wong, Olga Pozdnyakova, Mariano Severgnini, Alexander Stafford, and Georg N. Duda.

The study was funded by the National Cancer Institute of the National Institutes of Health (Grant CA214369), National Institute of Dental & Craniofacial Research of the National Institutes of Health (grants DE025292 and DE030084), Food and Drug Administration (Grant FD006589), and Harvard University Materials Research Science and Engineering Center (Grant DMR 1420570).

Link:
Deconstructing the mechanics of bone marrow disease | Penn Today - Penn Today

Bone Marrow Stem Cells Comments Off on Deconstructing the mechanics of bone marrow disease | Penn Today – Penn Today | July 16th, 2022

Krabbe disease is one of many hundreds of inherited metabolic disorders. Named after the Danish neurologist Knud Krabbe, the disease causes progressive damage to the nervous system, eventually resulting in the death of the individual. The disease is common in newborns before they reach six months of age and treatment must start at the earliest. Most newborns affected by Krabbe disease do not reach the age of two.

Krabbe disease is caused due to genetic mutation on the 14th chromosome in an infant. A child needs to inherit two copies of the abnormal genome from both its parents, after which it has a 25 percent chance of inheriting both the recessive genes and developing the disease.

On inheriting the defective genome, the body doesnt produce enough of the enzyme galactosylceramidase (GALC). Galactosylceramidase is essential for breaking down unmetabolised lipids like glycosphingolipid and psychosine in the brain. These unmetabolised lipids are toxic to some of the non-neuron cells present in the brain.

Late-onset Krabbe disease, however, can be caused by a different genetic mutation which leads to a lack of a different enzyme, known as active saposin A.

Symptoms between early-onset and late-onset Krabbe disease differ slightly. Infants suffering from early-onset Krabbe disease suffer from symptoms like excessive irritability, difficulty swallowing, vomiting, unexplained fevers, and partial unconsciousness. Other common neuropathic symptoms include hypersensitivity to sound, muscle weakness, slowing of mental and motor development, spasticity, deafness, optic atrophy, optic nerve enlargement, blindness, and paralysis.

Late-onset Krabbe disease emerges with symptoms like the development of cross-eyes, slurred speech, slow development, and loss of motor functions.

The disease is diagnosed after a physician conducts a primary physical exam. A blood or skin tissue biopsy can test for GALC levels in the body and low levels can indicate the presence of Krabbe disease. Further testing through imaging scans (MRI), nerve conduction studies, eye examination, genetic testing and amniocentesis can also help diagnose the disease.

There is no cure for Krabbe disease. Treatment is mostly palliative in nature with a focus towards dealing with symptoms and providing supportive care. Experimental trials using hematopoietic stem cell transplant (HSCT), bone marrow transplantation, stem cell therapy, and gene therapy have seen some results in the small number of patients that they have been used on.

(Edited by : Shoma Bhattacharjee)

First Published:Jul 15, 2022, 06:32 AM IST

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Krabbe disease, which mostly affects newborns causes, symptoms, and treatment - CNBCTV18

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Under embargo until Thursday 14 July 2022 at 16:00 (London time), 14 July 2022 at 11:00 (US Eastern Time).

Newswise The discovery of 14 inherited genetic changes which significantly increase the risk of a person developing a symptomless blood disorder associated with the onset of some types of cancer and heart disease is published today in Nature Genetics. The finding, made in one of the largest studies of its kind through genetic data analysis on 421,738 people, could pave the way for potential new approaches for the prevention and early detection of cancers including leukaemia.

Led by scientists from the Universities of Bristol and Cambridge, the Wellcome Sanger Institute, the Health Research Institute of Asturias in Spain, and AstraZeneca, the study reveals that specific inherited genetic changes affect the likelihood of developing clonal haematopoiesis, a common condition characterised by the development of expanding clones of multiplying blood cells in the body, driven by mutations in their DNA.

Although symptomless, the disorder becomes ubiquitous with age and is a risk factor for developing blood cancer and other age-related diseases. Its onset is a result of genetic changes in our blood-making cells.

All human cells acquire genetic changes in their DNA throughout life, known as somatic mutations, with a specific subset of somatic mutations driving cells to multiply. This is particularly common in professional blood-making cells, known as blood stem cells, and results in the growth of populations of cells with identical mutations known as clones.

Using data from the UK Biobank, a large-scale biomedical database and research resource containing genetic and health information from half a million UK participants, the team were able to show how these genetic changes relate not only to blood cancers but also to tumours that develop elsewhere in the body such as lung, prostate and ovarian cancer.

The team found that clonal haematopoiesis accelerated the process of biological ageing itself and influenced the risk of developing atrial fibrillation, a condition marked by irregular heartbeats.

The findings also clearly established that smoking is one of the strongest modifiable risk factors for developing the disorder, emphasising the importance of reducing tobacco use to prevent the conditions onset and its harmful consequences.

Dr Siddhartha Kar, UKRI Future Leaders Fellow at the University of Bristol and one of the studys lead authors from Bristols MRC Integrative Epidemiology Unit(IEU), said: Our findings implicate genes and the mechanisms involved in the expansion of aberrant blood cell clones and can help guide treatment advances to avert or delay the health consequences of clonal haematopoiesis such as progression to cancer and the development of other diseases of ageing.

Professor George Vassiliou, Professor of Haematological Medicine at the University of Cambridge and one of the studys lead authors, added: Our study reveals that the cellular mechanisms driving clonal haematopoiesis can differ depending on the mutated gene responsible. This is a challenge as we have many leads to follow, but also an opportunity as we may be able to develop treatments specific to each of the main subtypes of this common phenomenon.

Dr Pedro M. Quiros, formerly researcher at the Wellcome Sanger Institute and the University of Cambridge, and now Group Leader at the Health Research Institute of Asturias (Spain) and another of the studys lead authors says: We were particularly pleased to see that some of the genetic pathways driving clonal haematopoiesis appear to be susceptible to pharmacological manipulation and represent prioritised targets for the development of new treatments.

The study was funded by UK Research and Innovation (UKRI), Cancer Research UK (CRUK), Wellcome, the Royal Society, the Carlos III Health Institute, the Leukaemia and Lymphoma Society, and the Rising Tide Foundation for Clinical Cancer Research.

Paper

Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis by Kar SP, et al. in Nature Genetics.

Ends

Further information:

Clonal haematopoiesis is the development of mutations in genes involved in blood cell production. It is diagnosedwhen a test on a person's blood or bone marrow sample shows that blood cells are carrying one of the genetic mutations associated with the condition. Clonal haematopoiesis becomes increasingly common with age, affecting more than one in every ten individuals older than 60 years.

Notes to editors

Paper: an embargoed copy of the paper is available to download here.

Issued by the University of Bristol Media Team.

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Scientists Discover Genes That Affect the Risk of Developing Pre-Leukemia - Newswise

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In this free webinar, learn how live cell metabolic analysis paves the way not only for metabolic research, but also the manufacturing of significant cell and gene therapy (CGT) products. Attendees will learn how glycolysis metabolic process can be measured directly through the continuous measuring of glucose and lactate amounts in the culture media using electrochemical sensors which provides new scientific insights. The featured speakers will discuss how continuous monitoring is effectively utilized for the process development stage of CGT products and quality control during the manufacturing stage of CGT products. The speakers will also discuss how glucose and lactate can be monitored in the traditional lab environment using conventional 24-well plate and CO2 incubators without any sampling.

TORONTO (PRWEB) July 12, 2022

Among the various biological functions cells carry out to maintain life, metabolism is the key activity used to process nutrient molecules. It is also closely associated with cell proliferation and differentiation. Cell metabolic analysis would be very helpful to monitor these activities.

In the field of cancer immunotherapy such as CAR T and TCR-T therapy, stem cell research including embryonic stem (ES) and induced pluripotent stem (iPS) cells and commercial cell and gene therapy (CGT) manufacturing process development investigating and understanding the metabolic activities of cells are critical. To meet this need in the field, PHC Corporation will launch a continuous metabolic analyzer which leads to real-time visualization of the metabolic condition of living cells. This development will encourage new discoveries that have not been seen in previous studies.

Register for this webinar to learn how live cell metabolic analysis paves the way not only for metabolic research, but also the manufacturing of significant CGT products.

Join experts from PHC Corporation of North America, Ryosuke Takahashi, PhD VP, Cell and Gene Therapy Business; and Kenan Moss, Application Specialist, for the live webinar on Tuesday, July 26, 2022, at 11am EDT (4pm BST).

For more information, or to register for this event, visit Live Cell Metabolic Analysis Paving the Way for Metabolic Research and Cell & Gene Therapy.

ABOUT XTALKS

Xtalks, powered by Honeycomb Worldwide Inc., is a leading provider of educational webinars to the global life science, food and medical device community. Every year, thousands of industry practitioners (from life science, food and medical device companies, private & academic research institutions, healthcare centers, etc.) turn to Xtalks for access to quality content. Xtalks helps Life Science professionals stay current with industry developments, trends and regulations. Xtalks webinars also provide perspectives on key issues from top industry thought leaders and service providers.

To learn more about Xtalks visit http://xtalks.comFor information about hosting a webinar visit http://xtalks.com/why-host-a-webinar/

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Live Cell Metabolic Analysis Paving the Way for Metabolic Research and Cell & Gene Therapy, Upcoming Webinar Hosted by Xtalks - Benzinga

IPS Cell Therapy Comments Off on Live Cell Metabolic Analysis Paving the Way for Metabolic Research and Cell & Gene Therapy, Upcoming Webinar Hosted by Xtalks – Benzinga | July 16th, 2022

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By Nathan Sager

Published July 14, 2022 at 5:16 pm

A renowned burns specialist and his entire lab are continuing their work to develop 3-D printed skin at McMaster University in Hamilton.

Earlier this month, Dr. Marc Jeschke began a dual role at McMaster and Hamilton Health Sciences (HHS). Jeschke, who previously worked at the University of Toronto and Sunnybrook hospital, is now a professor of surgery at Mac and vice-president, research at HHS as well as medical director of its burns unit.

As part of the move, Jeschke is bringing his nearly 20-scientist burn research lab to Hamilton. The lab is supported by a gift from Charles and Margaret Juravinski through the Juravinski Research Institute. In a release from the university, Jeschke said McMaster is uniquely positioned for work across verious medical disciplines, since there are many partnerships with HHS and St. Josephs Healthcare Hmailton.

(McMaster) offers a more intimate environment than other institutions of its calibre and the quality of collaboration here is outstanding, said Jeschke.

People who suffer extensive and serious burns often end up with scarring for life. The Jeschke-headed lab has been developing a skin derivative that uses a patients own stem cells. It might one day greatly reduce scarring for people with extensive burns.

In 2020, researchers and developers from U of T and Sunnybrook became the first Canadian team to be honoured with a top prize from the 3D Pioneers Challenge for building and refining of the ReverTome handheld 3D skin printer. The printer can make new skin grown from stem cells in order to improve healing. Jeschke and his team contributed stem cell research to help inform development of the device.

The 3D Pioneers Challenge honours innovations in digital printing. The U of T-Sunnybrook team won from among a field of 52 finalists from 28 nations.

Jeschke said in the release that the therapy his lab is testing proved effective in porcine models. The clinical trial stage would be next.

The human body is so complex, but this stem-cell based therapy, if successful, will certainly change the way we care for burns and other injuries, he said.

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McMaster in Hamilton founds burn injury research program that is working on 3-D skin | inTheHammer - insauga.com

Skin Stem Cells Comments Off on McMaster in Hamilton founds burn injury research program that is working on 3-D skin | inTheHammer – insauga.com | July 16th, 2022

Endometriosis is a condition that can occur when tissue that is normally found lining the uterus, known as the endometrium, begins to grow outside of that organ. With this disorder, the tissue can be found growing around other nearby organs the ovaries, intestines, and even tissue that lines your pelvis.

Because endometrial tissue is affected by hormonal changes during the menstrual cycle, its not uncommon for people with endometriosis to experience pain and discomfort just like they would with endometrial tissue in the uterus. And just like that tissue, this tissue breaks down too but isnt expelled.

As a result, endometriosis can lead to the growth of scar tissue, irritation, and even infertility. But while much is known about endometriosis in adult women, the condition isnt as well-researched in children or adolescents.

Officially, there is no known cause of endometriosis regardless of the age at which its discovered. And almost all researchers agree that limited studies in younger age groups, as well as healthcare professionals delaying diagnosis by several years, can contribute to its progression that often leads to infertility and other negative outcomes.

There are a few theories that highlight potential reasons, but no theory has proven to be conclusive yet. Well take a closer look at the best supported theories to-date:

Retrograde menstruation is a condition in which blood that is expelled from the uterus flows back toward the fallopian tubes rather than out of the body through the vagina. This scenario is more common than you may expect, with roughly 90% of women experiencing it at some point during their menstruating lives.

But for some, this backflow can lead to endometrial cells adhering to organs or cavity tissues, or whats known as endometrial lesions. This is why it is currently considered a key factor in developing endometriosis.

A 2013 study conducted in Japan found a link between the incidence of menstrual pain and the need for medical interventions. While the study found that roughly a third of all menstruating Japanese women experienced pain significant enough to require medication, of that group, 6% did not experience any improvement after taking medication.

More importantly, this study found that roughly 25 to 38% of adolescents that complained of chronic pelvic pain were later diagnosed with endometriosis. Meanwhile, the most common solution offered to adolescents is pain medications, which will not treat the cause of the pain.

That same 2013 Japanese study noted that some respondents were diagnosed with endometriosis while having never menstruated (premenarchal). This discovery has encouraged researchers to consider that other underlying mechanisms might contribute to endometriosis rather than retrograde menstruation.

Some researchers further hypothesized that endometriosis diagnoses in premenarchal participants could be caused by stem cells that later develop into endometrial tissue and are later activated when menstruation begins.

While we often think of endometriosis as a condition exclusively impacting women, the reality is that it can also develop in nonbinary or transmasculine (people assigned female at birth that later transition to boys) adolescents as well.

A 2020 study reviewed previous research that focused on 35 trans participants ages 26 and younger that were diagnosed with dysmenorrhea (or menstruation-related pain) and treated for that condition. Of the 35, seven of the patients were evaluated and found to have endometriosis some of which were diagnosed after transitioning and included one participant that had already begun testosterone treatment.

Of the seven patients, treatment varied from oral contraceptives, testosterone treatment, and other drugs such as danazol and progestins. The study found that results were mixed. While some respondents found success with testosterone therapy for resolving symptoms, this wasnt the case for everyone.

Ultimately, the study recommended that trans masculine people experiencing dysmenorrhea symptoms should be screened for endometriosis, and that testosterone therapy alone isnt necessarily a complete solution.

Although less is known about endometriosis in adolescent or teenage populations, symptoms tend to be consistent with those found in adult women. These include:

If you or your child is experiencing symptoms of endometriosis, keep reading to learn about getting diagnosed.

Consistently, the research and medical communities agree that early detection of endometriosis is the best way to prevent acute spread which can lead to infertility. Checking for endometriosis on your own is not possible. But letting your doctor know that youre experiencing chronic pelvic pain, heavy or long periods, or any of the other common symptoms associated with endometriosis is important.

Your physician might start the diagnostic process by performing a pelvic ultrasound to ensure that any other underlying conditions or infections arent causing your symptoms. Usually, endometriosis is diagnosed with laparoscopy. This is a minimally invasive procedure where your physician inserts a thin tube with a light and lens through a small incision into the lower abdomen. With this procedure, they can look for endometrial lesions to determine if endometriosis is present.

Unfortunately, its common for period pain to be dismissed as a regular part of life, and for many people it can take more than a decade to receive a proper diagnosis. If this is the case for you, dont hesitate to advocate for yourself and seek a second opinion if youre unable to find a treatment plan that works for you.

Currently, there is no cure for endometriosis. However, just as in adults, the goal of treating adolescent endometriosis is to control and prevent disease progression, provide symptom relief, and preserve fertility.

Several treatment methods may be recommended depending on the amount of endometrial tissue that is present (disease progression).

Treatment options can center on hormonal therapy to control estrogen levels a key factor that influences endometrial growth. For some patients, this might include taking oral contraception, or a progestin-only agent to prevent or minimize the onset of periods, as well as nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management.

Be aware that you might need to try several different types of hormonal therapies before you find the right option that controls your condition.

Some patients might also be prescribed Gonadotropin-releasing hormone (GnRH) agonist therapy. But this is usually reserved for adults, because research suggests that this treatment can impact bone mineralization in adolescents.

Surgery is often used for both diagnosis and treatment. While some surgeries can remove endometrial lesions, this is not a permanent solution for everyone.

Research has proven that even with surgery, endometrial lesions can return.

Most endometriosis conversations center around female patients. But its important to remember that trans men as well as those born male are also at risk of developing this disease.

Once thought to only be an issue for menstruating females, research suggests that endometriosis can also be detected in premenarchal youth.

Theres no cure for endometriosis. But experts, advocates, and the medical community agree that early interventions for the condition are critical for limiting its spread, controlling symptoms that can impact everyday life, and preserving fertility especially in adolescents.

Excerpt from:
Endometriosis in Teens: Causes, Symptoms, and Treatment - Healthline

Skin Stem Cells Comments Off on Endometriosis in Teens: Causes, Symptoms, and Treatment – Healthline | July 16th, 2022

ICYMI: Amazon Prime Day is coming to an end tonight and truth be told, the sales appear to be gifts that keep on giving. One of our favorite skin-care tools is having a major discount across all of its devices and treatments. Yep, you guessed it, it's NuFace.

If you're unfamiliar with the brand and the magic it can do, let us school you quickly. NuFace devices use microcurrent technology that the brand calls "fitness for your face." In the same way that consistently hitting weights and cardio whips our body's muscles into shape, the metal nodes on the head of the tools send electrical currents through the various layers of facial skin, down to the muscles, to basically give them a workout.

Into it? Well, lucky for you NuFace products will be available at a discount throughout this two-day epic sale. Starting right now through July 13, you can snag devices, boosters, and activators for up to 36 percent off. The sale includes top-selling products like the Trinity, NuBody, Fix, and more.

So what are you waiting for? This luxury tool rarely goes on sale so get to shopping because these discounts end later on when Prime Day closes its virtual doors.

NuFace Trinity Starter Kit

NuFace Trinity Complete Kit

Both the Trinity Starter Kit and Complete Kit are essentially the same thing, but the complete kit comes with some additional attachments. Both kits feature a NuFace device and a gel primer to apply prior in order to activate the current. However, the Complete Kit holds a dual wand that targets specific areas like around the lips and eyes and a LED light attachment that helps reduce the appearance of fine lines and wrinkles.

If you're not into breaking the $200 mark, consider the Mini Starter Kit it holds the same device and gel primer, just in a smaller (more portable!) version that achieves the same results.

The NuBody features those same nodes on the head as the Trinity but in a handheld body version that utilizes four nodes. With four electrical currents, this device sends waves through the skin down to the muscles to help sculpt and tone the body. Plus, you get a 10-ounce gel primer to ensure the device glides smoothly and evenly.

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NuFace Is Having a Major Sale During Amazon Prime Day 2022 See Deals on Trinity, NuBody, and More - Allure

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In molecular biologist David Sinclair's lab at Harvard Medical School, old mice are growing young again.

Using proteins that can turn an adult cell into a stem cell, Sinclair and his team have reset aging cells in mice to earlier versions of themselves. In his team's first breakthrough, published in late 2020, old mice with poor eyesight and damaged retinas could suddenly see again, with vision that at times rivaled their offspring's.

"It's a permanent reset, as far as we can tell, and we think it may be a universal process that could be applied across the body to reset our age," said Sinclair, who has spent the last 20 years studying ways to reverse the ravages of time.

"If we reverse aging, these diseases should not happen. We have the technology today to be able to go into your hundreds without worrying about getting cancer in your 70s, heart disease in your 80s and Alzheimer's in your 90s." Sinclair told an audience at Life Itself, a health and wellness event presented in partnership with CNN.

"This is the world that is coming. It's literally a question of when and for most of us, it's going to happen in our lifetimes," Sinclair told the audience.

"His research shows you can change aging to make lives younger for longer. Now he wants to change the world and make aging a disease," said Whitney Casey, an investor who is partnering with Sinclair to create a do-it-yourself biological age test.

While modern medicine addresses sickness, it doesn't address the underlying cause, "which for most diseases, is aging itself," Sinclair said. "We know that when we reverse the age of an organ like the brain in a mouse, the diseases of aging then go away. Memory comes back; there is no more dementia.

"I believe that in the future, delaying and reversing aging will be the best way to treat the diseases that plague most of us."

A reset button

In Sinclair's lab, two mice sit side by side. One is the picture of youth, the other gray and feeble. Yet they are brother and sister, born from the same litter -- only one has been genetically altered to age faster.

If that could be done, Sinclair asked his team, could the reverse be accomplished as well? Japanese biomedical researcher Dr. Shinya Yamanaka had already reprogrammed human adult skin cells to behave like embryonic or pluripotent stem cells, capable of developing into any cell in the body. The 2007 discovery won the scientist a Nobel Prize, and his "induced pluripotent stem cells," soon became known as "Yamanaka factors."

However, adult cells fully switched back to stem cells via Yamanaka factors lose their identity. They forget they are blood, heart and skin cells, making them perfect for rebirth as "cell du jour," but lousy at rejuvenation. You don't want Brad Pitt in "The Curious Case of Benjamin Button" to become a baby all at once; you want him to age backward while still remembering who he is.

Labs around the world jumped on the problem. A study published in 2016 by researchers at the Salk Institute for Biological Studies in La Jolla, California, showed signs of aging could be expunged in genetically aged mice, exposed for a short time to four main Yamanaka factors, without erasing the cells' identity.

But there was a downside in all this research: In certain situations, the altered mice developed cancerous tumors.

Looking for a safer alternative, Sinclair lab geneticist Yuancheng Lu chose three of the four factors and genetically added them to a harmless virus. The virus was designed to deliver the rejuvenating Yamanaka factors to damaged retinal ganglion cells at the back of an aged mouse's eye. After injecting the virus into the eye, the pluripotent genes were then switched on by feeding the mouse an antibiotic.

"The antibiotic is just a tool. It could be any chemical really, just a way to be sure the three genes are switched on," Sinclair said. "Normally they are only on in very young developing embryos and then turn off as we age."

Amazingly, damaged neurons in the eyes of mice injected with the three cells rejuvenated, even growing new axons, or projections from the eye into the brain. Since that original study, Sinclair said his lab has reversed aging in the muscles and brains of mice and is now working on rejuvenating a mouse's entire body.

"Somehow the cells know the body can reset itself, and they still know which genes should be on when they were young," Sinclair said. "We think we're tapping into an ancient regeneration system that some animals use -- when you cut the limb off a salamander, it regrows the limb. The tail of a fish will grow back; a finger of a mouse will grow back."

That discovery indicates there is a "backup copy" of youthfulness information stored in the body, he added.

"I call it the information theory of aging," he said. "It's a loss of information that drives aging cells to forget how to function, to forget what type of cell they are. And now we can tap into a reset switch that restores the cell's ability to read the genome correctly again, as if it was young."

While the changes have lasted for months in mice, renewed cells don't freeze in time and never age (like, say, vampires or superheroes), Sinclair said. "It's as permanent as aging is. It's a reset, and then we see the mice age out again, so then we just repeat the process.

"We believe we have found the master control switch, a way to rewind the clock," he added. "The body will then wake up, remember how to behave, remember how to regenerate and will be young again, even if you're already old and have an illness."

Science already knows how to slow human aging

Studies on whether the genetic intervention that revitalized mice will do the same for people are in early stages, Sinclair said. It will be years before human trials are finished, analyzed and, if safe and successful, scaled to the mass needed for a federal stamp of approval.

While we wait for science to determine if we too can reset our genes, there are many other ways to slow the aging process and reset our biological clocks, Sinclair said.

"The top tips are simply: Focus on plants for food, eat less often, get sufficient sleep, lose your breath for 10 minutes three times a week by exercising to maintain your muscle mass, don't sweat the small stuff and have a good social group," Sinclair said.

What controls the epigenome? Human behavior and one's environment play a key role. Let's say you were born with a genetic predisposition for heart disease and diabetes. But because you exercised, ate a plant-focused diet, slept well and managed your stress during most of your life, it's possible those genes would never be activated. That, experts say, is how we can take some of our genetic fate into our own hands.

Cutting back on food -- without inducing malnutrition -- has been a scientifically known way to lengthen life for nearly a century. Studies on worms, crabs, snails, fruit flies and rodents have found restricting calories "delay the onset of age-related disorders" such as cancer, heart disease and diabetes, according to the National Institute on Aging. Some studies have also found extensions in life span: In a 1986 study, mice fed only a third of a typical day's calories lived to 53 months -- a mouse kept as a pet may live to about 24 months.

Studies in people, however, have been less enlightening, partly because many have focused on weight loss instead of longevity. For Sinclair, however, cutting back on meals was a significant factor in resetting his personal clock: Recent tests show he has a biological age of 42 in a body born 53 years ago.

"I've been doing a biological test for 10 years now, and I've been getting steadily younger for the last decade," Sinclair said. "The biggest change in my biological clock occurred when I ate less often -- I only eat one meal a day now. That made the biggest difference to my biochemistry."

Additional ways to turn back the clock

Sinclair incorporates other tools into his life, based on research from his lab and others. In his book "Lifespan: Why We Age and Why We Don't Have To," he writes that little of what he does has undergone the sort of "rigorous long-term clinical testing" needed to have a "complete understanding of the wide range of potential outcomes." In fact, he added, "I have no idea if this is even the right thing for me to be doing."

With that caveat, Sinclair is willing to share his tips: He keeps his starches and sugars to a minimum and gave up desserts at age 40 (although he does admit to stealing a taste on occasion). He eats a good amount of plants, avoids eating other mammals and keeps his body weight at the low end of optimal.

He exercises by taking a lot of steps each day, walks upstairs instead of taking an elevator and visits the gym with his son to lift weights and jog before taking a sauna and a dip in an ice-cold pool. "I've got my 20-year-old body back," he said with a smile.

Speaking of cold, science has long thought lower temperatures increased longevity in many species, but whether it is true or not may come down to one's genome, according to a 2018 study. Regardless, it appears cold can increase brown fat in humans, which is the type of fat bears use to stay warm during hibernation. Brown fat has been shown to improve metabolism and combat obesity.

Sinclair takes vitamins D and K2 and baby aspirin daily, along with supplements that have shown promise in extending longevity in yeast, mice and human cells in test tubes.

One supplement he takes after discovering its benefits is 1 gram of resveratrol, the antioxidant-like substance found in the skin of grapes, blueberries, raspberries, mulberries and peanuts.

He also takes 1 gram of metformin, a staple in the arsenal of drugs used to lower blood sugars in people with diabetes. He added it after studies showed it might reduce inflammation, oxidative damage and cellular senescence, in which cells are damaged but refuse to die, remaining in the body as a type of malfunctioning "zombie cell."

However, some scientists quibble about the use of metformin, pointing to rare cases of lactic acid buildup and a lack of knowledge on how it functions in the body.

Sinclair also takes 1 gram of NMN, or nicotinamide mononucleotide, which in the body turns into NAD+, or nicotinamide adenine dinucleotide. A coenzyme that exists in all living cells, NAD+ plays a central role in the body's biological processes, such as regulating cellular energy, increasing insulin sensitivity and reversing mitochondrial dysfunction.

When the body ages, NAD+ levels significantly decrease, dropping by middle age to about half the levels of youth, contributing to age-related metabolic diseases and neurodegenerative disorders. Numerous studies have shown restoring NAD+ levels safely improves overall health and increases life span in yeast, mice and dogs. Clinical trials testing the molecule in humans have been underway for three years, Sinclair said.

"These supplements, and the lifestyle that I am doing, is designed to turn on our defenses against aging," he said. "Now, if you do that, you don't necessarily turn back the clock. These are just things that slow down epigenetic damage and these other horrible hallmarks of aging.

"But the real advance, in my view, was the ability to just tell the body, 'Forget all that. Just be young again,' by just flipping a switch. Now I'm not saying that we're going to all be 20 years old again," Sinclair said.

"But I'm optimistic that we can duplicate this very fundamental process that exists in everything from a bat to a sheep to a whale to a human. We've done it in a mouse. There's no reason I can think of why it shouldn't work in a person, too."

& 2022 Cable News Network, Inc., a WarnerMedia Company. All rights reserved.

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The 'Benjamin Button' effect: Scientists can reverse aging in mice. The goal is to do the same for humans - KITV Honolulu

Skin Stem Cells Comments Off on The ‘Benjamin Button’ effect: Scientists can reverse aging in mice. The goal is to do the same for humans – KITV Honolulu | July 16th, 2022

Almost one out of 100 babies are born with a heart defect each year in the United States. Many of these babies will need surgery within weeks of birth, followed by more surgeries throughout their lives. Now, doctors are turning to stem cells to give big hope for little hearts.

Hypoplastic left heart syndrome is a complex congenital heart disease. It is where the left ventricle does not develop, Sunjay Kaushal, MD, Ph.D., Chief of Pediatric Cardiac Surgery at Lurie Childrens Hospital in Chicago, explained.

Hypoplastic left heart syndrome

Those newborns depend solely on their right ventricles to pump blood throughout their bodies.

Kaushal emphasizes, These babies need surgical intervention in the first weeks of life.

Between 15% and 20% of those babies will not live to see their first birthday. For the little ones who do, medications and implanted devices can help, but ultimately, those children will need a heart transplant to survive.

That right ventricle becomes tired. It doesn't pump blood efficiently, Kaushal further explains.

The latest news from around North Texas.

Pediatric cardiac surgeons at Lurie Childrens Hospital are injecting stem cells directly into the heart to revitalize the worn-out right ventricle.

We're trying to see if we can actually put stem cells in there in order to remodel, rejuvenate that right ventricle in order to pump blood more efficiently for that baby, Kaushal said.

In the long run, stem cell therapy could possibly prevent those children from needing a heart transplant at all.

Kaushal added, I think that these studies could be game-changing for our babies.

They said 38 patients will be enrolled at seven clinical sites across the United States for a phase two clinical trial this year. Researchers hope that eventually, the stem cell injections will not have to be given as an injection into the heart, but as an intravenous injection like other medicine.

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Stem Cells Used to Repair Heart Defects in Children - NBC 5 Dallas-Fort Worth

Cardiac Stem Cells Comments Off on Stem Cells Used to Repair Heart Defects in Children – NBC 5 Dallas-Fort Worth | July 16th, 2022

Your heart and lungs share a close relationship, each relying on the other to replenish your blood with oxygen, remove wastes, and move blood and nutrients around your body.

When one of these players is underperforming or damaged, the other is quickly affected.

Pneumonia is an infection in one or both lungs. The tiny air sacs (alveoli) that move gases like oxygen in and out of your blood fill with fluid or pus.

This article will explore how pneumonia can affect how well your heart works and what can happen if you already have heart disease and then develop pneumonia.

Coronary artery disease is the most common form of heart disease in the United States. It develops when cholesterol and other substances build up in your blood vessels specifically the coronary arteries that supply blood to your heart.

Many things can lead to this buildup, including diet, lifestyle choices, and genetics.

The buildup of substances in your blood vessels is dangerous on its own since it can restrict blood flow to the heart and other body parts. But its even more serious when pieces of this buildup called plaques break off from the walls of your blood vessels.

When these pieces break off, they can travel to other areas of the body like the brain or heart, cutting off the blood supply to these organs resulting in a stroke or heart attack.

On its own, pneumonia is not a heart disease. Its a lung infection caused by bacteria or viruses.

However, heart disease complications like congestive heart failure can cause a condition similar to pneumonia.

Certain types of heart failure can lead to pulmonary edema. In this case, the heart is too weak to effectively pump blood out to the body, so the blood backs up into the heart and eventually into the lungs.

As this backed-up blood builds up in the lungs, pressure in the blood vessels of your lungs increases, and it can cause fluid buildup in the alveoli.

This results in an effect similar to pneumonia, where these air sacs fill with fluid.

Pneumonia is an infection that can cause inflammation throughout the body. This inflammation can lead to other complications, including an increased risk that bits of plaque can break free from your vessel walls and lead to heart attack or stroke.

Even without existing coronary artery disease or plaque buildup, the body-wide inflammation that pneumonia triggers can cause its own problems.

Inflammation can interfere with the normal function of all kinds of systems in your body especially the heart. This makes heart failure one of the most common complications of pneumonia.

About 30% of people hospitalized with community-acquired pneumonia develop heart failure and other cardiovascular problems, but the risk isnt always immediate. Research indicates that the greatest risk of heart complications occurs in the month after a pneumonia diagnosis, and the risk can continue for up to a decade.

It can be difficult to tell when pneumonia is affecting your heart, as pneumonia and heart disease can share symptoms including:

Additional symptoms you may experience with pneumonia that are not as common with heart disease include:

Inflammation in response to a pneumonia infection has some of the greatest impact on your heart.

Although heart damage from pneumonia can happen in anyone, it affects people with preexisting heart disease the most.

Among people who develop pneumonia with preexisting heart failure, about 1.4% who are treated in the outpatient setting find their heart failure gets worse after pneumonia. That percentage increases to 24% in people with more severe pneumonia that requires hospitalization.

Aside from inflammation, some individual cardiac symptoms or complications that can develop after a bout with pneumonia include:

The relationship between pneumonia and cardiovascular disease goes both ways: Pneumonia can increase the risk of heart disease, and a history of heart disease can increase the risk of pneumonia.

One 2018 study found that people with cardiovascular diseases heart failure in particular are three times more likely than others to develop community-acquired pneumonia.

Generally, the best way to prevent problems like pneumonia and heart failure is to take care of your overall health.

This means:

People with heart disease are generally recommended to stay up-to-date on various vaccinations, too. This can prevent acute infection and its complications.

However, there may be little difference in mortality rates among people with heart failure and pneumonia who had been vaccinated against things like influenza and pneumonia.

With every heartbeat and every breath, your lungs and heart work in tandem. Infections and chronic diseases that affect one organ can affect the other.

Pneumonia can increase your risk of developing heart disease or having your existing heart disease worsen. Likewise, heart disease can increase your risk of developing several types of pneumonia.

Talk with your doctor about your overall health and how to avoid chronic heart disease and acute infections like pneumonia.

Vaccines are one part of the equation, but the best strategy involves other health and diet strategies, too.

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Pneumonia and Heart Disease: What You Should Know - Healthline

Cardiac Stem Cells Comments Off on Pneumonia and Heart Disease: What You Should Know – Healthline | July 16th, 2022

Affecting one in 5,000 male births worldwide, Duchenne Muscular Dystrophy (DMD) is a fatal genetic disorder that currently doesnt have a cure, but published research conducted at the University of Nevada, Reno School of Medicine shows promise and may lead to the eventual development of a new molecular therapeutic.

The latest, significant research finding, published in Human Molecular Genetics, February 2022, involves the small-molecule sunitinib which has been shown to mitigate DMD-related skeletal muscle disease in a number of ways.

As patients with DMD grow older, muscular dystrophy worsens, causing respiratory and cardiac muscle failure resulting in premature death. There are no effective treatments to prevent DMD-related cardiac failure, however continued research in the lab of UNR Med Professor of Pharmacology Dean Burkin is pointing to protein and molecular-based solutions, including sunitinib which is already FDA approved and used in cancer treatments.

Burkin conducted the latest research with Ph.D. student Ariany Oliveira-Santos. Based on a mouse model, they found that sunitinib improved major negative symptoms that stem from DMD, such as cardiac muscle damage, without depressing the immune system completely. Oliveira-Santos was lead author on the published results. The study was supported by a grant from the Muscular Dystrophy Association and the National Institutes of Health.

Burkins lab focuses mainly on studying two key proteins 71 integrinand laminin and understanding the role they play in muscle development and disease. The lab primarily studies two muscle-damaging diseases: DMD and Laminin-2 related congenital muscular dystrophy (LAMA2-CMD).

Were interested in the biology of the 71 integrin, that's really the central focus of [our research], Burkin said. But we also have other big interests in these muscle diseases where the integrin [protein] is normally found.

Burkin explains that through this translational research, which he also calls the lab bench to bedside approach, researchers attempt to understand the biology of a system as much as possible, and then continue through the development steps that lead to therapeutic treatments.

Patients with DMD lack dystrophin which causes progressive muscle degeneration and weakness. This means the more these muscles are used, the more damage occurs. While there are repair cells in muscles, these cells eventually tire out. Burkin and Oliveira-Santos noted that the heart, an organ being used all the time, does not have this repair system, making the damage severe in cardiac muscles as well. Currently some therapeutic approaches have been beneficial for skeletal muscles but not for the heart; therefore, its important to have a drug or treatment that can target and be beneficial to skeletal and cardiac muscle at the same time, Oliveira-Santos explained.

We looked to the electrical and mechanical function of the heart and both were improved, Oliveira-Santos said. Sunitinib helped the cardiac function [and reduced] cardiac damage, and inflammation. I don't think theres really many drugs out there that do that right now.

Oliveira-Santos remembers wanting to be a scientist as early as eight years old. She went on to earn degrees in Brazil, including a bachelors in biomedicine and a masters in the scientific fields of immunology and pharmacology as they relate to transplant rejection. While earning her masters degree, Burkin was invited to Brazil by Oliveira-Santoss supervisor to give a talk, and the two met in-person and discussed her masters project. At the time, they were studying the same molecule, but in different models, so Oliveira-Santos had read some of Burkins papers.

Oliveira-Santos had always been interested in the physiology and pathology of disease and thought it would be a great area to study for a doctoral degree. She knew Burkin was working in this field, so about five years after their in-person meeting, Oliveira-Santos reached out to Burkin. He told her about an open position in his lab for a Ph.D. student, and their project of understanding the role of an FDA-approved small molecule for the treatment of DMD cardiomyopathy. She felt this project was a good match for what she was looking for and joined the lab in January 2019.

Oliveira-Santos said the mentorship and support shes received from Burkin and the rest of the lab has been invaluable.

Dean is always available to discuss and very happy to help [the lab members] with everything we need, Oliveira-Santos said. Everyone had an important opinion about the project and that was essential for the projects success.

While working in science oftentimes can come with struggles, Oliveira-Santos expressed how much these experiences have taught her.

Being in science is a big challenge, because you have to learn how to deal with problems all the time, she said. There are more failures than success [so] it teaches you how to deal with failure. Failure is normal. You just need to try to find a way around to get a solution.

Oliveira-Santos is set to finish her Ph.D. in Cellular and Molecular Pharmacology & Physiology in the fall 2022.

When I bring a student to the lab, I say I can supply everything but enthusiasm. And that's one thing that Ariany brings in abundance, Burkin said. I'm putting my students in contact with other principal investigators that I know to try and make sure that the next level on their career is achieved. She can go anywhere right now and move forward. The world is her oyster.

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Promising solution to fatal genetic-disorder complications discovered by University professor and Ph.D. candidate - Nevada Today

Cardiac Stem Cells Comments Off on Promising solution to fatal genetic-disorder complications discovered by University professor and Ph.D. candidate – Nevada Today | July 16th, 2022

After reading this article, you should be able to:

A wound is any injury that disrupts the structure of healthy skin tissue caused by chemical, mechanical, biological or thermal trauma. Wounds can be classified as acute or chronic, depending on their period of healing[1]. Acute wounds usually heal without complication within ten days; however, chronic wounds do not undergo normal healing processes, commonly have exaggerated inflammation, persistent infections or microbial biofilm formation and persist longer than six weeks[24]. The most frequent causes of chronic wounds are pressure, diabetes and vascular diseases[5].

Chronic wounds are a global problem, with annual cases rising dramatically owing to the ageing population and increased prevalence of diabetes and obesity[6]. It is estimated that up to 7% of the UK adult population has a chronic wound, costing the NHS 8.3bn each year in staff costs, wound dressings and medication[7]. Individual costs for wound management have been reported to vary, from 358 to 4,684 per patient for a wound that follows the normal healing trajectory, increasing to 831 to 7,886 per patient for a chronic, non-healing wound[7]. The majority of the costs account for GP and nursing time, with infected wounds costing an additional 1.39bn on antibiotics[7].

Results from one study, published in 2020, found that 59% of chronic wounds healed if there was no evidence of infection, compared with 45% if infection was present or suspected[7].Health conditions, such as diabetes mellitus and vascular disease, can predispose people to wounds that are difficult to heal, which can become chronic unless the underlying causes are addressed. For example, people with diabetes are prone to have a high incidence of wounds on their feet, which are slow to heal because of the impact of diabetes on the immune system, circulation and diabetic neuropathy. Complex chronic wounds, such as venous leg ulcers and diabetic ulcers, can significantly impact quality of life, morbidity and mortality[7].

Wound healing is a complex series of physiological reactions and interactions between numerous cell types and chemical mediators[8,9]. It comprises four coordinated and overlapping phases: haemostasis, inflammation, proliferation and remodelling[10].

The Figure below shows the phases of wound healing[11].

The first stage, haemostasis, is instantly activated after injury to stop bleeding at the site and prevent the entry of pathogens. In primary haemostasis, within seconds of an injury occurring, damaged blood vessels vasoconstrict to reduce blood flow through the wound area and diminish blood loss. Platelets adhere to the sub-endothelium of the impaired vessels, initiated by the presence of von Willebrand factor. This binds to glycoprotein Ib receptors on the surface of platelets, causing a conformational change on the platelet surface, activating platelets. These activated platelets release chemicals, such as adenosine diphosphate,serotonin andthromboxane A2, from their dense granules to stimulate platelet recruitment and adhesion to form a platelet plug[12,13]. Secondary haemostasis is a sequence of events, described as a coagulation cascade, that consequently converts soluble fibrinogen into insoluble fibrin. A fibrin mesh sticks to the platelet plug producing a haemostatic plug to seal the inside of wound[12,14].

At the beginning of the inflammatory phase, activated platelets also release pro-inflammatory cytokines and growth factors to stimulate the recruitment of immune cells to clean the wound area, initially involving infiltration of neutrophils and monocytes[15]. Monocytes undergo a phenotypic change to become macrophages. The previously constricted blood vessels also vasodilate because of increased prostaglandins, facilitating the chemotaxis of inflammatory cells[16,17]. The proliferation phase is charactered by re-epithelialization, capillary regeneration and the formation of granulation tissue(18). Fibroblasts and endothelial cells proliferate during this phase, stimulated by the numerous cytokines and growth factors released by the platelets and macrophages. This leads to the formation of new blood vessels in a process called angiogenesis[18].

After migration to the wound site, fibroblasts begin to proliferate and synthesize collagen and extracellular matrix components, such as proteoglycans, hyaluronic acid, glycosaminoglycans, and fibronectin, to form granulation tissue[1618]. The final stage is remodelling, which can last for several years. The formation of new capillaries slows, facilitating maturation of blood vessels in the wound. Type III collagen is replaced by type I collagen in the extracellular matrix to create a denser matrix with a higher tensile strength. The differentiation of fibroblasts into myofibroblasts causes the wound to physically contract. However, owing to differences in collagen type, new tissue after healing does not fully regain its original strength[1618].

Delayed wound healing can be caused by local and/or systemic factors. Local factors in the wound site include oxygen deficiency (causing chronic hypoxia), excessive exudate (causing maceration) or insufficient exudate (leading to desiccation), local infection, foreign bodies intensifying the inflammatory response, repetitive trauma, pressure/shear, and impaired vascular supply to the injury area[16,19].

Systemic factors that delay the healing process include the following[16,19]:

Oestrogen insufficiency, for instance in postmenopausal women, is known to impair all stages of wound repair process, especially inflammation and regranulation, with improved wound healing being a potential benefit of hormone replacement therapy. Androgens can repress cutaneous repair in both acute and chronic wounds, retarding the healing process and increasing inflammation[20].

The process can also be delayed in people with immunocompromised conditions, such as acquired immunodeficiency syndrome, cancer and malnutrition, with deficiencies in protein, carbohydrates, amino acids, vitamins A, C and E, zinc, iron, magnesium all having an effect[16,19,21]. Certain medicines can also delay the process, such as glucocorticoid steroids, chemotherapeutic drugs and non-steroidal anti-inflammatory drugs[19,21].

The most common causes of delayed chronic wound healing are infection and biofilm formation: biofilms are microscopically identifiable in up to 60% of chronic and recurrent wounds,leading to significant morbidity and mortality and an escalated healthcare cost[5,22,23].

A wound is considered infected when there are sufficiently large numbers of microbes presenting in wound environment or sufficient virulence to raise either a local or systemic immune response.

The wound-infection continuum has three stages: contamination, colonisation and infection. In the contamination phase, micro-organisms are unlikely to replicate because of an unfavourable environment. Colonisation happens when microbes successfully multiply, but not in sufficient levels to destroy host defences. However, the accelerated loads and persistence of microbes in wound environments may prolong the inflammatory phase and delay wound healing. When bacteria invade deeper into the wound bed and proliferate speedily, they can provoke an immune reaction and initiate local infection. As pathogens proliferate beyond the boundaries of the wound, infection may spread into deeper tissues, adjacent tissues, fascia, muscle or local organs. Eventually, systemic infection, such as sepsis, can occur when microbes invade into the body via vascular vessels or lymphatic systems, affecting the entirety of the body[24,25].

Biofilm is an extracellular polymeric substance produced by bacteria that acts as a physical barrier, enveloping bacteria and protecting them from host defences and antimicrobial agents. Several pathogens isolated from chronic wounds are typically capable of forming biofilms, such asStaphylococcus aureusandPseudomonas spp[5,23,24,26]. Biofilms persisting within chronic wounds can continuously stimulate host immunity, resulting in the prolonged release of nitric oxide, pro-inflammatory cytokines such as interleukin-1 and TNF-, and free radicals, and activation of immune complexes and complement, causing the healing process to fail and convert to a chronic state[23,27]. Sustained inflammatory reactions also trigger an escalated level of matrix metalloproteases, which can disrupt the extracellular matrix[16].

Most of the time, wound infection is diagnosed via visual inspection based on clinical signs and symptoms, including the classic signs of heat, pain, swelling, suppuration, erythema and fever. Typical characteristics of an acute infected wound are pain, erythema, swelling, purulent drainage, heat and malodour. In addition, a chronic wound may display signs of delayed healing, wound breakdown, friable granulation, epithelial bridging and pocketing in granulation tissue, increasing pain and serious odour.

Microbiological analysis of a specimen from wound cultures (using tissue biopsy or wound swab, pus collection or debrided viable tissue) is performed to identify causative microorganisms and guide the choice of antimicrobial therapy. Traditional diagnostics can be time consuming, and some organisms can be difficult to culture, so molecular techniques including DNA sequencing may help with characterising genetic markers[25]. Other laboratory markers, such as C-reactive protein, have also been used as markers and imaging techniques, such as CT scanning and autofluorescence imaging, may help with real-time diagnosis[25,28].

In clinical practice, the evaluation and identification of underlying conditions that affect wound healing are vital to optimising wound care. Accurate assessment of causes and comorbidities will inform the best course of treatment, such as compression therapy for venous leg ulcers or offloading (relief of pressure points) for people with diabetic foot ulcers[29]. The underlying pathologies of wounds are numerous and failure to address them can lead to a failure in healing[2,29].

Once any underlying conditions are identified, the wound bed should be prepared to optimise the chance of healing. A wound hygiene approach should be considered; its core principle is to remove or minimise unwanted materials, such as biofilm, devitalised tissue and foreign debris, from the wound bed to kickstart the healing process[30]. A holistic patient and wound assessment will ensure wound pathology and wound biofilm are managed simultaneously[30]. The TIME framework (tissue, infection/inflammation, moisture balance, edges) is a systematic approach to wound management[31]. Wound-bed preparation and the TIME approach should be used alongside a holistic assessment of other patient factors such as pain, nutrition and hydration[2].

Effective management of infection in chronic wounds involves the removal of necrotic tissue, debris and biofilms using debridement plus the appropriate use of antimicrobials (including topical antiseptics and systemic antibiotics)[1,32].

Antiseptics have a broad spectrum of bactericidal activity and are used externally for the purposes of eliminating bacterial colonisation, preventing infection, and potentially stimulating wound healing. They are less likely to cause antimicrobial resistance (AMR) than antibioticsand inhibit the development of microbes by disrupting cell walls and cytoplasmic membranes, denaturing proteins, and damaging bacterial DNA and RNA[5,23,33,34]. An ideal antiseptic agent should have broad-spectrum activity, a fast onset of action, long-lasting activity, be safe for healthy surrounding tissue, possess minimal allergenicity, be stable in blood and tissue protein, persistently remain within the wound bed, and potentially be active against biofilms[23,35]. Antiseptics, antimicrobial washes or surfactants can be used to clean the wound and peri-wound skin and prepare the wound bed for debridement[30].

A variety of antiseptic agents are used in clinical practice[23,34]:

Antiseptics can also be used as an adjunct to other therapies (e.g. negative pressure therapies) in treating complicated wound types(e.g.diabetic foot ulcers,venous leg ulcers and sternal wounds)[36].

All open wounds will be colonised with bacteria, but antibiotic therapy is only required for those that are clinically infected[37]. Systemic antibiotic therapy should only be considered for the treatment of cellulitis, osteomyelitis, sepsis, lymphangitis, abscess, and invasive tissue infection. Inappropriate use of systemic antibiotics may increase the risk of side effects and contributes to emergence of AMR[5]. The choice of initial therapy and the duration is frequently empirical and should take into account the type of wound, severity of infection, suspected pathogens and local AMR[38]. With severe infections, broad-spectrum antibiotics should be used against both gram-positive and gram-negative organisms, while a relatively narrow spectrum agent is enough for most mild and many moderate infections[5].

A systematic review assessed the clinical and cost-effective efficacy of systemic and topical antibiotic agents in the treatment of chronic skin wounds. The authors of the review suggested that there was insufficient evidence to support any routine use of systemic antibiotics in specific chronic wounds[39].

Appropriate and judicious use of antimicrobials must be considered when managing wounds. The use of topical antibiotics is not recommended for eliminating bacterial colonisation or wound infections because of their limited effectiveness, high risk of resistance and potential to cause contact allergy[5,35].

AMR occurs when microorganisms naturally evolve in ways that cause medicines used to treat infections to become ineffective, and these micro-organisms become resistant to most[40,41]. The misuse and overuse of antibiotics is a major cause of the emergence of AMR, via four main mechanisms[42]:

Moreover, the multicellular nature of biofilm matrix is likely to give extra protection to bacteria communities, makes them resistant to antibiotics. There are several proposed mechanisms for AMR related to biofilm: the alteration of chemical environment within biofilm, slow or inadequate diffusion of the antibiotics into the biofilm, and a differentiated biofilm subpopulation[43].

Topical antimicrobial use plays an important role when the wound is clinically infected or there is a suspected biofilm. The British Society for Antimicrobial Chemotherapy and European Wound Management Association position paper highlighted antimicrobial stewardship (AMS) a set of strategies to improve the appropriateness and minimise the adverse effects of antibiotic use as being central to wound care treatment to improving patient outcomes, reducing microbial resistance and decreasing the spread of infections caused by multidrug-resistant organisms[37]. Effective AMS avoids the use of antimicrobial therapy when not indicated while enabling the prescribing of appropriate antimicrobial interventions when they are indicated to treat infection.

The UK government has outlined a 20-year vision for reducing AMR, proposing a lower burden of infection through better treatment of resistant infections[44]. This includes the optimal use of antimicrobials and good stewardship across all sectors and appropriate use of new diagnostics, therapies, vaccines and interventions in use, combined with a full AMR research and development pipeline for antimicrobials, alternatives, diagnostics, vaccines and infection prevention across all sectors.

The use of alternatives to traditional antibiotic therapy is of huge interest for combating increasing AMR, including bacteriophage therapy, phage-encoded products, monoclonal antibodies and immunotherapy[45]. Among these, endolysins phage-encoded peptidoglycan hydrolases selectively targeting bacterial taxa have been identified as promising antimicrobial agents because of their ability to kill antimicrobial-resistant bacteria and lack of reported resistance However, challenges restrict the widespread use of endolysin therapy, such as limited drug-delivery methods, their specificity to particular bacteria types, and bioavailability via IV administration[46,47].

Debridement is the physical removal of biofilm, devitalisedtissue, debris and organic matter and is a crucial component of wound care. The presence of non-viable tissue in the wound bed prevents the formation of granulation tissue and delays the wound healing process. The removal of non-viable tissue encourages wound healing. The type of tissue found in the wound bed (e.g. whether necrotic or sloughy) will determine whether debridement is required. Factors such as bioburden, wound edges and the condition of peri-wound skin can also influence whether debridement is required[48]. A range of techniques can be used, dependent on the clinicians ability level: these include autolytic, larval, mechanical, sharp and surgical methods[49,50].

The concept of moist wound healing is not newand can lead to healing up to 23 times quicker than that of dry wound healing[51,52].Wound dressings such as cotton wool, gauze, plasters, bandages, tulle or lint should not be used, as they do not promote a moist wound healing environment, require excessive changes, and can cause skin damage and pain during dressing changes. They have therefore been replaced by newer types of wound dressingsthat can play a role in autolysis and debridement, maintain a relatively stable local temperature, keep the wound hydrated, promote wound repair and prevent bacterial infection[14,53,54].

Wound dressings should keep the wound free from infections, excessive slough, contaminants and poisons, keep the wound at the ideal temperature and optimum pH for healing, be permeable to water, but not microbes, come away from wound trauma during dressing changes, not be painful and be comfortable[55]. There are a variety of dressings available for managing chronic wounds, such as hydrogels, hydrocolloids, alginates, foams, and film dressings[56]. Dressings can also be used carriers for active agents including growth factors, antimicrobial agents, anti-inflammatory agents, monoterpenes, silver sulfadiazine or silver nanoparticles[57].

Potential factors that may influence dressing selection include:

Antimicrobial dressings impregnated with iodine, silver and honey are available[58]. They can be divided into two categories: those that release an antimicrobial into the wound and those that bind bacteria and remove them from the wound into the dressing. A more detailed overview can be found in a recent consensus document on wound care and dressing selection for pharmacists[57].

It is essential wound dressings do not inadvertently lead to moisture-associated skin damage an umbrella term encapsulating incontinence-associated dermatitis, intertriginous dermatitis (or intertrigo), peri-wound maceration and peristomal dermatitis. Practitioners should ensure the dressing can manage any exudate and protects the peri-wound area. Skin barriers can be used to protect the peri-wound area and prevent skin damage[59].

Widely used to aid the healing of acute, chronic and traumatic wounds, negative-pressure wound therapy (NPWT) removes interstitial fluid/oedema and excessive exudate, provides a moist environment, improves blood flow and tissue perfusion, and stimulates angiogenesis and granulation tissue formation[4,60]. Results from several studies have demonstrated the selective effect of NPWT in eliminating non-fermentative gram-negative bacilli in wounds[36]. Additionally, NPWT can be combined with additional topical antimicrobial solutions, reducing bacteria load, stimulating wound closure and decreasing wound size faster than conventional NPWT[36,61,62].

Hyperbaric oxygen therapy wasfirst proposed as an additional treatment for chronic wounds in the mid-1960s. Treatment involves the intermittent exposure of the body within a large chamber to 100% oxygen at a pressure between 2.0 and 2.5 atmosphere absolute, leading to an increase in oxygen levels within haemoglobin and elevating oxygen tissue tension at the wound site[63].A Cochrane reviewpublished in 2015 reported a significant improvement in the healing of diabetes ulcers in the short term when treated with hyperbaric oxygen therapy. However, further high-quality studies are needed before clinical benefits can be proven[64].

For chronic wound healing, electrical stimulation is the most frequently studied biophysical therapy[4]. It uses direct current, alternative current, and pulsed current. Electrical stimulation has been shown to benefit every stage of the wound-healing process, both at cellular and systemic levels. During the inflammation phase, electrical stimulation promotes vasodilation and increases the permeability of blood vessels, thereby facilitating cellular movement to the wound site and so promoting a shorter inflammatory response.

Studies have reported an inhibition in bacterial proliferation after electric stimulation. In the proliferation phase, electrical stimulation raises the migration, proliferation and differentiation of endothelial cells, keratinocytes, myofibroblasts and fibroblasts. At the systemic level, it promotes revascularisation, angiogenesis, collagen matrix organisation, wound contraction, and re-epithelialisation. Ultimately,electrical stimulation promotes the contractility of myofibroblast and converts type III collagen into type I, along with rearranging collagen fibres to optimise the scars tensile strength[8,65,66].

A prospective clinical study conducted across the UK suggested that using an externally applied electroceutical device, combined with compression bandaging and dressings, was a cost-effective treatment for venous leg ulcers, compared with conventional treatments[67].

Low-frequency ultrasound has been used as an adjunct treatment for chronic wounds. It has a debriding effect, removing debris and necrotic tissue (primarily via cavitational and acoustic streaming phenomena). Ultrasound is also reported to disrupt biofilmin vitro, thus increasing the sensitivity of bacteria to antimicrobials[68]. It is proposed to be effective instimulating collagen synthesis, increasing angiogenesis,diminishing the inflammatory phase as well as promoting cellular proliferation[69].Several clinical studies have shown a reduction in wound size when wounds are treated with low-frequency ultrasound therapy[7072].

Extracorporeal shock wave therapy (ESWT) has been proposed to aid wound healing by transmitting acoustic pulsed energy to tissues. ESWT seems to promote angiogenesis, stimulate circulation, reduce anti-inflammatory response, and upregulate cytokine and growth-factor reactions[4]. A clinical trial demonstrated the feasibility and tolerability of ESWT in wounds with different aetiologies[73]. Furthermore, a review concluded that ESWT brings more benefits for patients with diabetic foot ulcers than hyperbaric oxygen therapy, based on increased angiogenesis, tissue perfusion and cellular reactions with reduced cell apoptosis, as well as a higher ulcer healing rate[74].

More recent developments include introducing nanomedicine to wound-healing approaches. It has been used to achieve controlled delivery, stimulate chronic wound healing and control microbial infections[14,75]. Nanotechnology-based wound dressings like nanogels and nanofibers offer a larger surface area and greater porosity, potentially enhancing absorption of wound exudate. They can also facilitate collagen synthesis and ultimately re-epithelisation through supporting the migration and proliferation of fibroblasts and keratinocytes.

Nanomedicines also seem to aid healing through molecular and cellular pathways[75]. For example, a methacrylated gelatin (MeGel)/poly(L-lactic acid) hybrid nanofiber synthesised has been reported to stimulate the recruitment and proliferation of human dermal fibroblasts, thereby promoting wound healing[76]. Nanoparticles can not only act as carriers of antimicrobial agents, they can also have an intrinsic antimicrobial effect[75,77,78]. In 2021, Qiu et al. successfully developed an antibacterial photodynamic gold nanoparticle (AP-AuNPs) that demonstrated antibacterial effects on both Gram-negativeEscherichia coliand Gram-positiveStaphylococcus aureus,as well as potentially inhibiting biofilm formationin vitro[79].

Growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) are down-regulated in chronic wounds, suggesting that topical administration of growth factors and cytokines could improve wound healing[80].

Growth factors can improve wound repair through several mechanisms[81]:

Growth factors that have been studied in wound healing are EGF, VEGF, FGF, PDGF, transforming growth factor-beta 1 (TGF-1) and granulocyte-macrophage colony stimulating factor[82]. Becaplermin (rhPDGF-BB) was the first growth-factor therapy approved by the US Food and Drug Administration, after it demonstrated effectiveness in treating complex wounds when combined with standard wound care[80]. A systematic review and meta-analysis indicated that growth factors were effective in healing venous stasis ulcers, increasing wound healing by 48.8% compared with placebo and showing no difference in adverse effects compared with controls[83].

Stem cells may have certain advantages in wound healing because of their ability to differentiate into specialised cells and secrete numerous mediators including cytokines, chemokines, and growth factors[84,85]. This makes them a promising approach for treating chronic wounds.

Mesenchymal stem cells can be extracted from bone marrow, adipose tissue, umbilical cord blood, nerve tissue, or dermis and used both systemically and locally[86]. They release growth factors that stimulate blood-vessel and granulation tissue formation, fibroblast and keratinocyte migration, collagen synthesis, and fibroblast activation, increase re-epithelialisation, exert immunomodulatory properties, regulate inflammatory responses, and display antibacterial activities[85,8789].

Many studies have investigated the efficacy of stem-cell therapies for a variety of wounds, including burns, non-healing ulcers, and critical limb ischemia[9096]. A systematic review published in 2020 that investigated the clinical application of stem-cell therapy for the treatment of chronic wounds showed the potential of a variety of stem cells in the restoration of impaired wound healing, bothin vitroandin vivo, despite the clinical evidence being very limited. As the recorded studies were on case-by-case basis, there is a lack of comprehensive guidelines for the use of stem cells in different wounds[97].

Auto-transplantationof adipose tissue-derived mesenchymal stromal cells has been proposed as a safe, alternative method to treat chronic venous ulcers[96]. Bioscaffold matrices comprising hyaluronic acid, collagen or other bio-polymeric materials have increasingly been applied for stem-cell transplantation. These matrices not only provide wound coverage, but also offer protection for stem cells and controlled delivery[86].

Skin equivalents are polymeric biomaterials increasingly adopted for both acute and non-healing ulcers, such as venous ulcers, diabetic foot ulcers or pressure ulcers, to temporarily or permanently substitute the structure and function of human skin. Skin substitutes are designed to increase wound healing, provide a physical barrier that protects the wound from trauma or bacteria, provide a moist environment for the repair process, replace impaired skin components and decrease morbidity from more invasive treatments like skin grafting[98,99].

They can usually be classified as one of three major types: dermal replacement, epidermal replacement, and dermal/epidermal replacement[98]. Epidermal replacements (substitutes) comprising isolated autogeneous keratinocytes cultured on top of fibroblasts include Myskin (Regenerys), Laserskin(Fidia Advanced Biopolymers) and Epicel(Genzyme Tissue Repair Corporation). Dermal replacements include Dermagraft (Smith and Nephew) and Transcyte(Shire Regenerative Medicine)[98].

Epidermal/dermal skin replacements (also called composite skin substitutes) contain both epidermal and dermal layers that mimic the histological structure of original skin. The bi-layered bioengineering skin Apligraf (Organogenesis) was the first living skin equivalent for the management of complex chronic wounds like diabetic foot ulcers and venous leg ulcers. It is made up of a dermal layer of human fibroblasts embedded in a bovine type I collagen matrix and an epidermal layer generated by human keratinocytes[100]. Some other commercial products of composite substitutes are OrCel(Forticell Bioscience) andPermaDerm(Regenicin)[98]. In general, the current high cost of such dressings and limited evidence on effectiveness restricts them from being widely adopted[101]. Recently, technologies such as electrospinning or 3D-printing have been used to fabricate skin substitutes. Electrospinning can create nanofibers with high oxygen permeability, variable porosity, a large, exposed surface area and a morphology similar to the extracellular matrix, making them interesting candidates for skin substitutes[102,103].

TheNational Wound Care Strategy Programme, which was implemented by NHS England in 2018, has made progress in reducing unwanted variation in care and addressing suboptimal wound care.

Through its workstreams, the involvement of stakeholders, patients and carers, and the publication of the core capabilities for educating a multi-professional workforce, wound care has become a national priority. There are still many challenges in the management of chronic wounds the complexity of wound environment, limited knowledge of the biological, biochemical, and immunological healing processes, and the increasing complexity of disease pathophysiology that comes with ageing populations.

The development of standardised and clinically relevant testing for wound dressings, along with high-quality clinical trials, would enable useful comparisons of treatments. The whole episode of care should be considered in assessments of the cost-effectiveness of different dressings and devices, rather the simple cost of the individual entity. All these complex concerns restrict success in wound management, which in turn negatively impacts the quality of life of the patients and places a burden on global healthcare systems[75,104]. Organisations and healthcare providers should share best practice and education of healthcare professionals is needed to get the best outcomes for patients with preventable chronic wounds.

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Bhagavan N, Ha C-E. Biochemistry of hemostasis. In: Essentials of Medical Biochemistry . Academic Press 2015. 752.

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Current and advanced therapies for chronic wound infection - The Pharmaceutical Journal

Cardiac Stem Cells Comments Off on Current and advanced therapies for chronic wound infection – The Pharmaceutical Journal | July 16th, 2022

Have something to say? Lookout welcomes letters to the editor, within our policies, from readers. Guidelines here.

Like many moms, UC Santa Cruz stem cell biologist Lindsay Hinck struggled to make enough milk to feed her infant daughter.

Frustrated by her low supply, she went to a lactation consultant, who advised her to wake up every night at 3 a.m. an optimal time in the hormone cycle to pump precious drops of liquid gold for her baby.

Hinck did it, but she also wondered, why was she having so much trouble and losing so much sleep while other moms had no problem feeding their newborns?

After many exhausting early hours with the pump, Hinck did what she does best: research. She found something remarkable: More than 25% of women worldwide struggle to produce enough milk to feed their infant children.

But when she looked to scientific literature for an explanation, it came up empty.

Hinck, who got a masters degree in biochemistry from UC Davis and her Ph.D. in cancer biology from Stanford University, was shocked to realize scientists have barely studied human lactation. There was almost no information for scientists or moms about how human breast tissue makes milk.

Hinck decided to change that.

She switched her UCSC labs research focus from breast cancer to lactation, specifically looking into how stem cells in breast tissue create milk and why some womens supply comes out low.

Its a topic some view with skepticism; lactation and breastfeeding are still treated by many as uncomfortable or inappropriate. In fact, in the early days of her research, Hinck had to get funding from an animal health firm interested in increasing milk production in cows.

We sexualize breasts in the most amazing ways, and people dont seem to have a problem talking about that, says Hinck, who has been at UCSC since 1998 and serves as co-director of the universitys Institute for the Biology of Stem Cells. Yet when it gets down to their biological function which is to provide nutrition for infants somehow the world clams up.

With the a nationwide baby formula shortage having affected millions of families, Hincks work funded by the National Institutes of Health takes on even greater importance. Parents whose infants have allergies or metabolic conditions rely on formula, and women particularly those who are already struggling to breastfeed cant suddenly build a milk supply overnight when formula is not available.

Hinck spoke with Lookout from her office at UCSC; this interview has been edited for clarity.

Lookout: What is lactation insufficiency?

Lindsay Hinck: Lactation insufficiency is the inability of a woman to produce the breast milk in daily volumes that meet the nutritional needs of her infant.

The statistics that we have are very broad. Somewhere between 25% and 67% of women will experience this worldwide. And this statistic is so broad because lactation insufficiency is understudied, and its hard to study.

A lot of scientists would agree that breast milk does confer an immunological advantage, and that it is filled with immune cells that the mother is giving to her infant; milk is also filled with microbes. Those are two of the major deliveries to children that come through breast milk, not to mention all the comfort of the breastfeeding cycle, psychological comfort and connectedness through the skin on skin feeling of being fed that way.

Lookout: How do you feel about your research in the context of the baby formula shortage?

Hinck: A lot of women rely on formula because they have trouble building a milk supply. Currently there are no FDA (U.S. Food and Drug Administration)-approved drugs in the United States for lactation insufficiency. My research is identifying therapeutically relevant drug targets, so that maybe we will be able to address this issue. We hope that one day women can take a drug to better build a milk supply.

Were working on a nonhormonal drug. The current drugs work on the hormone prolactin, whereas my lab studies stem cells. None of the drugs targeting prolactin have been approved, because they have terrible side effects.

Hormones have wide-ranging effects. Theyre released and they spread throughout the body. I think maybe we have an opportunity to identify a therapeutic that wont have so many deleterious side effects.

(Mel Melcon / Los Angeles Times)

Lookout: Because of the baby formula shortage, an easy answer might be to tell mothers they should just breastfeed. Why might that not be a compassionate or realistic response?

Hinck: No, thats not a compassionate or realistic response. I mean, especially if you havent built your milk supply, its not a trivial thing. If you didnt build a milk supply from the beginning, and even if you are breastfeeding, if you cant meet the daily needs of your infant, you simply dont have the milk. Its just not there.

Building a milk supply doesnt occur over 24 hours, you cant just latch the child on more often and have more milk in a day. Eventually the milk supply will increase, but its complicated. Its hard for some women to initiate and build a milk supply.

Lookout: In the U.S., lactation and breastfeeding seem to be treated as somewhat taboo or uncomfortable topics. How do you respond to that?

Hinck: We dont want to see women doing it. It seems to make people uncomfortable, so at best we provide women a room somewhere, and at worst there are no accommodations. We certainly dont appear as a society that welcomes breastfeeding in public. I am bemused at this, and find it tragic at the same time.

I myself, when I breastfed, I just breastfed. I just got to the point where tough, you know? I know I made people uncomfortable. My mother-in-law would try to drape a huge blanket over me and my child in the summer in the heat, and it was like 100 degrees underneath that blanket. I would just be like, This is crazy! Its just an infant at my breast eating. Seems fine to me. And I dont think the climate has dramatically changed in many places in the world. My daughter is 22 years old, and in 22 years I have not seen that needle budge. It still seems like breastfeeding makes people uncomfortable, and I dont know why.

Lookout: Have you faced any skepticism about this as a research topic, or faced any particular challenges in studying lactation compared to other topics, like cancer?

Hinck: I would say that I have had a harder time getting my lactation research funded. But recently, I received a NIH grant from the National Institutes for Child Health and Human Development, so thats been terrific. There has been a gaining interest in a number of whats been classified as womens diseases that have been understudied for a long time.

But in the early days, I got money from an animal health firm because they were interested in increasing milk supply in cows. The biology is the same, however. So that worked out for me, and we were able to have a project that involves looking to see if this would work for building milk supply in cows, and then we were able to unravel the basic pathways, and now were applying that.

Lookout: What would you say are the big questions driving your current research?

Hinck: How does the breast tissue know how many progenitor cells to release or recruit to expand and to build the milk supply?

Breast stem/progenitor cells have to last a whole lifetime, and they have limited potential. Theyre stemlike in that they undergo an asymmetric cell division, which is a special type of cell division that recreates the stem/progenitor cells and gives rise to daughter cells that can go on to expand and become the milk producing cells.

So how many of those asymmetric cell divisions occur? How many cells are recruited to undergo those asymmetric cell divisions? All of that is unknown. Remember, the stem cell, the progenitor cell, wants to divide as infrequently as possible. Every time they replicate their DNA, it is opening up the possibility of damage that could lead to cancer.

Lookout: How would understanding these progenitor cell pathways help improve peoples lives, or pursue a solution to lactation insufficiency?

Hinck: Its early days. We dont understand a lot, and of course giving drugs to women who are pregnant is tough. There are drugs on the market for lactation domperidone is the best medicine to build milk supply, but its not approved by the FDA in America. It has side effects, cardiac side effects.

So its not unheard of that there would be drugs that could help build a milk supply. I think that would be the ultimate goal of our research, to understand if there is any pharmacological intervention that could help.

Lookout: What do you think nursing mothers who are struggling with lactation need? What can we do as a society to support them?

Hinck: Well, in the short term, certainly make workplace rules that change the climate. I mean, even if the rules are in place, if women dont feel welcome to take the breaks to pump then it doesnt happen. I mean, we all know how that goes.

Give mothers more time off. Create more welcoming environments when they come back to work to support them and their desire to breastfeed their child.

And in the longer term, we could understand the biology of building milk supply, which is still quite mysterious in humans. What are some of the factors that may impinge on that during pregnancy or after pregnancy?

Lookout: What did you have to do in order to feed your child when you were having trouble making enough milk?

Hinck: I saw the lactation consultant and I was told to pump at 3 a.m. when prolactin levels are the highest. I would set the alarm and get up and pump every night. I was also working full time, pumping every four hours. But I could barely pump the amount of milk for the next day.

Thats a burden, you know? Its just hard to balance. Youve got an infant, and youve got this other role, but youre also providing all the food for them. It doesnt always work seamlessly, thats for sure. I went to work to do my science, and I did the best I could.

It was a lot of work. Its so much to expect of mothers. And we just dont give parents, mothers, the space and time to breastfeed at work. Its also underappreciated that there could be other people who want to breastfeed, and we need to open doors for them for non-birth moms, trans people. Why do we keep lactation in just the realm of women? I think that if we understood lactation physiology better, we could help people breastfeed.

Guanan Gmez-Van Cortright is a 2022 graduate of the UC Santa Cruz Science Communication masters program. She has written for Good Times, KQED radio and the San Jose Mercury News.

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Why do some women struggle to breastfeed? A UCSC researcher on what we know, and don't - Lookout Santa Cruz

Cardiac Stem Cells Comments Off on Why do some women struggle to breastfeed? A UCSC researcher on what we know, and don’t – Lookout Santa Cruz | July 16th, 2022

This bone marrow market report provides details of new recent developments, trade regulations, import export analysis, production analysis, value chain optimization, market share, impact of domestic and localised market players, analyses opportunities in terms of emerging revenue pockets, changes in market regulations, strategic market growth analysis, market size, category market growths, application niches and dominance, product approvals, product launches, geographic expansions, technological innovations in the market. To gain more info on the bone marrow market contact Data Bridge Market Research for anAnalyst Brief,our team will help you take an informed market decision to achieve market growth.

The bone marrow market is expected to gain market growth in the forecast period of 2021 to 2028. Data Bridge Market Research analyses that the market is growing with the CAGR of 5.22% in the forecast period of 2021 to 2028 and is estimated to reach 13,899.60 USD Million by 2028. The growing amount of bone marrow diseases will help in escalating the growth of the bone marrow market. Bone marrow transplant also referred to as hematopoietic stem cell. It is a soft vascular tissue present in the interior of long bones. It comprises of two types of stem cells, that are hematopoietic and mesenchymal stem cells. Bone marrow is mainly responsible for the haematopoiesis, (formation of blood cells), production of lymphocytes, and the storage of fats. The bone marrow transplant is the last alternative generally recommended by the physicians in the cases of fatal bone marrow diseases and bone or skin cancer.

Get a Sample PDF of the report https://www.databridgemarketresearch.com/request-a-sample/?dbmr=global-bone-marrow-market

Major factors that are boosting the growth of the bone marrow market in the forecast period are the growing of the incidences of non-Hodgkin and Hodgkin lymphoma, thalassemia, and leukemia, along with the common bone marrow diseases around the world, the developments in the technology and the enhancing of the healthcare infrastructure. Furthermore, the advancing signs of bone marrow transplant for heart and neuronal disorders, increasing funding in the logistic services and the growing per capita of the healthcare expenses are some of the other factors anticipated to further propel the growth of the bone marrow market in the coming years. However, the high expenditure for the treatment, shortage of the bone marrow donors and instability of the repayment are few of the factors further responsible for the impeding the growth of the bone marrow market in the near future.

Bone MarrowMarket Scope and Market Size

The bone marrow market is segmented on the basis of transplantation type, disease indication and end user. The growth amongst these segments will help you analyse meagre growth segments in the industries, and provide the users with valuable market overview and market insights to help them in making strategic decisions for identification of core market applications.

To Gain More Insights into the Market Analysis, Browse Summary of the Research Report@ https://www.databridgemarketresearch.com/reports/global-bone-marrow-market

Bone MarrowMarket Country Level Analysis

The bone marrow market is analysed and market size insights and trends are provided by country, transplantation type, disease indication and end user as referenced above. The countries covered in the bone marrow market report are the U.S., Canada and Mexico in North America, Germany, France, U.K., Netherlands, Switzerland, Belgium, Russia, Italy, Spain, Turkey, Rest of Europe in Europe, China, Japan, India, South Korea, Singapore, Malaysia, Australia, Thailand, Indonesia, Philippines, Rest of Asia-Pacific (APAC) in the Asia-Pacific (APAC), Saudi Arabia, U.A.E, South Africa, Egypt, Israel, Rest of Middle East and Africa (MEA) as a part of Middle East and Africa (MEA), Brazil, Argentina and Rest of South America as part of South America.

Europe dominates the bone marrow market because of the occurrence of the increasing number of innovative healthcare centers. Furthermore, the healthcare systems have introduced the bone marrow transplant in their contributions and the state-of-the-art public facilities which will further boost the growth of the bone marrow market in the region during the forecast period. North America is projected to observe significant amount of growth in the bone marrow market because of the growing cases of chronic diseases such as blood cancer. Moreover, the increasing of the geriatric population is one of the factors anticipated to propel the growth of the bone marrow market in the region in the coming years.

The country section of the bone marrow market report also provides individual market impacting factors and changes in regulation in the market domestically that impacts the current and future trends of the market. Data points such as consumption volumes, production sites and volumes, import export analysis, price trend analysis, cost of raw materials, down-stream and upstream value chain analysis are some of the major pointers used to forecast the market scenario for individual countries. Also, presence and availability of global brands and their challenges faced due to large or scarce competition from local and domestic brands, impact of domestic tariffs and trade routes are considered while providing forecast analysis of the country data.

Competitive Landscape and Bone MarrowMarket Share Analysis

The bone marrow market competitive landscape provides details by competitor. Details included are company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, global presence, production sites and facilities, production capacities, company strengths and weaknesses, product launch, product width and breadth, application dominance. The above data points provided are only related to the companies focus related to bone marrow market.

The major players covered in the bone marrow market report are AGendia, Agilent Technologies, Inc., Ambrilia Biopharma Inc., Astellas Pharma Inc., diaDexus, Illumina, Inc., QIAGEN, F Hoffmann-La Roche Ltd, Sanofi, Stryker Corporation, PromoCell GmbH, STEMCELL Technologies Inc., Lonza, ReachBio LLC, AllCells, ATCC, Lifeline Cell Technology., Conversant bio, HemaCare, Mesoblast Ltd., Merck KGaA, Discovery Life Sciences., ReeLabs Pvt. Ltd., Gamida Cell, among other domestic and global players. Market share data is available for global, North America, Europe, Asia-Pacific (APAC), Middle East and Africa (MEA) and South America separately. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

Browse the complete table of contents at https://www.databridgemarketresearch.com/toc/?dbmr=global-bone-marrow-market

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Bone Marrow Market Global Projection By Key Players AGendia, Agilent Technologies, Inc., Ambrilia Biopharma Inc Analysis and Forecast to 2028 ...

Bone Marrow Stem Cells Comments Off on Bone Marrow Market Global Projection By Key Players AGendia, Agilent Technologies, Inc., Ambrilia Biopharma Inc Analysis and Forecast to 2028 … | July 8th, 2022

Sickle cell disease (SCD) is a debilitating illness affecting up to 40% of the population in some African countries. Its caused by mutations in the gene that makes haemoglobin the protein that carries oxygen in red blood cells.

It might one day be possible to treat this disease using gene editing by switching back on the production of a healthy form of haemoglobin called foetal haemoglobin, which is usually only produced by the body when were in the womb.

But a new study testing this promising new treatment in mice has found that scientists still have a long way to go before it can be attempted in humans. The research has been published in Disease Models & Mechanisms.

Healthy red blood cells (RBCs) are shaped similar to a donut but with an indentation instead of a hole.

In sickle cell disease the abnormal haemoglobin distorts the RBCs shape when they arent carrying oxygen. Instead, sickled RBCs are C-shaped, like the farm tool called a sickle, and they become hard and sticky, and die earlier.

Because of their shape, sickled RBCs can become stuck and stop blood flow when travelling through small blood vessels. This causes patients to suffer from episodes of excruciating pain, organ damage and a reduced life-expectancy.

Although current treatments have reduced complications and extended the life expectancies of affected children, most still die prematurely.

Red blood cells are made from haematopoietic stem cells in our bone marrow. These stem cells are able to develop into more than one cell type, in a process called haematopoiesis.

Researchers hope to edit the genes of these stem cells so that they produce RBCs with foetal haemoglobin instead of the abnormal protein and can be reintroduced into the body to alleviate the symptoms of SCD.

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Unfortunately, they found that although two types of lab mice had the symptoms of sickle cell disease, their foetal haemoglobin gene and surrounding DNA were not properly configured, making the stem-cell treatment ineffective or even harmful.

These mice called Berkley and Townes mice were genetically engineered in different ways to carry several human haemoglobin genes (replacing the mice genes) so scientists could study sickle cell disease in an animal model.

The researchers removed stem cells from the mice and used CRISPIR-Cas9 to try to turn on the healthy foetal haemoglobin gene. They then put the reprogrammed stem cells back into the mice and monitored the animals for 18 weeks to find out how the treatment affected them.

Surprisingly, 70% of Berkley mice died from the therapy and production of foetal haemoglobin was activated in only 3.1% of the stem cells. On the other hand, treatment did not affect the survival of Townes mice and even activated the foetal haemoglobin gene in 57% of RBCs.

Even then, the levels of foetal haemoglobin produced were seven to 10 times lower than seen when this approach was used in human cells grown in the laboratory and were not high enough to reduce clinical signs of sickle cell disease.

We realised that we did not know enough about the genetic configurations of these mice, says senior author Dr Mitchell Weiss, chair of the haematology department at St Jude Childrens Research Hospital, US.

The researchers sequenced the mices haemoglobin genes and surrounding DNA, and discovered that Berkley mice instead of having a single copy of the mutated human gene had 22 randomly arranged, broken-up copies of the mutated human sickle cell disease gene and 27 copies of the human foetal haemoglobin.

This caused the fatal effects seen and meant that the mice cannot be used to test this treatment in the future.

Our findings will help scientists using the Berkeley and Townes mice decide which to use to address their specific research question relating to sickle cell disease or haemoglobin, concludes Weiss.

Additionally, this work provides a reminder for scientists to carefully consider the genetics of the mice that they are using to study human diseases and find the right mouse for the job.

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Sickle cell disease gene therapy study set back by the mice - Cosmos

Bone Marrow Stem Cells Comments Off on Sickle cell disease gene therapy study set back by the mice – Cosmos | July 8th, 2022

Returning home after a Fathers Day trip to New York City with his daughter in 2016, Scott Kesel thought he had come down with the flu. Bloodwork showed his blood platelets were lower than normal. He followed up with his regular physician and was given the news: he had chronic myelomonocytic leukemia (CMML).

CMML is a rare type of blood cancer that starts in the bone marrow, where blood cells are made. It can involve other areas of the body. There are only about 1,100 cases in the U.S. each year and its more common in people over age 60.

As a Canandaigua resident, Scott started his cancer journey at Wilmot Cancer Institutes Sands Cancer Center at F.F. Thompson. His oncologist laid out all the options: chemo and a stem cell transplant.

Knowing he would need a transplant, his team at Sands had him transfer to Wilmots Hematology team, where he began seeing Jason Mendler, M.D., and his transplant doctor, Omar Aljitawi, M.B.B.S.

He had chemotherapy at Wilmot, where he got to know the infusion nursing staff.

They have put a mindset in place thats so beneficial to the patient, he says.

For a stem cell transplant, his brother was the closest match they could find, although he was only a half-match. That left the option for a haplo-identical transplant available. Historically, it was required to have a closer match in order to do a transplant. With a haploidentical transplant, the donor is only half-matched. Its a newer procedure that is not available at all transplant centers, but the doctors at Wilmot have been performing the surgery since 2015.

He underwent the transplant but, unfortunately, in Scotts case, it didnt work.

For a short period, Scott went to another institution for a clinical trial. Unfortunately, that didnt work either. He developed pancreatitis and had to drop out of the trial. He also experienced cold agglutinin disease, which caused his immune system to attack his red blood cells. Cold temperatures can trigger it and he had to stay at Wilmot for about a month in a temperature-controlled room, set at 80 degrees at all times, to overcome it.

Once that resolved, the team at Wilmot suggested another treatment option to try on Scotts leukemia: a transplant with stem cells from an umbilical cord donation. Umbilical cord blood stem cells came from Australia and Spain to try to save Scotts life. He had only two cord blood units available and he needed both to have a successful transplant, which was his only viable chance to potentially cure his leukemia. Along with the cord blood, he also had radiation therapy with Louis Constine, M.D.

He had nothing but good things to say about the team that took care of him while he was hospitalized on Wilmot Cancer Centers sixth floor, the Blood and Marrow Transplant Unit.

It was exceptional. They were so friendly and accommodating right from the very beginning, he says. It wasnt limited to nurses. Theres medical technicians on the floor that were so friendly and became very good friends.

Scott Kesel (right) with Jason Mendler, M.D., at the 2019 Wilmot Warrior Walk

Thankfully, this time the transplant took. As of June 2022, Scott has been in remission for three-and-a-half years. He credits his team for getting him there.

Its an incredible group of people, he says.

But its not just his team hes grateful for. He appreciates that his life has returned basically back to normal, despite the tumultuous COVID pandemic that happened shortly after his transplant.

Hes gotten back to work and to hobbies he enjoys outside work.

I happen to be the worlds greatest tuba playing car salesman, he jokes.

This summer and fall, he has 28 gigs lined up, with different music groups around the region to keep him busy, and he looks forward to hunting and fishing during his free time.

For it all, he feels fortunate.

You have to be grateful for the outcome, he says. I got a lot of support remotely from people in my community who used the opportunity to promote bone marrow registration and blood drives, which was awful nice.

He adds, Im grateful that I ended up at Wilmot. I really couldnt have been in a better place.

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'World's Greatest Tuba-Playing Car Salesman' Bounces Back after Leukemia, Thanks to Wilmot Team - URMC

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The Global Rheumatoid Arthritis Stem Cell Therapy Market is replete with new growth opportunities and expansion avenues. There has been an increase in the use of products and services falling under the ambit of Rheumatoid Arthritis Stem Cell Therapy, giving a thrust to the growth of the global Rheumatoid Arthritis Stem Cell Therapy market. The unprecedented use of these products can be attributed to the increasing paying capacity of the masses.

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Growing Prevalence & Recurrence Of Rheumatoid Arthritis Is Expected To Growth Of The Rheumatoid Arthritis Stem Cell Therapy Market Designer Women...

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Preclinical evaluation of FasT CAR-T cellsFasT CAR-T (F-CAR-T) proliferation in vitro

To characterize the in vitro proliferative capacity of F-CAR-T cells, F-CAR-T and C-CAR-T cells were manufactured in parallel (Supplementary Methods, and Fig. S1) using T-cells from 6 B-ALL patients. To investigate the ex vivo proliferation of F-CAR-T, frozen CD19 F-CAR-T and C-CAR-T cells from each patient were thawed and stimulated with irradiated CD19-expressing K562 cells. The number of CD19-targeting CAR-T cells was then determined during the course of cell expansion in vitro. As shown in Fig. 1A, upon CD19 antigen stimulation, F-CAR-T proliferation was much more robust compared to C-CAR-T proliferation. On day 17 post co-culture, F-CAR-T expanded 1205.61226.3 fold (MeanSD), while C-CAR-T expanded only 116.437.2 fold (MeanSD), (p=0.001). To characterize the mechanism underlying the superior proliferative ability of F-CAR-T, we purified CD19+ CAR-T cells from both F-CAR-T and C-CAR-T. The expression of genes involved in cell proliferation, cell cycle, and apoptosis was analyzed using Nanostring (detailed gene sets are in Table S2). Gene expression profiles showed higher F-CAR-T expression scores for genes associated with cell cycle regulation (F-CAR-T vs. C-CAR-T, p<0.01) and lower expression scores for apoptosis-related genes (F-CAR-T vs. C-CAR-T, p<0.05) in F-CAR-T cells (Fig. S2A).

A Ex vivo cell proliferation of F-CAR-T and C-CAR-T derived from B-ALL patients (n=6) (***P=0.001, F-CAR-T vs. C-CAR-T, d17, unpaired student two-tailed t-test). B Tscm, Tcm, and Tem were characterized by surface staining of CD45RO and CD62L and analyzed with flow cytometry (***P<0.001 comparing F-CAR-T and C-CAR-T). C T-cell exhaustion was characterized by PD-1, LAG3, and TIM-3 staining; Statistical analyses of the percentage of PD1+ LAG3+ Tim3+ (***P<0.001, comparing F-CAR-T and C-CAR-T), unpaired student two-tailed t-test). D RTCA assay was used to examine the specific killing of HeLa-CD19 cells. Growth of target HeLa-CD19 or HeLa cells were monitored dynamically. E CD19+ target Nalm6-Luc cells or F Raji-Luc cells were co-cultured with either F-CAR-T or C-CAR-T for 6h. Target cell killing efficacy was calculated by luciferase activity. NS, P>0.05 F-CAR-T vs. C-CAR-T (unpaired student t-test, two-tailed). F-CAR-T FasT CAR-T, C-CAR-T conventional CAR-T, Tcm (CD45RO+CD62L+) T central memory cells, Tem (CD45RO+CD62L) T effector memory cells, Tscm (CD45ROCD62L+) T stem cell memory, PD1 programmed cell death protein 1, TIM-3 T cell immunoglobulin and mucin domain containing-3, LAG3 lymphocyte-activation gene 3, RTCA real-time cell analyzer, E:T effector cells: target cells, NT normal T-cell.

Phenotypes of unstimulated F-CAR-T from three healthy donors were analyzed by flow cytometry. The CD45ROCD62L+ population was 45.7%2.2% which was comparable to the un-transduced T-cells (data not shown). Upon stimulation with CD19+ tumor cells for 9 days, C-CAR-T central memory cells (Tcm, CD45RO+CD62L+ and effector memory cells (Tem, CD45RO+CD62L) were 56.62%11.97% and 40.48%9.70%, respectively, among the C-CAR-T cells (Fig. 1B and Figs. S2B and S2). In contrast, Tcm cells (87.92%4.36%) was predominant in F-CAR-T, with only a small fraction of Tem (7.84%3.79%). In addition, F-CAR-T cells demonstrated more abundant T stem cell memory (Tscm) (3.841.22% vs 2.342.48%, p<0.05) than C-CAR-T cells. We also examined the exhaustion status of the stimulated CAR-T cells. A higher percentage of PD-1+LAG3+Tim3+T-cells were detected in the C-CAR-T (11.19%2.54%) compared to F-CAR-T (3.59%2.51%, p<0.001) (Fig. 1C). Together these data indicated that the F-CAR-T exhibited a younger phenotype and was less exhausted compared to C-CAR-T.

We used a real-time cell analyzer (RTCA) assay to measure the cytotoxicity of F-CAR-T and C-CAR-T against CD19+ cells in vitro. F-CAR-T and C-CAR-T killing of Hela-CD19 target cells were comparable using this assay (Fig. 1D). Similar levels of IFN- and IL-2 production were also observed (Fig. S2D). In a luciferase-based cytotoxicity assay, CD19+ B leukemia cell lines, Raji and Nalm6, were both effectively killed to similar or better levels at different E:T ratios (Fig. 1E, F).

To compare the in vivo cytotoxicity of F-CAR-T and C-CAR-T, severe immunodeficient NOG mice were engrafted with Raji-luciferase cells. One week after the tumor grafts were established, F-CAR-T and C-CAR-T were intravenously injected at various doses. The engrafted tumors progressed aggressively in control groups with either vehicle alone or control T-cells (Fig. 2A). In contrast, F-CAR-T or C-CAR-T treatment greatly suppressed tumor growth in a dose-dependent manner (Fig. 2A). In the high dose group (2106/mice), both F-CAR-T and C-CAR-T eliminated the tumor rapidly. However, in the low dose group (5105/mice), F-CAR-T showed more effective tumor-killing compared to C-CAR-T. On day 20, mice in the low dose F-CAR-T group became tumor-free, while C-CAR-T treated mice exhibited tumor relapse (Fig. 2A). We examined the CAR-T cell expansion in vivo after infusion. As shown in Fig. 2B, both F-CAR-T and C-CAR-T began to expand in the peripheral blood 7 days after infusion. C-CAR-T cell numbers reached their peak on day 14 and receded on day 21. In contrast, the F-CAR-T cell number peaked on day 21 and declined to a baseline level on day 28. F-CAR-T not only persisted longer but also underwent 26 folds greater expansion than C-CAR-T (Fig. 2B).

A Raji-Luc cell engraftment NOG mice were given high dose (2106/mice, n=3) and low dose (5105/mice, n=3) F-CAR-T/C-CAR-T along with control groups. Tumor growth was monitored with IVIS scan once every 3 days; B CAR-T expansion in peripheral blood of mice was analyzed by flow cytometry (n=6). ***P<0.001 for F-CAR-T HD vs. C-CAR-T HD; F-CAR-T LD vs. C-CAR-T LD; F-CAR-T HD vs. F-CAR-T LD; C-CAR-T HD vs. C-CAR-T LD (two-way ANOVA statistical analysis); C Schematic of the Nalm6 (1106) xenograft model, CAR-T (2106) infused 1 day after cyclophosphamide (20mg/kg) treatment. Bone marrow infiltration of F-CAR-T was analyzed 10 days after CAR-T infusion (n=3); D CD45+CD2 F-CAR-T vs. C-CAR-T in peripheral blood of mice were analyzed by flow cytometry; *P<0.05 (unpaired student two-tailed t-test). IVIS in vivo imaging system, PB peripheral blood, i.v. intravenous, HD high dose, LD low dose, Cy cyclophosphamide; *p<0.05; #: number.

We examined the BM infiltration of F-CAR-T cells after infusion into Nalm6-bearing mice (Fig. 2C). A larger population of CAR-T cells was observed 10 days after infusion in BM in F-CAR-T infused group than that in the C-CAR-T group (p<0.05) (Fig. 2D), suggesting F-CAR-T cells possessed a better BM homing capability than C-CAR-T.

The chemokine receptor CXCR4 is known to be critical for BM homing of T-cells [25, 26]. Indeed, a higher percentage of CXCR4+ T cells were detected in F-CAR-T than in the C-CAR-T. Interestingly, this phenotype was more pronounced for CD4+ T cells than CD8+ T cells (Fig. S3A). In a two-chamber system, more F-CAR-T cells could be detected in the lower chamber than their C-CAR-T counterparts (Fig. S3B).

Between Jan. 2019 and Oct. 2019, 25 pediatric and adult patients with CD19+R/R B-ALL were enrolled onto our phase 1 trial, including two patients who had relapsed following a prior allo-HSCT. Patient characteristics are detailed in Table 1. The median age of patients was 20 (range: 344) years old. Twenty patients were >14 years old, and five were 14 years old. The median percentage of pre-treatment BM blasts was 9.05% (range: 0.1982.9%). As our pre-clinical studies demonstrated that F-CAR-T cells had a superior expansion capability as compared to C-CAR-T, we infused a relatively low doses of F-CAR-T cells, ranging from 104105 cells/kg: 3.0104 cells/kg (n=2), 6.5 (5.867.43)104 cells/kg (n=9), 1.01 (1.01.16)105 cells/kg (n=12), 1.52(1.471.56)105 cells/kg (n=2), (Fig. S4). The median time from apheresis to the infusion of CD19+F-CAR-T cells was 14 days (range: 1220). Although the manufacturing time of F-CAR-T was next day, the quality control time and detailed final product releases including sterility testing require a minimum of 710 days to complete. In addition, transportation of cell products requires approximately two days. Of the 25 patients who received CD19 F-CAR-T infusion, 22 (88%) received bridging chemotherapy between apheresis and lymphodepleting chemotherapy to control rapid disease progression (Table S3).

F-CAR-T cells were manufactured successfully for all patients. The mean transduction efficiency of F-CAR-T was 35.4% (range: 13.170.3%) (Fig. S5A). Both CD4+/CAR+ (mean, 49.6%; range: 13.673.2%) and CD8+/CAR+ (mean, 41.5%; range: 20.677.7%) subsets were present in the CD3+CAR+ T cell subsets of all products. The mean proportion of Tscm, Tem, and Tcm cells in the CD3+CAR+ T cell subsets of all products was 23.3% (range: 3.5545.3%), 33.2% (range: 17.267.9%), and 36.1% (range: 20.758.1%), respectively (Fig. S5B). F-CAR-T products exerted significant IFN- release and cytotoxic effects against the CD19+ cell line HELA-CD19 (Fig. S5, C, D).

All 25 infused patients experienced adverse events (AEs) of any grade, with 25 (100%) experiencing grade 3 or higher adverse events. No grade 5 events related to F-CAR-T treatment were observed (Table 2).

CRS occurred in 24 (96%) patients with 18 (72%) grade 12 CRS,6 (24%) of grade 3, and no grade 4 or higher CRS (Fig. S6). In the >14 years old group, 16/20 (80%) patients developed mild CRS, and only 2/20 (10%) developed grade 3 CRS. For 14 years old patients, 2/5 (40%) had mild CRS, yet 3/5 (60%) experienced grade 3 CRS (Table S4). ICANS was observed in 7 (28%) patients, with 2 (8%) grade 3 ICANS occurring in patients >14 years old and 5 (20%) grade 4 ICANS all occurring in patients 14 years old. No grade 5 ICANS was developed (Fig. S7 and Table S4). The most frequent presentation of CRS was fever, particularly a high fever of >39C. The first onset of CRS symptoms occurred between day 3 and 8 post-CAR-T infusion with a median onset at day 4 (range: 110 days). The most common symptoms of ICANS were seizure (5/7) and depressed consciousness (5/7). The median time to ICANS onset from CAR-T cell infusion was 7 days (range: 58), and the median time to resolution was 2 days (Fig. S7). All CRS and ICANS events were managed including early intervention when fever of 39C persisted for 24h. Sixteen (64%) patients received tocilizumab with a median total dose of 160mg (range: 160320mg). Twenty-one (84%) patients received corticosteroids including dexamethasone (median total dose, 43mg; range: 4127mg) and or methylprednisolone (median total dose, 190mg; range: 401070mg). The vast majority of these patients discontinued corticosteroids within 2 weeks. The change in IL-6, IFN-, IL-10, and GM-CSF levels after infusion are selectively shown in Fig. S8. The peak levels of these four cytokines were observed between day 710. Among all 21 cytokines examined, only post-infusion IL-6 levels were associated with moderate to severe CRS and/or ICANS (Figs. S9 and S10).

Superior in vivo proliferation and persistence of F-CAR-T compared to C-CAR-T cells were observed regardless of dose levels. The median peak level was reached on day 10 (range: 714 days) with 1.9105 transgene copies/g of genomic DNA (range: 0.225.2105 transgene copies/g of genomic DNA) by qPCR and 83 F-CAR-T cells per l blood (range: 42102 F-CAR-T cells per l blood) by FCM (Fig. 3A, B). No significant differences were observed among the different dose groups in the mean F-CAR-T copies peak (Fig. 3C). Importantly, there was no significant difference in the mean F-CAR-T copies peak between patients who received corticosteroids compared to those who did not (Fig. 3D).

A F-CAR-T cells in peripheral blood by qPCR. Purple, dose level 1; black, dose level 2; blue, dose level 3; red, dose level 4; B F-CAR-T cells in peripheral blood by flow cytometry. Purple, dose level 1; black, dose level 2; blue, dose level 3; red, dose level 4; C Comparison of the mean peak copy number of F-CAR-T cells in peripheral blood at each dose level. Statistical significance was determined by the MannWhitney test. D Comparison of the mean peak copy number of F-CAR-T cells in peripheral blood with or without steroids. Statistical significance was determined by the MannWhitney test.

Fourteen days after F-CAR-T cell infusion, all patients achieved morphologic CR including 2/25 with CR and 23/25 CR with incomplete hematologic recovery (CRi), which further improved to 11/25 CR and 14/25 CRi 28 days post F-CAR-T (Table 1 and Fig. 4). More importantly, 23/25 (92%) had the minimal residual disease (MRD)-negative remission on day 14 and day 28 after F-CAR-T treatment. Patients achieving remission through CAR-T were given the option to proceed to allo-HSCT. With a median time of 54 days (range: 4581 days) post F-CAR-T infusion, 20 of 23 patients with MRD-negative status decided to pursue consolidative allo-HSCT including one patient who received a 2nd transplant. As of 18 October 2021, with a median follow-up duration of 693 days (range: 84973 days) among the 20 patients who had received allo-HSCT, one patient relapsed on day 172 and died 3 months after relapse, and four patients died from transplant-related mortality (TRM) including infection (n=3) and chronic GVHD (n=1) on day 84, day 215, day 220, and day 312, respectively. The other 15 patients remained in MRD-negative CR with a median remission duration of 734 days (range: 208973) except for one who became MRD-positive on day 294 with CD19+ disease. Among the other three patients (F05, F06, F16), one remained in MRD-negative CR on day 304, one remained in MRD-negative CR until day 303, received allo-HSCT but died from an infection on day 505, and one was lost to follow-up after day 114. Two patients who had MRD-positive CR after infusion withdrew from the study on day 42 and day 44, respectively, to seek other studies.

Clinical outcomes and consolidative allo-HSCT for the 25 patients who were treated with F-CAR-T therapy are shown. On day 28, 23/25 patients achieved MRD-negative CR/CRi. With a median time of 54 days (range: 4581) post F-CAR-T infusion, 20 of 23 patients with MRD-negative status received consolidative allo-HSCT. Among the 20 patients, 1 patient (F23) relapsed on day 172 and died 3 months after relapse. Four patients (F04, F09, F11, F12) died from transplant-related mortality (TRM) including infection (n=3) and chronic GVHD (n=1) on day 84, day 215, day 220, and day 312, respectively. The remaining 15 patients were in MRD-negative CR except for one (F18) who became MRD-positive on day 294. Among the other 3 patients (F05, F06, F16), 1 remained MRD-negative CR on day 304, 1 remained in MRD-negative CR until day 303, received allo-HSCT, and subsequently died from an infection on day 505. One patient was lost to follow-up after day 114. MRD minimal residual disease, CR complete remission, Allo-HSCT allogeneic hematopoietic stem cell transplantation.

F-CAR-T/T ratio in cerebrospinal fluid (CSF) was evaluated by FCM in 13/25 patients with available samples (Table S5). Between days 10 and 32, 9 patients were found to have considerable F-CAR-T penetration in their CSF, ranging from 40.65 to 79.2%, including 4 who developed severe ICANS. Among the other 4 patients, F-CAR-T cell abundance in the CSF ranged from 1.29% to 3.57%, and none experienced severe ICANS. Patients with higher levels of CAR-T in PB on day 10 consistently had higher levels of CAR-T in CSF with the exception of patient F15. Notably, CAR-T cells were still detectable in the CSF on day 101 with a 2.36% CAR-T/T ratio in patient F06, who also had undetectable circulating CAR-T cells at the same time.

In addition, concentrations of seven cytokines (IL-1b, IL-6, IL-10, IFN-, TNF-, MCP-1, and GM-CSF) in CSF samples from the above 10 of 13 patients were measured. Specifically, IL-1b was not detected in any of the 10 patients, and only one patient had detectable GM-CSF. For the other five cytokines, patients with severe ICANS had higher IL-6 levels in contrast to patients without severe ICANS, and the difference between the median level of IL-6 among these two groups of patients was statistically significant (Fig. S11). We did not observe significant differences among the other 4 cytokines between the two groups of patients. No clear relation between the CSF cytokine levels and the F-CAR-T/T % was observed.

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Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study | Blood Cancer Journal...

Bone Marrow Stem Cells Comments Off on Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study | Blood Cancer Journal… | July 8th, 2022

REDWOOD CITY, Calif., June 07, 2022 (GLOBE NEWSWIRE) -- Jasper Therapeutics, Inc. ( JSPR), a biotechnology company focused on enabling cures with stem cell therapies, today announced that the Company is participating in the William Blair 42nd Annual Growth Stock Conference, to be held in Chicago from June 6-9, 2022.

Ronald Martell, Jaspers Chief Executive Officer, is scheduled to present on Thursday, June 9th at 8:00AM CT, with a breakout session to follow at 8:40AM CT. A live webcast of the presentation will be available at https://wsw.com/webcast/blair66/jasp/1933236 and at the Companys Investor Events webpage.

About Jasper TherapeuticsJasper Therapeutics, Inc. is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The company is advancing two potentially groundbreaking programs. JSP191, an anti-CD117 monoclonal antibody, is in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow in patients undergoing hematopoietic cell transplantation. It is designed to enable safer and more effective, and potentially curative, allogeneic hematopoietic cell transplants and gene therapies. A clinical study of JSP191 as a novel, disease-modifying, therapeutic for patients with lower risk MDS is also planned to begin in 2022. In parallel, Jasper Therapeutics, Inc. is advancing its preclinical mRNA hematopoietic stem cell grafts platform, which is designed to overcome key limitations of allogeneic and autologous gene-edited stem cell grafts. Both innovative programs have the potential to transform the field and expand hematopoietic stem cell therapy cures to a greater number of patients with life-threatening cancers, genetic diseases and autoimmune diseases than is possible today. For more information, please visit us at jaspertherapeutics.com.

Forward-Looking StatementsCertain statements included in this press release that are not historical facts are forward-looking statements for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements are sometimes accompanied by words such as believe, may, will, estimate, continue, anticipate, intend, expect, should, would, plan, predict, potential, seem, seek, future, outlook and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements include, but are not limited to, statements regarding the potential of the Companys JSP191 and mRNA engineered stem cell graft programs. These statements are based on various assumptions, whether or not identified in this press release, and on the current expectations of Jasper and are not predictions of actual performance. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on by an investor as, a guarantee, an assurance, a prediction or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and will differ from assumptions. Many actual events and circumstances are beyond the control of Jasper. These forward-looking statements are subject to a number of risks and uncertainties, including general economic, political and business conditions; the risk that the potential product candidates that Jasper develops may not progress through clinical development or receive required regulatory approvals within expected timelines or at all; risks relating to uncertainty regarding the regulatory pathway for Jaspers product candidates; the risk that prior study results may not be replicated; the risk that clinical trials may not confirm any safety, potency or other product characteristics described or assumed in this press release; the risk that Jasper will be unable to successfully market or gain market acceptance of its product candidates; the risk that Jaspers product candidates may not be beneficial to patients or successfully commercialized; patients willingness to try new therapies and the willingness of physicians to prescribe these therapies; the effects of competition on Jaspers business; the risk that third parties on which Jasper depends for laboratory, clinical development, manufacturing and other critical services will fail to perform satisfactorily; the risk that Jaspers business, operations, clinical development plans and timelines, and supply chain could be adversely affected by the effects of health epidemics, including the ongoing COVID-19 pandemic; the risk that Jasper will be unable to obtain and maintain sufficient intellectual property protection for its investigational products or will infringe the intellectual property protection of others; and other risks and uncertainties indicated from time to time in Jaspers filings with the SEC. If any of these risks materialize or Jaspers assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. While Jasper may elect to update these forward-looking statements at some point in the future, Jasper specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Jaspers assessments of any date subsequent to the date of this press release. Accordingly, undue reliance should not be placed upon the forward-looking statements.

Contacts:

John Mullaly (investors)LifeSci Advisors617-429-3548[emailprotected]

Jeet Mahal (investors)Jasper Therapeutics650-549-1403[emailprotected]

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Jasper Therapeutics to Participate in the William Blair 42nd Annual Growth Stock Conference - GuruFocus.com

Bone Marrow Stem Cells Comments Off on Jasper Therapeutics to Participate in the William Blair 42nd Annual Growth Stock Conference – GuruFocus.com | July 8th, 2022

The very thought of getting someone elses poop transfused in your body may make you cringe but stool transplant has not only helped patients with gastrointestinal tract issues, it has also saved those who have had bone marrow transplants.

At Deenanath Mangeshkar Hospitals Centre of Excellence in Infectious Diseases and Department of Haematology, Pune, seven of the 11 patients of bone marrow transplants developed Clostridium difficile infection. They were treated with faecal microbial transplant (FMT), also referred to as stool transplant, over the past year.

Research worldwide has shown that a faecal transplant can restore healthy bacteria in the lower intestine which can help control Clostridium difficile or C. diff. According to the Johns Hopkins University School of Medicine, FMT can be more effective than antibiotics for keeping C. diff in check in some cases.

Since C. diff infection can recur and cause colitis (inflammation in the colon), FMT restores good and healthy bacteria, said Dr Parikshit Prayag, infectious disease consultant and in-charge of the Centre of Excellence in Infectious Diseases at Deenanath Mangeshkar hospital.

Dr Sameer Melinkeri, head of the department of haemotology at the hospital, said C. diff infection-related diarrhoea can occur in a normal setting in which antibiotics can be used for treatment. However, antibiotic treatment for recurrent infections can involve one or more courses of medication and their effectiveness comes down with each subsequent bout. FMT can arrest such infections post bone marrow transplant as it can be life-threatening, he added.

FMT is also done for certain disease conditions like Graft vs host disease (GvHD). Most people who undergo a bone marrow transplant suffer from blood cancer. Graft vs host disease can occur at any time after an allogeneic transplant where the donated bone marrow or peripheral stem cells can attack the recipients body. It can develop in the GI tract, skin or liver, Dr Prayag said.

Latest research published in the Journal of International Medical Research and others has shown how FMT is a promising treatment for patients with steroid-resistant GvHD. We have seen clinically relevant results in six of our patients, Dr Prayag said.

So, who can be donors? They are selected based on certain parameters. They should not be immune-compromised or have taken antibiotics over the past six months, says Dr Sampada Patwardhan, head of the department of microbiology at the hospital. Donor screening has to be done carefully. We need to rule out infections, she said.

Procedures on the transplant delivery methods may vary like colonoscopy and use of nasojejunal tube. The recovery may take a week or more and in most cases there are at least two weekly installations of the stool (in liquid form).

Very few centres conduct FMT and among them, the centre at Deenanath Hospital actively treats cases involving bone marrow transplants. At a recent virtual meeting of the International Society of Blood Transfusion, Dr Prayag made a strong case for encouraging stool transplants. The condition of C. diff is also underdiagnosed in the country as there isnt adequate infrastructure to correctly detect the problem, he pointed out.

In fact, FMT is being touted as a treatment option for many gut health issues. In an opinion article published on June 30 in the journal Trends in Molecular Medicine, a team from Harvard Medical School and Brigham and Womens Hospital (BWH) proposes that individuals bank samples of their own gut microbiota when they are young and healthy for potential use later in life in an autologous FMT.

A report in Science Daily quotes corresponding author Yang-Yu Liu, an associate professor of medicine at Harvard and an associate scientist in the Channing Division of Network Medicine at BWH, as saying, The idea of rewilding the human microbiome has taken off in recent years and has been hotly debated from medical, ethical and evolutionary perspectives. It is still unknown if people in industrialized societies can gain some health benefit by restoring their microbiome to an ancestral state. In this paper, we proposed a way to rejuvenate the human gut microbiome.

The report also listed OpenBiome, a non-profit stool bank based in Somerville, Massachusetts, as the first stool bank to offer an option for individuals to bank their own stool for future treatment of C. diff infection. Yang and his colleagues are now looking at if this treatment can be used for other diseases.

Conceptually, the idea of stool banking for autologous FMT is similar to when parents bank their babys cord blood for possible future use. However, there is greater potential for stool banking, and we anticipate that the chance of using stool samples is much higher than for cord blood. But there are many practical issues to implementing this idea, Yang is quoted as saying, hinting at optimal storage and cryopreservation issues.

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Cutting Edge: Poop therapy can save your gut, and your life - The Indian Express

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